Dysregulated expression of neuregulin-1 by cortical pyramidal neurons disrupts synaptic plasticity.

PubMed

Agarwal, Amit; Zhang, Mingyue; Trembak-Duff, Irina; Unterbarnscheidt, Tilmann; Radyushkin, Konstantin; Dibaj, Payam; Martins de Souza, Daniel; Boretius, Susann; Brzózka, Magdalena M; Steffens, Heinz; Berning, Sebastian; Teng, Zenghui; Gummert, Maike N; Tantra, Martesa; Guest, Peter C; Willig, Katrin I; Frahm, Jens; Hell, Stefan W; Bahn, Sabine; Rossner, Moritz J; Nave, Klaus-Armin; Ehrenreich, Hannelore; Zhang, Weiqi; Schwab, Markus H

2014-08-21

Neuregulin-1 (NRG1) gene variants are associated with increased genetic risk for schizophrenia. It is unclear whether risk haplotypes cause elevated or decreased expression of NRG1 in the brains of schizophrenia patients, given that both findings have been reported from autopsy studies. To study NRG1 functions in vivo, we generated mouse mutants with reduced and elevated NRG1 levels and analyzed the impact on cortical functions. Loss of NRG1 from cortical projection neurons resulted in increased inhibitory neurotransmission, reduced synaptic plasticity, and hypoactivity. Neuronal overexpression of cysteine-rich domain (CRD)-NRG1, the major brain isoform, caused unbalanced excitatory-inhibitory neurotransmission, reduced synaptic plasticity, abnormal spine growth, altered steady-state levels of synaptic plasticity-related proteins, and impaired sensorimotor gating. We conclude that an "optimal" level of NRG1 signaling balances excitatory and inhibitory neurotransmission in the cortex. Our data provide a potential pathomechanism for impaired synaptic plasticity and suggest that human NRG1 risk haplotypes exert a gain-of-function effect. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Involvement of the kinesin family members KIF4A and KIF5C in intellectual disability and synaptic function.

PubMed

Willemsen, Marjolein H; Ba, Wei; Wissink-Lindhout, Willemijn M; de Brouwer, Arjan P M; Haas, Stefan A; Bienek, Melanie; Hu, Hao; Vissers, Lisenka E L M; van Bokhoven, Hans; Kalscheuer, Vera; Nadif Kasri, Nael; Kleefstra, Tjitske

2014-07-01

Kinesin superfamily (KIF) genes encode motor proteins that have fundamental roles in brain functioning, development, survival and plasticity by regulating the transport of cargo along microtubules within axons, dendrites and synapses. Mouse knockout studies support these important functions in the nervous system. The role of KIF genes in intellectual disability (ID) has so far received limited attention, although previous studies have suggested that many ID genes impinge on synaptic function. By applying next-generation sequencing (NGS) in ID patients, we identified likely pathogenic mutations in KIF4A and KIF5C. To further confirm the pathogenicity of these mutations, we performed functional studies at the level of synaptic function in primary rat hippocampal neurons. Four males from a single family with a disruptive mutation in the X-linked KIF4A (c.1489-8_1490delins10; p.?- exon skipping) showed mild to moderate ID and epilepsy. A female patient with a de novo missense mutation in KIF5C (c.11465A>C; p.(Glu237Lys)) presented with severe ID, epilepsy, microcephaly and cortical malformation. Knock-down of Kif4a in rat primary hippocampal neurons altered the balance between excitatory and inhibitory synaptic transmission, whereas the mutation in Kif5c affected its protein function at excitatory synapses. Our results suggest that mutations in KIF4A and KIF5C cause ID by tipping the balance between excitatory and inhibitory synaptic excitability. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Mechanisms of excitatory synapse maturation by trans-synaptic organizing complexes

PubMed Central

McMahon, Samuel A.; Díaz, Elva

2011-01-01

Synapses are specialized cell-cell adhesion contacts that mediate communication within neural networks. During development, excitatory synapses are generated by step-wise recruitment of pre- and postsynaptic proteins to sites of contact. Several classes of synaptic organizing complexes have been identified that function during the initial stages of synapse formation. However, mechanisms underlying the later stages of synapse development are less well understood. In recent years, molecules have been discovered that appear to play a role in synapse maturation. In this review, we highlight recent findings that have provided key insights for understanding postsynaptic maturation of developing excitatory synapses with a focus on recruitment of AMPA receptors to developing synapses. PMID:21242087

Location-dependent excitatory synaptic interactions in pyramidal neuron dendrites.

PubMed

Behabadi, Bardia F; Polsky, Alon; Jadi, Monika; Schiller, Jackie; Mel, Bartlett W

2012-01-01

Neocortical pyramidal neurons (PNs) receive thousands of excitatory synaptic contacts on their basal dendrites. Some act as classical driver inputs while others are thought to modulate PN responses based on sensory or behavioral context, but the biophysical mechanisms that mediate classical-contextual interactions in these dendrites remain poorly understood. We hypothesized that if two excitatory pathways bias their synaptic projections towards proximal vs. distal ends of the basal branches, the very different local spike thresholds and attenuation factors for inputs near and far from the soma might provide the basis for a classical-contextual functional asymmetry. Supporting this possibility, we found both in compartmental models and electrophysiological recordings in brain slices that the responses of basal dendrites to spatially separated inputs are indeed strongly asymmetric. Distal excitation lowers the local spike threshold for more proximal inputs, while having little effect on peak responses at the soma. In contrast, proximal excitation lowers the threshold, but also substantially increases the gain of distally-driven responses. Our findings support the view that PN basal dendrites possess significant analog computing capabilities, and suggest that the diverse forms of nonlinear response modulation seen in the neocortex, including uni-modal, cross-modal, and attentional effects, could depend in part on pathway-specific biases in the spatial distribution of excitatory synaptic contacts onto PN basal dendritic arbors.

Pten Knockdown in vivo Increases Excitatory Drive onto Dentate Granule Cells

PubMed Central

Luikart, Bryan W.; Schnell, Eric; Washburn, Eric K.; Bensen, AeSoon L.; Tovar, Kenneth R.; Westbrook, Gary L.

2011-01-01

Some cases of autism spectrum disorder (ASD) have mutations in the lipid phosphatase, Pten (phosphatase and tensin homolog on chromosome 10). Tissue specific deletion of Pten in the hippocampus and cortex of mice causes anatomical and behavioral abnormalities similar to human autism. However, the impact of reductions in Pten on synaptic and circuit function remains unexplored. We used in vivo stereotaxic injections of lentivirus expressing an shRNA to knockdown Pten in mouse neonatal and young adult dentate granule cells. We then assessed the morphology and synaptic physiology between two weeks and four months later. Confocal imaging of the hippocampus revealed a marked increase in granule cell size and an increase in dendritic spine density. The onset of morphological changes occurred earlier in neonatal mice than in young adults. We used whole-cell recordings from granule cells in acute slices to assess synaptic function following Pten knockdown. Consistent with the increase in dendritic spines, the frequency of excitatory miniature and spontaneous postsynaptic currents increased. However, there was little or no effect on inhibitory postsynaptic currents. Thus Pten knockdown results in an imbalance between excitatory and inhibitory synaptic activity. Because reductions in Pten affected mature granule cells as well as developing granule cells, we suggest that the disruption of circuit function by Pten hypofunction may be ongoing well beyond early development. PMID:21411674

Input transformation by dendritic spines of pyramidal neurons

PubMed Central

Araya, Roberto

2014-01-01

In the mammalian brain, most inputs received by a neuron are formed on the dendritic tree. In the neocortex, the dendrites of pyramidal neurons are covered by thousands of tiny protrusions known as dendritic spines, which are the major recipient sites for excitatory synaptic information in the brain. Their peculiar morphology, with a small head connected to the dendritic shaft by a slender neck, has inspired decades of theoretical and more recently experimental work in an attempt to understand how excitatory synaptic inputs are processed, stored and integrated in pyramidal neurons. Advances in electrophysiological, optical and genetic tools are now enabling us to unravel the biophysical and molecular mechanisms controlling spine function in health and disease. Here I highlight relevant findings, challenges and hypotheses on spine function, with an emphasis on the electrical properties of spines and on how these affect the storage and integration of excitatory synaptic inputs in pyramidal neurons. In an attempt to make sense of the published data, I propose that the raison d'etre for dendritic spines lies in their ability to undergo activity-dependent structural and molecular changes that can modify synaptic strength, and hence alter the gain of the linearly integrated sub-threshold depolarizations in pyramidal neuron dendrites before the generation of a dendritic spike. PMID:25520626

Synaptic E-I Balance Underlies Efficient Neural Coding.

PubMed

Zhou, Shanglin; Yu, Yuguo

2018-01-01

Both theoretical and experimental evidence indicate that synaptic excitation and inhibition in the cerebral cortex are well-balanced during the resting state and sensory processing. Here, we briefly summarize the evidence for how neural circuits are adjusted to achieve this balance. Then, we discuss how such excitatory and inhibitory balance shapes stimulus representation and information propagation, two basic functions of neural coding. We also point out the benefit of adopting such a balance during neural coding. We conclude that excitatory and inhibitory balance may be a fundamental mechanism underlying efficient coding.

Synaptic E-I Balance Underlies Efficient Neural Coding

PubMed Central

Zhou, Shanglin; Yu, Yuguo

2018-01-01

Both theoretical and experimental evidence indicate that synaptic excitation and inhibition in the cerebral cortex are well-balanced during the resting state and sensory processing. Here, we briefly summarize the evidence for how neural circuits are adjusted to achieve this balance. Then, we discuss how such excitatory and inhibitory balance shapes stimulus representation and information propagation, two basic functions of neural coding. We also point out the benefit of adopting such a balance during neural coding. We conclude that excitatory and inhibitory balance may be a fundamental mechanism underlying efficient coding. PMID:29456491

Regulation of Brain-Derived Neurotrophic Factor Exocytosis and Gamma-Aminobutyric Acidergic Interneuron Synapse by the Schizophrenia Susceptibility Gene Dysbindin-1.

PubMed

Yuan, Qiang; Yang, Feng; Xiao, Yixin; Tan, Shawn; Husain, Nilofer; Ren, Ming; Hu, Zhonghua; Martinowich, Keri; Ng, Julia S; Kim, Paul J; Han, Weiping; Nagata, Koh-Ichi; Weinberger, Daniel R; Je, H Shawn

2016-08-15

Genetic variations in dystrobrevin binding protein 1 (DTNBP1 or dysbindin-1) have been implicated as risk factors in the pathogenesis of schizophrenia. The encoded protein dysbindin-1 functions in the regulation of synaptic activity and synapse development. Intriguingly, a loss of function mutation in Dtnbp1 in mice disrupted both glutamatergic and gamma-aminobutyric acidergic transmission in the cerebral cortex; pyramidal neurons displayed enhanced excitability due to reductions in inhibitory synaptic inputs. However, the mechanism by which reduced dysbindin-1 activity causes inhibitory synaptic deficits remains unknown. We investigated the role of dysbindin-1 in the exocytosis of brain-derived neurotrophic factor (BDNF) from cortical excitatory neurons, organotypic brain slices, and acute slices from dysbindin-1 mutant mice and determined how this change in BDNF exocytosis transsynaptically affected the number of inhibitory synapses formed on excitatory neurons via whole-cell recordings, immunohistochemistry, and live-cell imaging using total internal reflection fluorescence microscopy. A decrease in dysbindin-1 reduces the exocytosis of BDNF from cortical excitatory neurons, and this reduction in BDNF exocytosis transsynaptically resulted in reduced inhibitory synapse numbers formed on excitatory neurons. Furthermore, application of exogenous BDNF rescued the inhibitory synaptic deficits caused by the reduced dysbindin-1 level in both cultured cortical neurons and slice cultures. Taken together, our results demonstrate that these two genes linked to risk for schizophrenia (BDNF and dysbindin-1) function together to regulate interneuron development and cortical network activity. This evidence supports the investigation of the association between dysbindin-1 and BDNF in humans with schizophrenia. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Caffeine Controls Glutamatergic Synaptic Transmission and Pyramidal Neuron Excitability in Human Neocortex

PubMed Central

Kerkhofs, Amber; Xavier, Ana C.; da Silva, Beatriz S.; Canas, Paula M.; Idema, Sander; Baayen, Johannes C.; Ferreira, Samira G.; Cunha, Rodrigo A.; Mansvelder, Huibert D.

2018-01-01

Caffeine is the most widely used psychoactive drug, bolstering attention and normalizing mood and cognition, all functions involving cerebral cortical circuits. Whereas studies in rodents showed that caffeine acts through the antagonism of inhibitory A1 adenosine receptors (A1R), neither the role of A1R nor the impact of caffeine on human cortical neurons is known. We here provide the first characterization of the impact of realistic concentrations of caffeine experienced by moderate coffee drinkers (50 μM) on excitability of pyramidal neurons and excitatory synaptic transmission in the human temporal cortex. Moderate concentrations of caffeine disinhibited several of the inhibitory A1R-mediated effects of adenosine, similar to previous observations in the rodent brain. Thus, caffeine restored the adenosine-induced decrease of both intrinsic membrane excitability and excitatory synaptic transmission in the human pyramidal neurons through antagonism of post-synaptic A1R. Indeed, the A1R-mediated effects of endogenous adenosine were more efficient to inhibit synaptic transmission than neuronal excitability. This was associated with a distinct affinity of caffeine for synaptic versus extra-synaptic human cortical A1R, probably resulting from a different molecular organization of A1R in human cortical synapses. These findings constitute the first neurophysiological description of the impact of caffeine on pyramidal neuron excitability and excitatory synaptic transmission in the human temporal cortex, providing adequate ground for the effects of caffeine on cognition in humans. PMID:29354052

Nitric oxide mediates local activity-dependent excitatory synapse development.

PubMed

Nikonenko, Irina; Nikonenko, Alexander; Mendez, Pablo; Michurina, Tatyana V; Enikolopov, Grigori; Muller, Dominique

2013-10-29

Learning related paradigms play an important role in shaping the development and specificity of synaptic networks, notably by regulating mechanisms of spine growth and pruning. The molecular events underlying these synaptic rearrangements remain poorly understood. Here we identify NO signaling as a key mediator of activity-dependent excitatory synapse development. We find that chronic blockade of NO production in vitro and in vivo interferes with the development of hippocampal and cortical excitatory spine synapses. The effect results from a selective loss of activity-mediated spine growth mechanisms and is associated with morphological and functional alterations of remaining synapses. These effects of NO are mediated by a cGMP cascade and can be reproduced or prevented by postsynaptic expression of vasodilator-stimulated phosphoprotein phospho-mimetic or phospho-resistant mutants. In vivo analyses show that absence of NO prevents the increase in excitatory synapse density induced by environmental enrichment and interferes with the formation of local clusters of excitatory synapses. We conclude that NO plays an important role in regulating the development of excitatory synapses by promoting local activity-dependent spine-growth mechanisms.

Synapsin-dependent development of glutamatergic synaptic vesicles and presynaptic plasticity in postnatal mouse brain.

PubMed

Bogen, I L; Jensen, V; Hvalby, O; Walaas, S I

2009-01-12

Inactivation of the genes encoding the neuronal, synaptic vesicle-associated proteins synapsin I and II leads to severe reductions in the number of synaptic vesicles in the CNS. We here define the postnatal developmental period during which the synapsin I and/or II proteins modulate synaptic vesicle number and function in excitatory glutamatergic synapses in mouse brain. In wild-type mice, brain levels of both synapsin I and synapsin IIb showed developmental increases during synaptogenesis from postnatal days 5-20, while synapsin IIa showed a protracted increase during postnatal days 20-30. The vesicular glutamate transporters (VGLUT) 1 and VGLUT2 showed synapsin-independent development during postnatal days 5-10, following which significant reductions were seen when synapsin-deficient brains were compared with wild-type brains following postnatal day 20. A similar, synapsin-dependent developmental profile of vesicular glutamate uptake occurred during the same age periods. Physiological analysis of the development of excitatory glutamatergic synapses, performed in the CA1 stratum radiatum of the hippocampus from the two genotypes, showed that both the synapsin-dependent part of the frequency facilitation and the synapsin-dependent delayed response enhancement were restricted to the period after postnatal day 10. Our data demonstrate that while both synaptic vesicle number and presynaptic short-term plasticity are essentially independent of synapsin I and II prior to postnatal day 10, maturation and function of excitatory synapses appear to be strongly dependent on synapsin I and II from postnatal day 20.

Activity-dependent regulation of release probability at excitatory hippocampal synapses: a crucial role of FMRP in neurotransmission

PubMed Central

Wang, Xiao-Sheng; Peng, Chun-Zi; Cai, Wei-Jun; Xia, Jian; Jin, Daozhong; Dai, Yuqiao; Luo, Xue-Gang; Klyachko, Vitaly A.; Deng, Pan-Yue

2014-01-01

Transcriptional silencing of the Fmr1 gene encoding fragile X mental retardation protein (FMRP) causes Fragile X Syndrome (FXS), the most common form of inherited intellectual disability and the leading genetic cause of autism. FMRP has been suggested to play important roles in regulating neurotransmission and short-term synaptic plasticity at excitatory hippocampal and cortical synapses. However, the origins and the mechanisms of these FMRP actions remain incompletely understood, and the role of FMRP in regulating synaptic release probability and presynaptic function remains debated. Here we used variance-mean analysis and peak scaled nonstationary variance analysis to examine changes in both pre- and postsynaptic parameters during repetitive activity at excitatory CA3-CA1 hippocampal synapses in a mouse model of FXS. Our analyses revealed that loss of FMRP did not affect the basal release probability or basal synaptic transmission, but caused an abnormally elevated release probability specifically during repetitive activity. These abnormalities were not accompanied by changes in EPSC kinetics, quantal size or postsynaptic AMPA receptor conductance. Our results thus indicate that FMRP regulates neurotransmission at excitatory hippocampal synapses specifically during repetitive activity via modulation of release probability in a presynaptic manner. Our study suggests that FMRP function in regulating neurotransmitter release is an activity-dependent phenomenon that may contribute to the pathophysiology of FXS. PMID:24646437

Stable learning of functional maps in self-organizing spiking neural networks with continuous synaptic plasticity

PubMed Central

Srinivasa, Narayan; Jiang, Qin

2013-01-01

This study describes a spiking model that self-organizes for stable formation and maintenance of orientation and ocular dominance maps in the visual cortex (V1). This self-organization process simulates three development phases: an early experience-independent phase, a late experience-independent phase and a subsequent refinement phase during which experience acts to shape the map properties. The ocular dominance maps that emerge accommodate the two sets of monocular inputs that arise from the lateral geniculate nucleus (LGN) to layer 4 of V1. The orientation selectivity maps that emerge feature well-developed iso-orientation domains and fractures. During the last two phases of development the orientation preferences at some locations appear to rotate continuously through ±180° along circular paths and referred to as pinwheel-like patterns but without any corresponding point discontinuities in the orientation gradient maps. The formation of these functional maps is driven by balanced excitatory and inhibitory currents that are established via synaptic plasticity based on spike timing for both excitatory and inhibitory synapses. The stability and maintenance of the formed maps with continuous synaptic plasticity is enabled by homeostasis caused by inhibitory plasticity. However, a prolonged exposure to repeated stimuli does alter the formed maps over time due to plasticity. The results from this study suggest that continuous synaptic plasticity in both excitatory neurons and interneurons could play a critical role in the formation, stability, and maintenance of functional maps in the cortex. PMID:23450808

Developmental profiles of the intrinsic properties and synaptic function of auditory neurons in preterm and term baboon neonates.

PubMed

Kim, Sei Eun; Lee, Seul Yi; Blanco, Cynthia L; Kim, Jun Hee

2014-08-20

The human fetus starts to hear and undergoes major developmental changes in the auditory system during the third trimester of pregnancy. Although there are significant data regarding development of the auditory system in rodents, changes in intrinsic properties and synaptic function of auditory neurons in developing primate brain at hearing onset are poorly understood. We performed whole-cell patch-clamp recordings of principal neurons in the medial nucleus of trapezoid body (MNTB) in preterm and term baboon brainstem slices to study the structural and functional maturation of auditory synapses. Each MNTB principal neuron received an excitatory input from a single calyx of Held terminal, and this one-to-one pattern of innervation was already formed in preterm baboons delivered at 67% of normal gestation. There was no difference in frequency or amplitude of spontaneous excitatory postsynaptic synaptic currents between preterm and term MNTB neurons. In contrast, the frequency of spontaneous GABA(A)/glycine receptor-mediated inhibitory postsynaptic synaptic currents, which were prevalent in preterm MNTB neurons, was significantly reduced in term MNTB neurons. Preterm MNTB neurons had a higher input resistance than term neurons and fired in bursts, whereas term MNTB neurons fired a single action potential in response to suprathreshold current injection. The maturation of intrinsic properties and dominance of excitatory inputs in the primate MNTB allow it to take on its mature role as a fast and reliable relay synapse. Copyright © 2014 the authors 0270-6474/14/3411399-06$15.00/0.

Optogenetic Examination of Prefrontal-Amygdala Synaptic Development.

PubMed

Arruda-Carvalho, Maithe; Wu, Wan-Chen; Cummings, Kirstie A; Clem, Roger L

2017-03-15

A brain network comprising the medial prefrontal cortex (mPFC) and amygdala plays important roles in developmentally regulated cognitive and emotional processes. However, very little is known about the maturation of mPFC-amygdala circuitry. We conducted anatomical tracing of mPFC projections and optogenetic interrogation of their synaptic connections with neurons in the basolateral amygdala (BLA) at neonatal to adult developmental stages in mice. Results indicate that mPFC-BLA projections exhibit delayed emergence relative to other mPFC pathways and establish synaptic transmission with BLA excitatory and inhibitory neurons in late infancy, events that coincide with a massive increase in overall synaptic drive. During subsequent adolescence, mPFC-BLA circuits are further modified by excitatory synaptic strengthening as well as a transient surge in feedforward inhibition. The latter was correlated with increased spontaneous inhibitory currents in excitatory neurons, suggesting that mPFC-BLA circuit maturation culminates in a period of exuberant GABAergic transmission. These findings establish a time course for the onset and refinement of mPFC-BLA transmission and point to potential sensitive periods in the development of this critical network. SIGNIFICANCE STATEMENT Human mPFC-amygdala functional connectivity is developmentally regulated and figures prominently in numerous psychiatric disorders with a high incidence of adolescent onset. However, it remains unclear when synaptic connections between these structures emerge or how their properties change with age. Our work establishes developmental windows and cellular substrates for synapse maturation in this pathway involving both excitatory and inhibitory circuits. The engagement of these substrates by early life experience may support the ontogeny of fundamental behaviors but could also lead to inappropriate circuit refinement and psychopathology in adverse situations. Copyright © 2017 the authors 0270-6474/17/372976-10$15.00/0.

TH-9 (a theophylline derivative) induces long-lasting enhancement in excitatory synaptic transmission in the rat hippocampus that is occluded by frequency-dependent plasticity in vitro.

PubMed

Nashawi, H; Bartl, T; Bartl, P; Novotny, L; Oriowo, M A; Kombian, S B

2012-09-18

Dementia, especially Alzheimer's disease, is a rapidly increasing medical condition that presents with enormous challenge for treatment. It is characterized by impairment in memory and cognitive function often accompanied by changes in synaptic transmission and plasticity in relevant brain regions such as the hippocampus. We recently synthesized TH-9, a conjugate racetam-methylxanthine compound and tested if it had potential for enhancing synaptic function and possibly, plasticity, by examining its effect on hippocampal fast excitatory synaptic transmission and plasticity. Field excitatory postsynaptic potentials (fEPSPs) were recorded in the CA1 hippocampal area of naïve juvenile male Sprague-Dawley rats using conventional electrophysiological recording techniques. TH-9 caused a concentration-dependent, long-lasting enhancement in fEPSPs. This effect was blocked by adenosine A1, acetylcholine (muscarinic and nicotinic) and glutamate (N-methyl-d-aspartate) receptor antagonists but not by a γ-aminobutyric acid receptor type B (GABA(B)) receptor antagonist. The TH-9 effect was also blocked by enhancing intracellular cyclic adenosine monophosphate and inhibiting protein kinase A. Pretreatment with TH-9 did not prevent the induction of long-term potentiation (LTP) or long-term depression (LTD). Conversely, induction of LTP or LTD completely occluded the ability of TH-9 to enhance fEPSPs. Thus, TH-9 utilizes cholinergic and adenosinergic mechanisms to cause long-lasting enhancement in fEPSPs which were occluded by LTP and LTD. TH-9 may therefore employ similar or convergent mechanisms with frequency-dependent synaptic plasticities to produce the observed long-lasting enhancement in synaptic transmission and may thus, have potential for use in improving memory. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

Synaptic damage underlies EEG abnormalities in postanoxic encephalopathy: A computational study.

PubMed

Ruijter, B J; Hofmeijer, J; Meijer, H G E; van Putten, M J A M

2017-09-01

In postanoxic coma, EEG patterns indicate the severity of encephalopathy and typically evolve in time. We aim to improve the understanding of pathophysiological mechanisms underlying these EEG abnormalities. We used a mean field model comprising excitatory and inhibitory neurons, local synaptic connections, and input from thalamic afferents. Anoxic damage is modeled as aggravated short-term synaptic depression, with gradual recovery over many hours. Additionally, excitatory neurotransmission is potentiated, scaling with the severity of anoxic encephalopathy. Simulations were compared with continuous EEG recordings of 155 comatose patients after cardiac arrest. The simulations agree well with six common categories of EEG rhythms in postanoxic encephalopathy, including typical transitions in time. Plausible results were only obtained if excitatory synapses were more severely affected by short-term synaptic depression than inhibitory synapses. In postanoxic encephalopathy, the evolution of EEG patterns presumably results from gradual improvement of complete synaptic failure, where excitatory synapses are more severely affected than inhibitory synapses. The range of EEG patterns depends on the excitation-inhibition imbalance, probably resulting from long-term potentiation of excitatory neurotransmission. Our study is the first to relate microscopic synaptic dynamics in anoxic brain injury to both typical EEG observations and their evolution in time. Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

A family of photoswitchable NMDA receptors

PubMed Central

Berlin, Shai; Szobota, Stephanie; Reiner, Andreas; Carroll, Elizabeth C; Kienzler, Michael A; Guyon, Alice; Xiao, Tong; Trauner, Dirk; Isacoff, Ehud Y

2016-01-01

NMDA receptors, which regulate synaptic strength and are implicated in learning and memory, consist of several subtypes with distinct subunit compositions and functional properties. To enable spatiotemporally defined, rapid and reproducible manipulation of function of specific subtypes, we engineered a set of photoswitchable GluN subunits ('LiGluNs'). Photo-agonism of GluN2A or GluN2B elicits an excitatory drive to hippocampal neurons that can be shaped in time to mimic synaptic activation. Photo-agonism of GluN2A at single dendritic spines evokes spine-specific calcium elevation and expansion, the morphological correlate of LTP. Photo-antagonism of GluN2A alone, or in combination with photo-antagonism of GluN1a, reversibly blocks excitatory synaptic currents, prevents the induction of long-term potentiation and prevents spine expansion. In addition, photo-antagonism in vivo disrupts synaptic pruning of developing retino-tectal projections in larval zebrafish. By providing precise and rapidly reversible optical control of NMDA receptor subtypes, LiGluNs should help unravel the contribution of specific NMDA receptors to synaptic transmission, integration and plasticity. DOI: http://dx.doi.org/10.7554/eLife.12040.001 PMID:26929991

NGL-2 Deletion Leads to Autistic-like Behaviors Responsive to NMDAR Modulation.

PubMed

Um, Seung Min; Ha, Seungmin; Lee, Hyejin; Kim, Jihye; Kim, Kyungdeok; Shin, Wangyong; Cho, Yi Sul; Roh, Junyeop Daniel; Kang, Jaeseung; Yoo, Taesun; Noh, Young Woo; Choi, Yeonsoo; Bae, Yong Chul; Kim, Eunjoon

2018-06-26

Netrin-G ligand 2 (NGL-2)/LRRC4, implicated in autism spectrum disorders and schizophrenia, is a leucine-rich repeat-containing postsynaptic adhesion molecule that interacts intracellularly with the excitatory postsynaptic scaffolding protein PSD-95 and trans-synaptically with the presynaptic adhesion molecule netrin-G2. Functionally, NGL-2 regulates excitatory synapse development and synaptic transmission. However, whether it regulates synaptic plasticity and disease-related specific behaviors is not known. Here, we report that mice lacking NGL-2 (Lrrc4 -/- mice) show suppressed N-Methyl-D-aspartate receptor (NMDAR)-dependent synaptic plasticity in the hippocampus. NGL-2 associates with NMDARs through both PSD-95-dependent and -independent mechanisms. Moreover, Lrrc4 -/- mice display mild social interaction deficits and repetitive behaviors that are rapidly improved by pharmacological NMDAR activation. These results suggest that NGL-2 promotes synaptic stabilization of NMDARs, regulates NMDAR-dependent synaptic plasticity, and prevents autistic-like behaviors from developing in mice, supporting the hypothesis that NMDAR dysfunction contributes to autism spectrum disorders. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Co-existence of Functionally Different Vesicular Neurotransmitter Transporters.

PubMed

Münster-Wandowski, Agnieszka; Zander, Johannes-Friedrich; Richter, Karin; Ahnert-Hilger, Gudrun

2016-01-01

The vesicular transmitter transporters VGLUT, VGAT, VMAT2 and VAChT, define phenotype and physiological properties of neuronal subtypes. VGLUTs concentrate the excitatory amino acid glutamate, VGAT the inhibitory amino acid GABA, VMAT2 monoamines, and VAChT acetylcholine (ACh) into synaptic vesicle (SV). Following membrane depolarization SV release their content into the synaptic cleft. A strict segregation of vesicular transporters is mandatory for the precise functioning of synaptic communication and of neuronal circuits. In the last years, evidence accumulates that subsets of neurons express more than one of these transporters leading to synaptic co-release of different and functionally opposing transmitters and modulation of synaptic plasticity. Synaptic co-existence of transporters may change during pathological scenarios in order to ameliorate misbalances in neuronal activity. In addition, evidence increases that transporters also co-exist on the same vesicle providing another layer of regulation. Generally, vesicular transmitter loading relies on an electrochemical gradient ΔμH(+) driven by the proton ATPase rendering the lumen of the vesicle with respect to the cytosol positive (Δψ) and acidic (ΔpH). While the activity of VGLUT mainly depends on the Δψ component, VMAT, VGAT and VAChT work best at a high ΔpH. Thus, a vesicular synergy of transporters depending on the combination may increase or decrease the filling of SV with the principal transmitter. We provide an overview on synaptic co-existence of vesicular transmitter transporters including changes in the excitatory/inhibitory balance under pathological conditions. Additionally, we discuss functional aspects of vesicular synergy of transmitter transporters.

Co-existence of Functionally Different Vesicular Neurotransmitter Transporters

PubMed Central

Münster-Wandowski, Agnieszka; Zander, Johannes-Friedrich; Richter, Karin; Ahnert-Hilger, Gudrun

2016-01-01

The vesicular transmitter transporters VGLUT, VGAT, VMAT2 and VAChT, define phenotype and physiological properties of neuronal subtypes. VGLUTs concentrate the excitatory amino acid glutamate, VGAT the inhibitory amino acid GABA, VMAT2 monoamines, and VAChT acetylcholine (ACh) into synaptic vesicle (SV). Following membrane depolarization SV release their content into the synaptic cleft. A strict segregation of vesicular transporters is mandatory for the precise functioning of synaptic communication and of neuronal circuits. In the last years, evidence accumulates that subsets of neurons express more than one of these transporters leading to synaptic co-release of different and functionally opposing transmitters and modulation of synaptic plasticity. Synaptic co-existence of transporters may change during pathological scenarios in order to ameliorate misbalances in neuronal activity. In addition, evidence increases that transporters also co-exist on the same vesicle providing another layer of regulation. Generally, vesicular transmitter loading relies on an electrochemical gradient ΔμH+ driven by the proton ATPase rendering the lumen of the vesicle with respect to the cytosol positive (Δψ) and acidic (ΔpH). While the activity of VGLUT mainly depends on the Δψ component, VMAT, VGAT and VAChT work best at a high ΔpH. Thus, a vesicular synergy of transporters depending on the combination may increase or decrease the filling of SV with the principal transmitter. We provide an overview on synaptic co-existence of vesicular transmitter transporters including changes in the excitatory/inhibitory balance under pathological conditions. Additionally, we discuss functional aspects of vesicular synergy of transmitter transporters. PMID:26909036

The LGI1–ADAM22 protein complex directs synapse maturation through regulation of PSD-95 function

PubMed Central

Lovero, Kathryn L.; Fukata, Yuko; Granger, Adam J.; Fukata, Masaki; Nicoll, Roger A.

2015-01-01

Synapse development is coordinated by a number of transmembrane and secreted proteins that come together to form synaptic organizing complexes. Whereas a variety of synaptogenic proteins have been characterized, much less is understood about the molecular networks that support the maintenance and functional maturation of nascent synapses. Here, we demonstrate that leucine-rich, glioma-inactivated protein 1 (LGI1), a secreted protein previously shown to modulate synaptic AMPA receptors, is a paracrine signal released from pre- and postsynaptic neurons that acts specifically through a disintegrin and metalloproteinase protein 22 (ADAM22) to set postsynaptic strength. We go on to describe a novel role for ADAM22 in maintaining excitatory synapses through PSD-95/Dlg1/zo-1 (PDZ) domain interactions. Finally, we show that in the absence of LGI1, the mature synapse scaffolding protein PSD-95, but not the immature synapse scaffolding protein SAP102, is unable to modulate synaptic transmission. These results indicate that LGI1 and ADAM22 form an essential synaptic organizing complex that coordinates the maturation of excitatory synapses by regulating the functional incorporation of PSD-95. PMID:26178195

Neural networks with excitatory and inhibitory components: Direct and inverse problems by a mean-field approach

NASA Astrophysics Data System (ADS)

di Volo, Matteo; Burioni, Raffaella; Casartelli, Mario; Livi, Roberto; Vezzani, Alessandro

2016-01-01

We study the dynamics of networks with inhibitory and excitatory leak-integrate-and-fire neurons with short-term synaptic plasticity in the presence of depressive and facilitating mechanisms. The dynamics is analyzed by a heterogeneous mean-field approximation, which allows us to keep track of the effects of structural disorder in the network. We describe the complex behavior of different classes of excitatory and inhibitory components, which give rise to a rich dynamical phase diagram as a function of the fraction of inhibitory neurons. Using the same mean-field approach, we study and solve a global inverse problem: reconstructing the degree probability distributions of the inhibitory and excitatory components and the fraction of inhibitory neurons from the knowledge of the average synaptic activity field. This approach unveils new perspectives on the numerical study of neural network dynamics and the possibility of using these models as a test bed for the analysis of experimental data.

Excitatory amino acid transporters tonically restrain nTS synaptic and neuronal activity to modulate cardiorespiratory function

PubMed Central

2015-01-01

The nucleus tractus solitarii (nTS) is the initial central termination site for visceral afferents and is important for modulation and integration of multiple reflexes including cardiorespiratory reflexes. Glutamate is the primary excitatory neurotransmitter in the nTS and is removed from the extracellular milieu by excitatory amino acid transporters (EAATs). The goal of this study was to elucidate the role of EAATs in the nTS on basal synaptic and neuronal function and cardiorespiratory regulation. The majority of glutamate clearance in the central nervous system is believed to be mediated by astrocytic EAAT 1 and 2. We confirmed the presence of EAAT 1 and 2 within the nTS and their colocalization with astrocytic markers. EAAT blockade with dl-threo-β-benzyloxyaspartic acid (TBOA) produced a concentration-related depolarization, increased spontaneous excitatory postsynaptic current (EPSC) frequency, and enhanced action potential discharge in nTS neurons. Solitary tract-evoked EPSCs were significantly reduced by EAAT blockade. Microinjection of TBOA into the nTS of anesthetized rats induced apneic, sympathoinhibitory, depressor, and bradycardic responses. These effects mimicked the response to microinjection of exogenous glutamate, and glutamate responses were enhanced by EAAT blockade. Together these data indicate that EAATs tonically restrain nTS excitability to modulate cardiorespiratory function. PMID:26719090

Structure and plasticity potential of neural networks in the cerebral cortex

NASA Astrophysics Data System (ADS)

Fares, Tarec Edmond

In this thesis, we first described a theoretical framework for the analysis of spine remodeling plasticity. We provided a quantitative description of two models of spine remodeling in which the presence of a bouton is either required or not for the formation of a new synapse. We derived expressions for the density of potential synapses in the neuropil, the connectivity fraction, which is the ratio of actual to potential synapses, and the number of structurally different circuits attainable with spine remodeling. We calculated these parameters in mouse occipital cortex, rat CA1, monkey V1, and human temporal cortex. We found that on average a dendritic spine can choose among 4-7 potential targets in rodents and 10-20 potential targets in primates. The neuropil's potential for structural circuit remodeling is highest in rat CA1 (7.1-8.6 bits/mum3) and lowest in monkey V1 (1.3-1.5 bits/mum 3 We next studied the role neuron morphology plays in defining synaptic connectivity. As previously stated it is clear that only pairs of neurons with closely positioned axonal and dendritic branches can be synaptically coupled. For excitatory neurons in the cerebral cortex, ). We also evaluated the lower bound of neuron selectivity in the choice of synaptic partners. Post-synaptic excitatory neurons in rodents make synaptic contacts with more than 21-30% of pre-synaptic axons encountered with new spine growth. Primate neurons appear to be more selective, making synaptic connections with more than 7-15% of encountered axons. We next studied the role neuron morphology plays in defining synaptic connectivity. As previously stated it is clear that only pairs of neurons with closely positioned axonal and dendritic branches can be synaptically coupled. For excitatory neurons in the cerebral cortex, such axo-dendritic oppositions, or potential synapses, must be bridged by dendritic spines to form synaptic connections. To explore the rules by which synaptic connections are formed within the constraints imposed by neuron morphology, we compared the distributions of the numbers of actual and potential synapses between pre- and post-synaptic neurons forming different laminar projections in rat barrel cortex. Quantitative comparison explicitly ruled out the hypothesis that individual synapses between neurons are formed independently of each other. Instead, the data are consistent with a cooperative scheme of synapse formation, where multiple-synaptic connections between neurons are stabilized, while neurons that do not establish a critical number of synapses are not likely to remain synaptically coupled. In the above two projects, analysis of potential synapse numbers played an important role in shaping our understanding of connectivity and structural plasticity. In the third part of this thesis, we shift our attention to the study of the distribution of potential synapse numbers. This distribution is dependent on the details of neuron morphology and it defines synaptic connectivity patterns attainable with spine remodeling. To better understand how the distribution of potential synapse numbers is influenced by the overlap and the shapes of axonal and dendritic arbors, we first analyzed uniform disconnected arbors generated in silico. The resulting distributions are well described by binomial functions. We used a dataset of neurons reconstructed in 3D and generated the potential synapse distributions for neurons of different classes. Quantitative analysis showed that the binomial distribution is a good fit to this data as well. All distributions considered clustered into two categories, inhibitory to inhibitory and excitatory to excitatory projections. We showed that the distributions of potential synapse numbers are universally described by a family of single parameter (p) binomial functions, where p = 0.08, and for the inhibitory and p = 0.19 for the excitatory projections. In the last part of this thesis an attempt is made to incorporate some of the biological constraints we considered thus far, into an artificial neural network model. It became clear that several features of synaptic connectivity are ubiquitous among different cortical networks: (1) neural networks are predominately excitatory, containing roughly 80% of excitatory neurons and synapses, (2) neural networks are only sparsely interconnected, where the probabilities of finding connected neurons are always less than 50% even for neighboring cells, (3) the distribution of connection strengths has been shown to have a slow non-exponential decay. In the attempt to understand the advantage of such network architecture for learning and memory, we analyzed the associative memory capacity of a biologically constrained perceptron-like neural network model. The artificial neural network we consider consists of robust excitatory and inhibitory McCulloch and Pitts neurons with a constant firing threshold. Our theoretical results show that the capacity for associative memory storage in such networks increases with an addition of a small fraction of inhibitory neurons, while the connection probability remains below 50%. (Abstract shortened by UMI.)

Contribution of intrinsic properties and synaptic inputs to motoneuron discharge patterns: a simulation study

PubMed Central

ElBasiouny, Sherif M.; Rymer, W. Zev; Heckman, C. J.

2012-01-01

Motoneuron discharge patterns reflect the interaction of synaptic inputs with intrinsic conductances. Recent work has focused on the contribution of conductances mediating persistent inward currents (PICs), which amplify and prolong the effects of synaptic inputs on motoneuron discharge. Certain features of human motor unit discharge are thought to reflect a relatively stereotyped activation of PICs by excitatory synaptic inputs; these features include rate saturation and de-recruitment at a lower level of net excitation than that required for recruitment. However, PIC activation is also influenced by the pattern and spatial distribution of inhibitory inputs that are activated concurrently with excitatory inputs. To estimate the potential contributions of PIC activation and synaptic input patterns to motor unit discharge patterns, we examined the responses of a set of cable motoneuron models to different patterns of excitatory and inhibitory inputs. The models were first tuned to approximate the current- and voltage-clamp responses of low- and medium-threshold spinal motoneurons studied in decerebrate cats and then driven with different patterns of excitatory and inhibitory inputs. The responses of the models to excitatory inputs reproduced a number of features of human motor unit discharge. However, the pattern of rate modulation was strongly influenced by the temporal and spatial pattern of concurrent inhibitory inputs. Thus, even though PIC activation is likely to exert a strong influence on firing rate modulation, PIC activation in combination with different patterns of excitatory and inhibitory synaptic inputs can produce a wide variety of motor unit discharge patterns. PMID:22031773

Acute pancreatitis decreases the sensitivity of pancreas-projecting dorsal motor nucleus of the vagus neurones to group II metabotropic glutamate receptor agonists in rats

PubMed Central

Babic, Tanja; Travagli, R Alberto

2014-01-01

Recent studies have shown that pancreatic exocrine secretions (PES) are modulated by dorsal motor nucleus of the vagus (DMV) neurones, whose activity is finely tuned by GABAergic and glutamatergic synaptic inputs. Group II metabotropic glutamate receptors (mGluR) decrease synaptic transmission to pancreas-projecting DMV neurones and increase PES. In the present study, we used a combination of in vivo and in vitro approaches aimed at characterising the effects of caerulein-induced acute pancreatitis (AP) on the vagal neurocircuitry modulating pancreatic functions. In control rats, microinjection of bicuculline into the DMV increased PES, whereas microinjections of kynurenic acid had no effect. Conversely, in AP rats, microinjection of bicuculline had no effect, whereas kynurenic acid decreased PES. DMV microinjections of the group II mGluR agonist APDC and whole cell recordings of excitatory currents in identified pancreas-projecting DMV neurones showed a reduced functional response in AP rats compared to controls. Moreover, these changes persisted up to 3 weeks following the induction of AP. These data demonstrate that AP increases the excitatory input to pancreas-projecting DMV neurones by decreasing the response of excitatory synaptic terminals to group II mGluR agonist. PMID:24445314

Inhibition to excitation ratio regulates visual system responses and behavior in vivo.

PubMed

Shen, Wanhua; McKeown, Caroline R; Demas, James A; Cline, Hollis T

2011-11-01

The balance of inhibitory to excitatory (I/E) synaptic inputs is thought to control information processing and behavioral output of the central nervous system. We sought to test the effects of the decreased or increased I/E ratio on visual circuit function and visually guided behavior in Xenopus tadpoles. We selectively decreased inhibitory synaptic transmission in optic tectal neurons by knocking down the γ2 subunit of the GABA(A) receptors (GABA(A)R) using antisense morpholino oligonucleotides or by expressing a peptide corresponding to an intracellular loop of the γ2 subunit, called ICL, which interferes with anchoring GABA(A)R at synapses. Recordings of miniature inhibitory postsynaptic currents (mIPSCs) and miniature excitatory PSCs (mEPSCs) showed that these treatments decreased the frequency of mIPSCs compared with control tectal neurons without affecting mEPSC frequency, resulting in an ∼50% decrease in the ratio of I/E synaptic input. ICL expression and γ2-subunit knockdown also decreased the ratio of optic nerve-evoked synaptic I/E responses. We recorded visually evoked responses from optic tectal neurons, in which the synaptic I/E ratio was decreased. Decreasing the synaptic I/E ratio in tectal neurons increased the variance of first spike latency in response to full-field visual stimulation, increased recurrent activity in the tectal circuit, enlarged spatial receptive fields, and lengthened the temporal integration window. We used the benzodiazepine, diazepam (DZ), to increase inhibitory synaptic activity. DZ increased optic nerve-evoked inhibitory transmission but did not affect evoked excitatory currents, resulting in an increase in the I/E ratio of ∼30%. Increasing the I/E ratio with DZ decreased the variance of first spike latency, decreased spatial receptive field size, and lengthened temporal receptive fields. Sequential recordings of spikes and excitatory and inhibitory synaptic inputs to the same visual stimuli demonstrated that decreasing or increasing the I/E ratio disrupted input/output relations. We assessed the effect of an altered I/E ratio on a visually guided behavior that requires the optic tectum. Increasing and decreasing I/E in tectal neurons blocked the tectally mediated visual avoidance behavior. Because ICL expression, γ2-subunit knockdown, and DZ did not directly affect excitatory synaptic transmission, we interpret the results of our study as evidence that partially decreasing or increasing the ratio of I/E disrupts several measures of visual system information processing and visually guided behavior in an intact vertebrate.

Matrix Metalloproteinase-9 as a Novel Player in Synaptic Plasticity and Schizophrenia

PubMed Central

Lepeta, Katarzyna; Kaczmarek, Leszek

2015-01-01

Recent findings implicate alterations in glutamate signaling, leading to aberrant synaptic plasticity, in schizophrenia. Matrix metalloproteinase-9 (MMP-9) has been shown to regulate glutamate receptors, be regulated by glutamate at excitatory synapses, and modulate physiological and morphological synaptic plasticity. By means of functional gene polymorphism, gene responsiveness to antipsychotics and blood plasma levels MMP-9 has recently been implicated in schizophrenia. This commentary critically reviews these findings based on the hypothesis that MMP-9 contributes to pathological synaptic plasticity in schizophrenia. PMID:25837304

Loss of Tsc1 in vivo impairs hippocampal mGluR-LTD and increases excitatory synaptic function.

PubMed

Bateup, Helen S; Takasaki, Kevin T; Saulnier, Jessica L; Denefrio, Cassandra L; Sabatini, Bernardo L

2011-06-15

The autism spectrum disorder tuberous sclerosis complex (TSC) is caused by mutations in the Tsc1 or Tsc2 genes, whose protein products form a heterodimeric complex that negatively regulates mammalian target of rapamycin-dependent protein translation. Although several forms of synaptic plasticity, including metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD), depend on protein translation at the time of induction, it is unknown whether these forms of plasticity require signaling through the Tsc1/2 complex. To examine this possibility, we postnatally deleted Tsc1 in vivo in a subset of hippocampal CA1 neurons using viral delivery of Cre recombinase in mice. We found that hippocampal mGluR-LTD was abolished by loss of Tsc1, whereas a protein synthesis-independent form of NMDA receptor-dependent LTD was preserved. Additionally, AMPA and NMDA receptor-mediated EPSCs and miniature spontaneous EPSC frequency were enhanced in Tsc1 KO neurons. These changes in synaptic function occurred in the absence of alterations in spine density, morphology, or presynaptic release probability. Our findings indicate that signaling through Tsc1/2 is required for the expression of specific forms of hippocampal synaptic plasticity as well as the maintenance of normal excitatory synaptic strength. Furthermore, these data suggest that perturbations of synaptic signaling may contribute to the pathogenesis of TSC.

Schaffer Collateral Inputs to CA1 Excitatory and Inhibitory Neurons Follow Different Connectivity Rules.

PubMed

Kwon, Osung; Feng, Linqing; Druckmann, Shaul; Kim, Jinhyun

2018-05-30

Neural circuits, governed by a complex interplay between excitatory and inhibitory neurons, are the substrate for information processing, and the organization of synaptic connectivity in neural network is an important determinant of circuit function. Here, we analyzed the fine structure of connectivity in hippocampal CA1 excitatory and inhibitory neurons innervated by Schaffer collaterals (SCs) using mGRASP in male mice. Our previous study revealed spatially structured synaptic connectivity between CA3 and CA1 pyramidal cells (PCs). Surprisingly, parvalbumin-positive interneurons (PVs) showed a significantly more random pattern spatial structure. Notably, application of Peters' rule for synapse prediction by random overlap between axons and dendrites enhanced structured connectivity in PCs, but, by contrast, made the connectivity pattern in PVs more random. In addition, PCs in a deep sublayer of striatum pyramidale appeared more highly structured than PCs in superficial layers, and little or no sublayer specificity was found in PVs. Our results show that CA1 excitatory PCs and inhibitory PVs innervated by the same SC inputs follow different connectivity rules. The different organizations of fine scale structured connectivity in hippocampal excitatory and inhibitory neurons provide important insights into the development and functions of neural networks. SIGNIFICANCE STATEMENT Understanding how neural circuits generate behavior is one of the central goals of neuroscience. An important component of this endeavor is the mapping of fine-scale connection patterns that underlie, and help us infer, signal processing in the brain. Here, using our recently developed synapse detection technology (mGRASP and neuTube), we provide detailed profiles of synaptic connectivity in excitatory (CA1 pyramidal) and inhibitory (CA1 parvalbumin-positive) neurons innervated by the same presynaptic inputs (CA3 Schaffer collaterals). Our results reveal that these two types of CA1 neurons follow different connectivity patterns. Our new evidence for differently structured connectivity at a fine scale in hippocampal excitatory and inhibitory neurons provides a better understanding of hippocampal networks and will guide theoretical and experimental studies. Copyright © 2018 the authors 0270-6474/18/385140-13$15.00/0.

Control of Excitation/Inhibition Balance in a Hippocampal Circuit by Calcium Sensor Protein Regulation of Presynaptic Calcium Channels.

PubMed

Nanou, Evanthia; Lee, Amy; Catterall, William A

2018-05-02

Activity-dependent regulation controls the balance of synaptic excitation to inhibition in neural circuits, and disruption of this regulation impairs learning and memory and causes many neurological disorders. The molecular mechanisms underlying short-term synaptic plasticity are incompletely understood, and their role in inhibitory synapses remains uncertain. Here we show that regulation of voltage-gated calcium (Ca 2+ ) channel type 2.1 (Ca V 2.1) by neuronal Ca 2+ sensor (CaS) proteins controls synaptic plasticity and excitation/inhibition balance in a hippocampal circuit. Prevention of CaS protein regulation by introducing the IM-AA mutation in Ca V 2.1 channels in male and female mice impairs short-term synaptic facilitation at excitatory synapses of CA3 pyramidal neurons onto parvalbumin (PV)-expressing basket cells. In sharp contrast, the IM-AA mutation abolishes rapid synaptic depression in the inhibitory synapses of PV basket cells onto CA1 pyramidal neurons. These results show that CaS protein regulation of facilitation and inactivation of Ca V 2.1 channels controls the direction of short-term plasticity at these two synapses. Deletion of the CaS protein CaBP1/caldendrin also blocks rapid depression at PV-CA1 synapses, implicating its upregulation of inactivation of Ca V 2.1 channels in control of short-term synaptic plasticity at this inhibitory synapse. Studies of local-circuit function revealed reduced inhibition of CA1 pyramidal neurons by the disynaptic pathway from CA3 pyramidal cells via PV basket cells and greatly increased excitation/inhibition ratio of the direct excitatory input versus indirect inhibitory input from CA3 pyramidal neurons to CA1 pyramidal neurons. This striking defect in local-circuit function may contribute to the dramatic impairment of spatial learning and memory in IM-AA mice. SIGNIFICANCE STATEMENT Many forms of short-term synaptic plasticity in neuronal circuits rely on regulation of presynaptic voltage-gated Ca 2+ (Ca V ) channels. Regulation of Ca V 2.1 channels by neuronal calcium sensor (CaS) proteins controls short-term synaptic plasticity. Here we demonstrate a direct link between regulation of Ca V 2.1 channels and short-term synaptic plasticity in native hippocampal excitatory and inhibitory synapses. We also identify CaBP1/caldendrin as the calcium sensor interacting with Ca V 2.1 channels to mediate rapid synaptic depression in the inhibitory hippocampal synapses of parvalbumin-expressing basket cells to CA1 pyramidal cells. Disruption of this regulation causes altered short-term plasticity and impaired balance of hippocampal excitatory to inhibitory circuits. Copyright © 2018 the authors 0270-6474/18/384430-11$15.00/0.

Signaling in large-scale neural networks.

PubMed

Berg, Rune W; Hounsgaard, Jørn

2009-02-01

We examine the recent finding that neurons in spinal motor circuits enter a high conductance state during functional network activity. The underlying concomitant increase in random inhibitory and excitatory synaptic activity leads to stochastic signal processing. The possible advantages of this metabolically costly organization are analyzed by comparing with synaptically less intense networks driven by the intrinsic response properties of the network neurons.

A subtype specific function for the extracellular domain of neuroligin 1 in hippocampal LTP

PubMed Central

Shipman, Seth L.; Nicoll, Roger A.

2014-01-01

Summary At neuronal excitatory synapses, two major subtypes of the synaptic adhesion molecule neuroligin are present. These subtypes, neuroligin 1 and neuroligin 3, have roles in synaptogenesis and synaptic maintenance that appear largely overlapping. In this study we combine electrophysiology with molecular deletion and replacement of these proteins to identify similarities and differences between these subtypes. In doing so, we identify a subtype specific role in LTP for neuroligin 1 in young CA1, which persists into adulthood in the dentate gyrus. As neuroligin 3 showed no requirement for LTP, we constructed chimeric proteins of the two excitatory neuroligin subtypes to identify the molecular determinants particular to the unique function of neuroligin 1. Using in vivo molecular replacement experiments, we find that these unique functions depend on a region in its extracellular domain containing the B site splice insertion previously shown to determine specificity of neurexin binding. PMID:23083734

Multiple effects of β-amyloid on single excitatory synaptic connections in the PFC.

PubMed

Wang, Yun; Zhou, Thomas H; Zhi, Zhina; Barakat, Amey; Hlatky, Lynn; Querfurth, Henry

2013-01-01

Prefrontal cortex (PFC) is recognized as an AD-vulnerable region responsible for defects in cognitive functioning. Pyramidal cell (PC) connections are typically facilitating (F) or depressing (D) in PFC. Excitatory post-synaptic potentials (EPSPs) were recorded using patch-clamp from single connections in PFC slices of rats and ferrets in the presence of β-amyloid (Aβ). Synaptic transmission was significantly enhanced or reduced depending on their intrinsic type (facilitating or depressing), Aβ species (Aβ 40 or Aβ 42) and concentration (1-200 nM vs. 0.3-1 μ M). Nanomolar Aβ 40 and Aβ 42 had opposite effects on F-connections, resulting in fewer or increased EPSP failure rates, strengthening or weakening EPSPs and enhancing or inhibiting short-term potentiation [STP: synaptic augmentation (SA) and post-tetanic potentiation (PTP)], respectively. High Aβ 40 concentrations induced inhibition regardless of synaptic type. D-connections were inhibited regardless of Aβ species or concentration. The inhibition induced with bath application was hard to recover by washout, but a complete recovery was obtained with brief local application and prompt washout. Our data suggests that Aβ 40 acts on the prefrontal neuronal network by modulating facilitating and depressing synapses. At higher levels, both Aβ 40 and Aβ 42 inhibit synaptic activity and cause irreversible toxicity once diffusely accumulated in the synaptic environment.

Altered Astrocyte-Neuron Interactions and Epileptogenesis in Tuberous Sclerosis Complex Disorder

DTIC Science & Technology

2014-06-01

Epileptogenesis in non-tuber neural tissue in TS may thus arise by an imbalance of decreased inhibitory and increased excitatory synaptic transmission...generation in TSC. Epileptogenesis in non-tuber neural tissue in TS may thus arise by an imbalance of decreased inhibitory and increased excitatory synaptic...synaptic damage induced by spontaneous seizures F) increased spine density on pyramidal neuron dendrites occurs before the onset of spontaneous seizures

Exposure to cocaine regulates inhibitory synaptic transmission from the ventral tegmental area to the nucleus accumbens

PubMed Central

Ishikawa, Masago; Otaka, Mami; Neumann, Peter A; Wang, Zhijian; Cook, James M; Schlüter, Oliver M; Dong, Yan; Huang, Yanhua H

2013-01-01

Synaptic projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) make up the backbone of the brain reward pathway, a neural circuit that mediates behavioural responses elicited by natural rewards as well as by cocaine and other drugs of abuse. In addition to the well-known modulatory dopaminergic projection, the VTA also provides fast excitatory and inhibitory synaptic input to the NAc, directly regulating NAc medium spiny neurons (MSNs). However, the cellular nature of VTA-to-NAc fast synaptic transmission and its roles in drug-induced adaptations are not well understood. Using viral-mediated in vivo expression of channelrhodopsin 2, the present study dissected fast excitatory and inhibitory synaptic transmission from the VTA to NAc MSNs in rats. Our results suggest that, following repeated exposure to cocaine (15 mg kg−1 day−1× 5 days, i.p., 1 or 21 day withdrawal), a presynaptic enhancement of excitatory transmission and suppression of inhibitory transmission occurred at different withdrawal time points at VTA-to-NAc core synapses. In contrast, no postsynaptic alterations were detected at either type of synapse. These results suggest that changes in VTA-to-NAc fast excitatory and inhibitory synaptic transmissions may contribute to cocaine-induced alteration of the brain reward circuitry. PMID:23918773

Endocannabinoid signaling and synaptic function

PubMed Central

Castillo, Pablo E.; Younts, Thomas J.; Chávez, Andrés E.; Hashimotodani, Yuki

2012-01-01

Endocannabinoids are key modulators of synaptic function. By activating cannabinoid receptors expressed in the central nervous system, these lipid messengers can regulate several neural functions and behaviors. As experimental tools advance, the repertoire of known endocannabinoid-mediated effects at the synapse, and their underlying mechanism, continues to expand. Retrograde signaling is the principal mode by which endocannabinoids mediate short- and long-term forms of plasticity at both excitatory and inhibitory synapses. However, growing evidence suggests that endocannabinoids can also signal in a non-retrograde manner. In addition to mediating synaptic plasticity, the endocannabinoid system is itself subject to plastic changes. Multiple points of interaction with other neuromodulatory and signaling systems have now been identified. Synaptic endocannabinoid signaling is thus mechanistically more complex and diverse than originally thought. In this review, we focus on new advances in endocannabinoid signaling and highlight their role as potent regulators of synaptic function in the mammalian brain. PMID:23040807

GRASP1 regulates synaptic plasticity and learning through endosomal recycling of AMPA receptors

PubMed Central

Chiu, Shu-Ling; Diering, Graham Hugh; Ye, Bing; Takamiya, Kogo; Chen, Chih-Ming; Jiang, Yuwu; Niranjan, Tejasvi; Schwartz, Charles E.; Wang, Tao; Huganir, Richard L.

2017-01-01

Summary Learning depends on experience-dependent modification of synaptic efficacy and neuronal connectivity in the brain. We provide direct evidence for physiological roles of the recycling endosome protein GRASP1 in glutamatergic synapse function and animal behavior. Mice lacking GRASP1 showed abnormal excitatory synapse number, synaptic plasticity and hippocampal-dependent learning and memory due to a failure in learning-induced synaptic AMPAR incorporation. We identified two GRASP1 point mutations from intellectual disability (ID) patients that showed convergent disruptive effects on AMPAR recycling and glutamate uncaging-induced structural and functional plasticity. Wild-type GRASP1, but not ID mutants, rescues spine loss in hippocampal CA1 neurons of Grasp1 knockout mice. Together, these results demonstrate a requirement for normal recycling endosome function in AMPAR-dependent synaptic function and neuronal connectivity in vivo, and suggest a potential role for GRASP1 in the pathophysiology of human cognitive disorders. PMID:28285821

The gray area between synapse structure and function-Gray's synapse types I and II revisited.

PubMed

Klemann, Cornelius J H M; Roubos, Eric W

2011-11-01

On the basis of ultrastructural parameters, the concept was formulated that asymmetric Type I and symmetric Type II synapses are excitatory and inhibitory, respectively. This "functional Gray synapses concept" received strong support from the demonstration of the excitatory neurotransmitter glutamate in Type I synapses and of the inhibitory neurotransmitter γ-aminobutyric acid in Type II synapses, and is still frequently used in modern literature. However, morphological and functional evidence has accumulated that the concept is less tenable. Typical features of synapses like shape and size of presynaptic vesicles and synaptic cleft and presence of a postsynaptic density (PsD) do not always fit the postulated (excitatory/inhibitory) function of Gray's synapses. Furthermore, synapse function depends on postsynaptic receptors and associated signal transduction mechanisms rather than on presynaptic morphology and neurotransmitter type. Moreover, the notion that many synapses are difficult to classify as either asymmetric or symmetric has cast doubt on the assumption that the presence of a PsD is a sign of excitatory synaptic transmission. In view of the morphological similarities of the PsD in asymmetric synapses with membrane junctional structures such as the zonula adherens and the desmosome, asymmetric synapses may play a role as links between the postsynaptic and presynaptic membrane, thus ensuring long-term maintenance of interneuronal communication. Symmetric synapses, on the other hand, might be sites of transient communication as takes place during development, learning, memory formation, and pathogenesis of brain disorders. Confirmation of this idea might help to return the functional Gray synapse concept its central place in neuroscience. Copyright © 2011 Wiley-Liss, Inc.

Dynamical model of long-term synaptic plasticity

PubMed Central

Abarbanel, Henry D. I.; Huerta, R.; Rabinovich, M. I.

2002-01-01

Long-term synaptic plasticity leading to enhancement in synaptic efficacy (long-term potentiation, LTP) or decrease in synaptic efficacy (long-term depression, LTD) is widely regarded as underlying learning and memory in nervous systems. LTP and LTD at excitatory neuronal synapses are observed to be induced by precise timing of pre- and postsynaptic events. Modification of synaptic transmission in long-term plasticity is a complex process involving many pathways; for example, it is also known that both forms of synaptic plasticity can be induced by various time courses of Ca2+ introduction into the postsynaptic cell. We present a phenomenological description of a two-component process for synaptic plasticity. Our dynamical model reproduces the spike time-dependent plasticity of excitatory synapses as a function of relative timing between pre- and postsynaptic events, as observed in recent experiments. The model accounts for LTP and LTD when the postsynaptic cell is voltage clamped and depolarized (LTP) or hyperpolarized (LTD) and no postsynaptic action potentials are evoked. We are also able to connect our model with the Bienenstock, Cooper, and Munro rule. We give model predictions for changes in synaptic strength when periodic spike trains of varying frequency and Poisson distributed spike trains with varying average frequency are presented pre- and postsynaptically. When the frequency of spike presentation exceeds ≈30–40 Hz, only LTP is induced. PMID:12114531

Structure and function of the amygdaloid NPY system: NPY Y2 receptors regulate excitatory and inhibitory synaptic transmission in the centromedial amygdala.

PubMed

Wood, J; Verma, D; Lach, G; Bonaventure, P; Herzog, H; Sperk, G; Tasan, R O

2016-09-01

The amygdala is essential for generating emotional-affective behaviors. It consists of several nuclei with highly selective, elaborate functions. In particular, the central extended amygdala, consisting of the central amygdala (CEA) and the bed nucleus of the stria terminalis (BNST) is an essential component actively controlling efferent connections to downstream effectors like hypothalamus and brain stem. Both, CEA and BNST contain high amounts of different neuropeptides that significantly contribute to synaptic transmission. Among these, neuropeptide Y (NPY) has emerged as an important anxiolytic and fear-reducing neuromodulator. Here, we characterized the expression, connectivity and electrophysiological function of NPY and Y2 receptors within the CEA. We identified several NPY-expressing neuronal populations, including somatostatin- and calretinin-expressing neurons. Furthermore, in the main intercalated nucleus, NPY is expressed primarily in dopamine D1 receptor-expressing neurons but also in interspersed somatostatin-expressing neurons. Interestingly, NPY neurons did not co-localize with the Y2 receptor. Retrograde tract tracing experiments revealed that NPY neurons reciprocally connect the CEA and BNST. Functionally, the Y2 receptor agonist PYY3-36, reduced both, inhibitory as well as excitatory synaptic transmission in the centromedial amygdala (CEm). However, we also provide evidence that lack of NPY or Y2 receptors results in increased GABA release specifically at inhibitory synapses in the CEm. Taken together, our findings suggest that NPY expressed by distinct populations of neurons can modulate afferent and efferent projections of the CEA via presynaptic Y2 receptors located at inhibitory and excitatory synapses.

From Synaptic Transmission to Cognition: An Intermediary Role for Dendritic Spines

ERIC Educational Resources Information Center

Gonzalez-Burgos, Ignacio

2012-01-01

Dendritic spines are cytoplasmic protrusions that develop directly or indirectly from the filopodia of neurons. Dendritic spines mediate excitatory neurotransmission and they can isolate the electrical activity generated by synaptic impulses, enabling them to translate excitatory afferent information via several types of plastic changes, including…

The Balance of Excitatory and Inhibitory Synaptic Inputs for Coding Sound Location

PubMed Central

Ono, Munenori

2014-01-01

The localization of high-frequency sounds in the horizontal plane uses an interaural-level difference (ILD) cue, yet little is known about the synaptic mechanisms that underlie processing this cue in the inferior colliculus (IC) of mouse. Here, we study the synaptic currents that process ILD in vivo and use stimuli in which ILD varies around a constant average binaural level (ABL) to approximate sounds on the horizontal plane. Monaural stimulation in either ear produced EPSCs and IPSCs in most neurons. The temporal properties of monaural responses were well matched, suggesting connected functional zones with matched inputs. The EPSCs had three patterns in response to ABL stimuli, preference for the sound field with the highest level stimulus: (1) contralateral; (2) bilateral highly lateralized; or (3) at the center near 0 ILD. EPSCs and IPSCs were well correlated except in center-preferred neurons. Summation of the monaural EPSCs predicted the binaural excitatory response but less well than the summation of monaural IPSCs. Binaural EPSCs often showed a nonlinearity that strengthened the response to specific ILDs. Extracellular spike and intracellular current recordings from the same neuron showed that the ILD tuning of the spikes was sharper than that of the EPSCs. Thus, in the IC, balanced excitatory and inhibitory inputs may be a general feature of synaptic coding for many types of sound processing. PMID:24599475

Neuronal pentraxin 1: A synaptic-derived plasma biomarker in Alzheimer's disease.

PubMed

Ma, Qiu-Lan; Teng, Edmond; Zuo, Xiaohong; Jones, Mychica; Teter, Bruce; Zhao, Evan Y; Zhu, Cansheng; Bilousova, Tina; Gylys, Karen H; Apostolova, Liana G; LaDu, Mary Jo; Hossain, Mir Ahamed; Frautschy, Sally A; Cole, Gregory M

2018-06-01

Synaptic neurodegeneration is thought to be an early event initiated by soluble β-amyloid (Aβ) aggregates that closely correlates with cognitive decline in Alzheimer disease (AD). Apolipoprotein ε4 (APOE4) is the most common genetic risk factor for both familial AD (FAD) and sporadic AD; it accelerates Aβ aggregation and selectively impairs glutamate receptor function and synaptic plasticity. However, its molecular mechanisms remain elusive and these synaptic deficits are difficult to monitor. AD- and APOE4-dependent plasma biomarkers have been proposed, but synapse-related plasma biomarkers are lacking. We evaluated neuronal pentraxin 1 (NP1), a potential CNS-derived plasma biomarker of excitatory synaptic pathology. NP1 is preferentially expressed in brain and involved in glutamate receptor internalization. NP1 is secreted presynaptically induced by Aβ oligomers, and implicated in excitatory synaptic and mitochondrial deficits. Levels of NP1 and its fragments were increased in a correlated fashion in both brain and plasma of 7-8 month-old E4FAD mice relative to E3FAD mice. NP1 was also found in exosome preparations and reduced by dietary DHA supplementation. Plasma NP1 was higher in E4FAD+ (APOE4 +/+ /FAD +/- ) relative to E4FAD- (non-carrier; APOE4 +/+ /FAD -/- ) mice, suggesting NP1 is modulated by Aβ expression. Finally, relative to normal elderly, plasma NP1 was also elevated in patients with mild cognitive impairment (MCI) and elevated further in the subset who progressed to early-stage AD. In those patients, there was a trend towards increased NP1 levels in APOE4 carriers relative to non-carriers. These findings indicate that NP1 may represent a potential synapse-derived plasma biomarker relevant to early alterations in excitatory synapses in MCI and early-stage AD. Copyright © 2018. Published by Elsevier Inc.

TGF-β Signaling in Dopaminergic Neurons Regulates Dendritic Growth, Excitatory-Inhibitory Synaptic Balance, and Reversal Learning.

PubMed

Luo, Sarah X; Timbang, Leah; Kim, Jae-Ick; Shang, Yulei; Sandoval, Kadellyn; Tang, Amy A; Whistler, Jennifer L; Ding, Jun B; Huang, Eric J

2016-12-20

Neural circuits involving midbrain dopaminergic (DA) neurons regulate reward and goal-directed behaviors. Although local GABAergic input is known to modulate DA circuits, the mechanism that controls excitatory/inhibitory synaptic balance in DA neurons remains unclear. Here, we show that DA neurons use autocrine transforming growth factor β (TGF-β) signaling to promote the growth of axons and dendrites. Surprisingly, removing TGF-β type II receptor in DA neurons also disrupts the balance in TGF-β1 expression in DA neurons and neighboring GABAergic neurons, which increases inhibitory input, reduces excitatory synaptic input, and alters phasic firing patterns in DA neurons. Mice lacking TGF-β signaling in DA neurons are hyperactive and exhibit inflexibility in relinquishing learned behaviors and re-establishing new stimulus-reward associations. These results support a role for TGF-β in regulating the delicate balance of excitatory/inhibitory synaptic input in local microcircuits involving DA and GABAergic neurons and its potential contributions to neuropsychiatric disorders. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Glucose rapidly induces different forms of excitatory synaptic plasticity in hypothalamic POMC neurons.

PubMed

Hu, Jun; Jiang, Lin; Low, Malcolm J; Rui, Liangyou

2014-01-01

Hypothalamic POMC neurons are required for glucose and energy homeostasis. POMC neurons have a wide synaptic connection with neurons both within and outside the hypothalamus, and their activity is controlled by a balance between excitatory and inhibitory synaptic inputs. Brain glucose-sensing plays an essential role in the maintenance of normal body weight and metabolism; however, the effect of glucose on synaptic transmission in POMC neurons is largely unknown. Here we identified three types of POMC neurons (EPSC(+), EPSC(-), and EPSC(+/-)) based on their glucose-regulated spontaneous excitatory postsynaptic currents (sEPSCs), using whole-cell patch-clamp recordings. Lowering extracellular glucose decreased the frequency of sEPSCs in EPSC(+) neurons, but increased it in EPSC(-) neurons. Unlike EPSC(+) and EPSC(-) neurons, EPSC(+/-) neurons displayed a bi-phasic sEPSC response to glucoprivation. In the first phase of glucoprivation, both the frequency and the amplitude of sEPSCs decreased, whereas in the second phase, they increased progressively to the levels above the baseline values. Accordingly, lowering glucose exerted a bi-phasic effect on spontaneous action potentials in EPSC(+/-) neurons. Glucoprivation decreased firing rates in the first phase, but increased them in the second phase. These data indicate that glucose induces distinct excitatory synaptic plasticity in different subpopulations of POMC neurons. This synaptic remodeling is likely to regulate the sensitivity of the melanocortin system to neuronal and hormonal signals.

Auditory cortical plasticity induced by intracortical microstimulation under pharmacological blockage of inhibitory synapses.

PubMed

Yokota, R; Takahashi, H; Funamizu, A; Uchihara, M; Suzurikawa, J; Kanzaki, R

2006-01-01

Electrical stimulation that can reorganize our neural system has a potential for promising neurorehabilitation. We previously demonstrated that temporally controlled intracortical microstimulation (ICMS) could induce the spike time-dependant plasticity and modify tuning properties of cortical neurons as desired. A 'pairing' ICMS following tone-induced excitatory post-synaptic potentials (EPSPs) produced potentiation in response to the paired tones, while an 'anti-pairing' ICMS preceding the tone-induced EPSPs resulted in depression. However, the conventional ICMS affected both excitatory and inhibitory synapses, and thereby could not quantify net excitatory synaptic effects. In the present work, we evaluated the ICMS effects under a pharmacological blockage of inhibitory inputs. The pharmacological blockage enhanced the ICMS effects, suggesting that inhibitory inputs determine a plastic degree of the neural system. Alternatively, the conventional ICMS had an inadequate timing to control excitatory synaptic inputs, because inhibitory synapse determined the latency of total neural inputs.

Radiation-induced alterations in synaptic neurotransmission of dentate granule cells depend on the dose and species of charged particles.

PubMed

Marty, V N; Vlkolinsky, R; Minassian, N; Cohen, T; Nelson, G A; Spigelman, I

2014-12-01

The evaluation of potential health risks associated with neuronal exposure to space radiation is critical for future long duration space travel. The purpose of this study was to evaluate and compare the effects of low-dose proton and high-energy charged particle (HZE) radiation on electrophysiological parameters of the granule cells in the dentate gyrus (DG) of the hippocampus and its associated functional consequences. We examined excitatory and inhibitory neurotransmission in DG granule cells (DGCs) in dorsal hippocampal slices from male C57BL/6 mice at 3 months after whole body irradiation with accelerated proton, silicon or iron particles. Multielectrode arrays were used to investigate evoked field synaptic potentials, an extracellular measurement of synaptic excitability in the perforant path to DG synaptic pathway. Whole-cell patch clamp recordings were used to measure miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) in DGCs. Exposure to proton radiation increased synaptic excitability and produced dose-dependent decreases in amplitude and charge transfer of mIPSCs, without affecting the expression of γ-aminobutyric acid type A receptor α2, β3 and γ2 subunits determined by Western blotting. Exposure to silicon radiation had no significant effects on synaptic excitability, mEPSCs or mIPSCs of DGCs. Exposure to iron radiation had no effect on synaptic excitability and mIPSCs, but significantly increased mEPSC frequency at 1 Gy, without changes in mEPSC kinetics, suggesting a presynaptic mechanism. Overall, the data suggest that proton and HZE exposure results in radiation dose- and species-dependent long-lasting alterations in synaptic neurotransmission, which could cause radiation-induced impairment of hippocampal-dependent cognitive functions.

Emerging Synaptic Molecules as Candidates in the Etiology of Neurological Disorders

PubMed Central

Torres, Viviana I.; Vallejo, Daniela

2017-01-01

Synapses are complex structures that allow communication between neurons in the central nervous system. Studies conducted in vertebrate and invertebrate models have contributed to the knowledge of the function of synaptic proteins. The functional synapse requires numerous protein complexes with specialized functions that are regulated in space and time to allow synaptic plasticity. However, their interplay during neuronal development, learning, and memory is poorly understood. Accumulating evidence links synapse proteins to neurodevelopmental, neuropsychiatric, and neurodegenerative diseases. In this review, we describe the way in which several proteins that participate in cell adhesion, scaffolding, exocytosis, and neurotransmitter reception from presynaptic and postsynaptic compartments, mainly from excitatory synapses, have been associated with several synaptopathies, and we relate their functions to the disease phenotype. PMID:28331639

P-type Ca2+ channels mediate excitatory and inhibitory synaptic transmitter release in crayfish muscle.

PubMed

Araque, A; Clarac, F; Buño, W

1994-05-10

The toxin fraction (FTX) and peptide omega-Aga-IVA from the venom of the funnel-web spider Agelenopsis aperta, as well as a synthetic analogue of FTX, specifically block the P-type voltage-dependent Ca2+ channel (VDCC). The effects of these toxins on synaptic transmission were studied in the neuromuscular synapses of the crayfish opener muscle, which has a single excitatory and a single inhibitory motoneuron. FTX selectively and reversibly blocked excitatory and inhibitory postsynaptic currents and potentials in a dose-dependent manner. FTX had no effect on (i) resting and postsynaptic membrane conductance, (ii) postsynaptic L-type VDCC, and (iii) both glutamate- and gamma-aminobutyric acid-induced postsynaptic responses. Mean amplitude and frequency of miniature postsynaptic potentials were unchanged by FTX. The postsynaptic VDCC was inhibited by nifedipine, a selective dihydropyridine antagonist of L-type VDCC, whereas synaptic transmission was unaffected. Transmission was also undisturbed by omega-conotoxin, suggesting that N-type VDCCs are not involved. The peptide omega-Aga-IVA blocked excitatory and inhibitory transmission without affecting postsynaptic VDCC. Synaptic transmission was also blocked by synthetic FTX. We conclude that presynaptic P-type VDCCs are involved in both evoked excitatory and inhibitory transmitter release in crayfish neuromuscular synapses.

P-type Ca2+ channels mediate excitatory and inhibitory synaptic transmitter release in crayfish muscle.

PubMed Central

Araque, A; Clarac, F; Buño, W

1994-01-01

The toxin fraction (FTX) and peptide omega-Aga-IVA from the venom of the funnel-web spider Agelenopsis aperta, as well as a synthetic analogue of FTX, specifically block the P-type voltage-dependent Ca2+ channel (VDCC). The effects of these toxins on synaptic transmission were studied in the neuromuscular synapses of the crayfish opener muscle, which has a single excitatory and a single inhibitory motoneuron. FTX selectively and reversibly blocked excitatory and inhibitory postsynaptic currents and potentials in a dose-dependent manner. FTX had no effect on (i) resting and postsynaptic membrane conductance, (ii) postsynaptic L-type VDCC, and (iii) both glutamate- and gamma-aminobutyric acid-induced postsynaptic responses. Mean amplitude and frequency of miniature postsynaptic potentials were unchanged by FTX. The postsynaptic VDCC was inhibited by nifedipine, a selective dihydropyridine antagonist of L-type VDCC, whereas synaptic transmission was unaffected. Transmission was also undisturbed by omega-conotoxin, suggesting that N-type VDCCs are not involved. The peptide omega-Aga-IVA blocked excitatory and inhibitory transmission without affecting postsynaptic VDCC. Synaptic transmission was also blocked by synthetic FTX. We conclude that presynaptic P-type VDCCs are involved in both evoked excitatory and inhibitory transmitter release in crayfish neuromuscular synapses. Images PMID:7910404

Differential distribution of voltage-gated ion channels in cortical neurons: implications for epilepsy.

PubMed

Child, Nicholas D; Benarroch, Eduardo E

2014-03-18

Neurons contain different functional somatodendritic and axonal domains, each with a characteristic distribution of voltage-gated ion channels, synaptic inputs, and function. The dendritic tree of a cortical pyramidal neuron has 2 distinct domains, the basal and the apical dendrites, both containing dendritic spines; the different domains of the axon are the axonal initial segment (AIS), axon proper (which in myelinated axons includes the node of Ranvier, paranodes, juxtaparanodes, and internodes), and the axon terminals. In the cerebral cortex, the dendritic spines of the pyramidal neurons receive most of the excitatory synapses; distinct populations of γ-aminobutyric acid (GABA)ergic interneurons target specific cellular domains and thus exert different influences on pyramidal neurons. The multiple synaptic inputs reaching the somatodendritic region and generating excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) sum and elicit changes in membrane potential at the AIS, the site of initiation of the action potential.

Oxide-based synaptic transistors gated by solution-processed gelatin electrolytes

NASA Astrophysics Data System (ADS)

He, Yinke; Sun, Jia; Qian, Chuan; Kong, Ling-An; Gou, Guangyang; Li, Hongjian

2017-04-01

In human brain, a large number of neurons are connected via synapses. Simulation of the synaptic behaviors using electronic devices is the most important step for neuromorphic systems. In this paper, proton conducting gelatin electrolyte-gated oxide field-effect transistors (FETs) were used for emulating synaptic functions, in which the gate electrode is regarded as pre-synaptic neuron and the channel layer as the post-synaptic neuron. In analogy to the biological synapse, a potential spike can be applied at the gate electrode and trigger ionic motion in the gelatin electrolyte, which in turn generates excitatory post-synaptic current (EPSC) in the channel layer. Basic synaptic behaviors including spike time-dependent EPSC, paired-pulse facilitation (PPF), self-adaptation, and frequency-dependent synaptic transmission were successfully mimicked. Such ionic/electronic hybrid devices are beneficial for synaptic electronics and brain-inspired neuromorphic systems.

Dynamical responses to external stimuli for both cases of excitatory and inhibitory synchronization in a complex neuronal network.

PubMed

Kim, Sang-Yoon; Lim, Woochang

2017-10-01

For studying how dynamical responses to external stimuli depend on the synaptic-coupling type, we consider two types of excitatory and inhibitory synchronization (i.e., synchronization via synaptic excitation and inhibition) in complex small-world networks of excitatory regular spiking (RS) pyramidal neurons and inhibitory fast spiking (FS) interneurons. For both cases of excitatory and inhibitory synchronization, effects of synaptic couplings on dynamical responses to external time-periodic stimuli S ( t ) (applied to a fraction of neurons) are investigated by varying the driving amplitude A of S ( t ). Stimulated neurons are phase-locked to external stimuli for both cases of excitatory and inhibitory couplings. On the other hand, the stimulation effect on non-stimulated neurons depends on the type of synaptic coupling. The external stimulus S ( t ) makes a constructive effect on excitatory non-stimulated RS neurons (i.e., it causes external phase lockings in the non-stimulated sub-population), while S ( t ) makes a destructive effect on inhibitory non-stimulated FS interneurons (i.e., it breaks up original inhibitory synchronization in the non-stimulated sub-population). As results of these different effects of S ( t ), the type and degree of dynamical response (e.g., synchronization enhancement or suppression), characterized by the dynamical response factor [Formula: see text] (given by the ratio of synchronization degree in the presence and absence of stimulus), are found to vary in a distinctly different way, depending on the synaptic-coupling type. Furthermore, we also measure the matching degree between the dynamics of the two sub-populations of stimulated and non-stimulated neurons in terms of a "cross-correlation" measure [Formula: see text]. With increasing A , based on [Formula: see text], we discuss the cross-correlations between the two sub-populations, affecting the dynamical responses to S ( t ).

Multiple effects of β-amyloid on single excitatory synaptic connections in the PFC

PubMed Central

Wang, Yun; Zhou, Thomas H.; Zhi, Zhina; Barakat, Amey; Hlatky, Lynn; Querfurth, Henry

2013-01-01

Prefrontal cortex (PFC) is recognized as an AD-vulnerable region responsible for defects in cognitive functioning. Pyramidal cell (PC) connections are typically facilitating (F) or depressing (D) in PFC. Excitatory post-synaptic potentials (EPSPs) were recorded using patch-clamp from single connections in PFC slices of rats and ferrets in the presence of β-amyloid (Aβ). Synaptic transmission was significantly enhanced or reduced depending on their intrinsic type (facilitating or depressing), Aβ species (Aβ 40 or Aβ 42) and concentration (1–200 nM vs. 0.3–1 μ M). Nanomolar Aβ 40 and Aβ 42 had opposite effects on F-connections, resulting in fewer or increased EPSP failure rates, strengthening or weakening EPSPs and enhancing or inhibiting short-term potentiation [STP: synaptic augmentation (SA) and post-tetanic potentiation (PTP)], respectively. High Aβ 40 concentrations induced inhibition regardless of synaptic type. D-connections were inhibited regardless of Aβ species or concentration. The inhibition induced with bath application was hard to recover by washout, but a complete recovery was obtained with brief local application and prompt washout. Our data suggests that Aβ 40 acts on the prefrontal neuronal network by modulating facilitating and depressing synapses. At higher levels, both Aβ 40 and Aβ 42 inhibit synaptic activity and cause irreversible toxicity once diffusely accumulated in the synaptic environment. PMID:24027495

Pannexin 1 regulates bidirectional hippocampal synaptic plasticity in adult mice.

PubMed

Ardiles, Alvaro O; Flores-Muñoz, Carolina; Toro-Ayala, Gabriela; Cárdenas, Ana M; Palacios, Adrian G; Muñoz, Pablo; Fuenzalida, Marco; Sáez, Juan C; Martínez, Agustín D

2014-01-01

The threshold for bidirectional modification of synaptic plasticity is known to be controlled by several factors, including the balance between protein phosphorylation and dephosphorylation, postsynaptic free Ca(2+) concentration and NMDA receptor (NMDAR) composition of GluN2 subunits. Pannexin 1 (Panx1), a member of the integral membrane protein family, has been shown to form non-selective channels and to regulate the induction of synaptic plasticity as well as hippocampal-dependent learning. Although Panx1 channels have been suggested to play a role in excitatory long-term potentiation (LTP), it remains unknown whether these channels also modulate long-term depression (LTD) or the balance between both types of synaptic plasticity. To study how Panx1 contributes to excitatory synaptic efficacy, we examined the age-dependent effects of eliminating or blocking Panx1 channels on excitatory synaptic plasticity within the CA1 region of the mouse hippocampus. By using different protocols to induce bidirectional synaptic plasticity, Panx1 channel blockade or lack of Panx1 were found to enhance LTP, whereas both conditions precluded the induction of LTD in adults, but not in young animals. These findings suggest that Panx1 channels restrain the sliding threshold for the induction of synaptic plasticity and underlying brain mechanisms of learning and memory.

Pannexin 1 regulates bidirectional hippocampal synaptic plasticity in adult mice

PubMed Central

Ardiles, Alvaro O.; Flores-Muñoz, Carolina; Toro-Ayala, Gabriela; Cárdenas, Ana M.; Palacios, Adrian G.; Muñoz, Pablo; Fuenzalida, Marco; Sáez, Juan C.; Martínez, Agustín D.

2014-01-01

The threshold for bidirectional modification of synaptic plasticity is known to be controlled by several factors, including the balance between protein phosphorylation and dephosphorylation, postsynaptic free Ca2+ concentration and NMDA receptor (NMDAR) composition of GluN2 subunits. Pannexin 1 (Panx1), a member of the integral membrane protein family, has been shown to form non-selective channels and to regulate the induction of synaptic plasticity as well as hippocampal-dependent learning. Although Panx1 channels have been suggested to play a role in excitatory long-term potentiation (LTP), it remains unknown whether these channels also modulate long-term depression (LTD) or the balance between both types of synaptic plasticity. To study how Panx1 contributes to excitatory synaptic efficacy, we examined the age-dependent effects of eliminating or blocking Panx1 channels on excitatory synaptic plasticity within the CA1 region of the mouse hippocampus. By using different protocols to induce bidirectional synaptic plasticity, Panx1 channel blockade or lack of Panx1 were found to enhance LTP, whereas both conditions precluded the induction of LTD in adults, but not in young animals. These findings suggest that Panx1 channels restrain the sliding threshold for the induction of synaptic plasticity and underlying brain mechanisms of learning and memory. PMID:25360084

Functional Evaluation of Biological Neurotoxins in Networked Cultures of Stem Cell-derived Central Nervous System Neurons

PubMed Central

Hubbard, Kyle; Beske, Phillip; Lyman, Megan; McNutt, Patrick

2015-01-01

Therapeutic and mechanistic studies of the presynaptically targeted clostridial neurotoxins (CNTs) have been limited by the need for a scalable, cell-based model that produces functioning synapses and undergoes physiological responses to intoxication. Here we describe a simple and robust method to efficiently differentiate murine embryonic stem cells (ESCs) into defined lineages of synaptically active, networked neurons. Following an 8 day differentiation protocol, mouse embryonic stem cell-derived neurons (ESNs) rapidly express and compartmentalize neurotypic proteins, form neuronal morphologies and develop intrinsic electrical responses. By 18 days after differentiation (DIV 18), ESNs exhibit active glutamatergic and γ-aminobutyric acid (GABA)ergic synapses and emergent network behaviors characterized by an excitatory:inhibitory balance. To determine whether intoxication with CNTs functionally antagonizes synaptic neurotransmission, thereby replicating the in vivo pathophysiology that is responsible for clinical manifestations of botulism or tetanus, whole-cell patch clamp electrophysiology was used to quantify spontaneous miniature excitatory post-synaptic currents (mEPSCs) in ESNs exposed to tetanus neurotoxin (TeNT) or botulinum neurotoxin (BoNT) serotypes /A-/G. In all cases, ESNs exhibited near-complete loss of synaptic activity within 20 hr. Intoxicated neurons remained viable, as demonstrated by unchanged resting membrane potentials and intrinsic electrical responses. To further characterize the sensitivity of this approach, dose-dependent effects of intoxication on synaptic activity were measured 20 hr after addition of BoNT/A. Intoxication with 0.005 pM BoNT/A resulted in a significant decrement in mEPSCs, with a median inhibitory concentration (IC50) of 0.013 pM. Comparisons of median doses indicate that functional measurements of synaptic inhibition are faster, more specific and more sensitive than SNARE cleavage assays or the mouse lethality assay. These data validate the use of synaptically coupled, stem cell-derived neurons for the highly specific and sensitive detection of CNTs. PMID:25742030

Transient oxytocin signaling primes the development and function of excitatory hippocampal neurons

PubMed Central

Ripamonti, Silvia; Ambrozkiewicz, Mateusz C; Guzzi, Francesca; Gravati, Marta; Biella, Gerardo; Bormuth, Ingo; Hammer, Matthieu; Tuffy, Liam P; Sigler, Albrecht; Kawabe, Hiroshi; Nishimori, Katsuhiko; Toselli, Mauro; Brose, Nils; Parenti, Marco; Rhee, JeongSeop

2017-01-01

Beyond its role in parturition and lactation, oxytocin influences higher brain processes that control social behavior of mammals, and perturbed oxytocin signaling has been linked to the pathogenesis of several psychiatric disorders. However, it is still largely unknown how oxytocin exactly regulates neuronal function. We show that early, transient oxytocin exposure in vitro inhibits the development of hippocampal glutamatergic neurons, leading to reduced dendrite complexity, synapse density, and excitatory transmission, while sparing GABAergic neurons. Conversely, genetic elimination of oxytocin receptors increases the expression of protein components of excitatory synapses and excitatory synaptic transmission in vitro. In vivo, oxytocin-receptor-deficient hippocampal pyramidal neurons develop more complex dendrites, which leads to increased spine number and reduced γ-oscillations. These results indicate that oxytocin controls the development of hippocampal excitatory neurons and contributes to the maintenance of a physiological excitation/inhibition balance, whose disruption can cause neurobehavioral disturbances. DOI: http://dx.doi.org/10.7554/eLife.22466.001 PMID:28231043

Role of GABAA-Mediated Inhibition and Functional Assortment of Synapses onto Individual Layer 4 Neurons in Regulating Plasticity Expression in Visual Cortex.

PubMed

Saez, Ignacio; Friedlander, Michael J

2016-01-01

Layer 4 (L4) of primary visual cortex (V1) is the main recipient of thalamocortical fibers from the dorsal lateral geniculate nucleus (LGNd). Thus, it is considered the main entry point of visual information into the neocortex and the first anatomical opportunity for intracortical visual processing before information leaves L4 and reaches supra- and infragranular cortical layers. The strength of monosynaptic connections from individual L4 excitatory cells onto adjacent L4 cells (unitary connections) is highly malleable, demonstrating that the initial stage of intracortical synaptic transmission of thalamocortical information can be altered by previous activity. However, the inhibitory network within L4 of V1 may act as an internal gate for induction of excitatory synaptic plasticity, thus providing either high fidelity throughput to supragranular layers or transmittal of a modified signal subject to recent activity-dependent plasticity. To evaluate this possibility, we compared the induction of synaptic plasticity using classical extracellular stimulation protocols that recruit a combination of excitatory and inhibitory synapses with stimulation of a single excitatory neuron onto a L4 cell. In order to induce plasticity, we paired pre- and postsynaptic activity (with the onset of postsynaptic spiking leading the presynaptic activation by 10ms) using extracellular stimulation (ECS) in acute slices of primary visual cortex and comparing the outcomes with our previously published results in which an identical protocol was used to induce synaptic plasticity between individual pre- and postsynaptic L4 excitatory neurons. Our results indicate that pairing of ECS with spiking in a L4 neuron fails to induce plasticity in L4-L4 connections if synaptic inhibition is intact. However, application of a similar pairing protocol under GABAARs inhibition by bath application of 2μM bicuculline does induce robust synaptic plasticity, long term potentiation (LTP) or long term depression (LTD), similar to our results with pairing of pre- and postsynaptic activation between individual excitatory L4 neurons in which inhibitory connections are not activated. These results are consistent with the well-established observation that inhibition limits the capacity for induction of plasticity at excitatory synapses and that pre- and postsynaptic activation at a fixed time interval can result in a variable range of plasticity outcomes. However, in the current study by virtue of having two sets of experimental data, we have provided a new insight into these processes. By randomly mixing the assorting of individual L4 neurons according to the frequency distribution of the experimentally determined plasticity outcome distribution based on the calculated convergence of multiple individual L4 neurons onto a single postsynaptic L4 neuron, we were able to compare then actual ECS plasticity outcomes to those predicted by randomly mixing individual pairs of neurons. Interestingly, the observed plasticity profiles with ECS cannot account for the random assortment of plasticity behaviors of synaptic connections between individual cell pairs. These results suggest that connections impinging onto a single postsynaptic cell may be grouped according to plasticity states.

Presynaptic establishment of the synaptic cleft extracellular matrix is required for post-synaptic differentiation

PubMed Central

Rohrbough, Jeffrey; Rushton, Emma; Woodruff, Elvin; Fergestad, Tim; Vigneswaran, Krishanthan; Broadie, Kendal

2007-01-01

Formation and regulation of excitatory glutamatergic synapses is essential for shaping neural circuits throughout development. In a Drosophila genetic screen for synaptogenesis mutants, we identified mind the gap (mtg), which encodes a secreted, extracellular N-glycosaminoglycan-binding protein. MTG is expressed neuronally and detected in the synaptic cleft, and is required to form the specialized transsynaptic matrix that links the presynaptic active zone with the post-synaptic glutamate receptor (GluR) domain. Null mtg embryonic mutant synapses exhibit greatly reduced GluR function, and a corresponding loss of localized GluR domains. All known post-synaptic signaling/scaffold proteins functioning upstream of GluR localization are also grossly reduced or mislocalized in mtg mutants, including the dPix–dPak–Dock cascade and the Dlg/PSD-95 scaffold. Ubiquitous or neuronally targeted mtg RNA interference (RNAi) similarly reduce post-synaptic assembly, whereas post-synaptically targeted RNAi has no effect, indicating that presynaptic MTG induces and maintains the post-synaptic pathways driving GluR domain formation. These findings suggest that MTG is secreted from the presynaptic terminal to shape the extracellular synaptic cleft domain, and that the cleft domain functions to mediate transsynaptic signals required for post-synaptic development. PMID:17901219

Spike Train Auto-Structure Impacts Post-Synaptic Firing and Timing-Based Plasticity

PubMed Central

Scheller, Bertram; Castellano, Marta; Vicente, Raul; Pipa, Gordon

2011-01-01

Cortical neurons are typically driven by several thousand synapses. The precise spatiotemporal pattern formed by these inputs can modulate the response of a post-synaptic cell. In this work, we explore how the temporal structure of pre-synaptic inhibitory and excitatory inputs impact the post-synaptic firing of a conductance-based integrate and fire neuron. Both the excitatory and inhibitory input was modeled by renewal gamma processes with varying shape factors for modeling regular and temporally random Poisson activity. We demonstrate that the temporal structure of mutually independent inputs affects the post-synaptic firing, while the strength of the effect depends on the firing rates of both the excitatory and inhibitory inputs. In a second step, we explore the effect of temporal structure of mutually independent inputs on a simple version of Hebbian learning, i.e., hard bound spike-timing-dependent plasticity. We explore both the equilibrium weight distribution and the speed of the transient weight dynamics for different mutually independent gamma processes. We find that both the equilibrium distribution of the synaptic weights and the speed of synaptic changes are modulated by the temporal structure of the input. Finally, we highlight that the sensitivity of both the post-synaptic firing as well as the spike-timing-dependent plasticity on the auto-structure of the input of a neuron could be used to modulate the learning rate of synaptic modification. PMID:22203800

Endocannabinoid signaling and synaptic function.

PubMed

Castillo, Pablo E; Younts, Thomas J; Chávez, Andrés E; Hashimotodani, Yuki

2012-10-04

Endocannabinoids are key modulators of synaptic function. By activating cannabinoid receptors expressed in the central nervous system, these lipid messengers can regulate several neural functions and behaviors. As experimental tools advance, the repertoire of known endocannabinoid-mediated effects at the synapse, and their underlying mechanism, continues to expand. Retrograde signaling is the principal mode by which endocannabinoids mediate short- and long-term forms of plasticity at both excitatory and inhibitory synapses. However, growing evidence suggests that endocannabinoids can also signal in a nonretrograde manner. In addition to mediating synaptic plasticity, the endocannabinoid system is itself subject to plastic changes. Multiple points of interaction with other neuromodulatory and signaling systems have now been identified. In this Review, we focus on new advances in synaptic endocannabinoid signaling in the mammalian brain. The emerging picture not only reinforces endocannabinoids as potent regulators of synaptic function but also reveals that endocannabinoid signaling is mechanistically more complex and diverse than originally thought. Copyright © 2012 Elsevier Inc. All rights reserved.

E-I balance emerges naturally from continuous Hebbian learning in autonomous neural networks.

PubMed

Trapp, Philip; Echeveste, Rodrigo; Gros, Claudius

2018-06-12

Spontaneous brain activity is characterized in part by a balanced asynchronous chaotic state. Cortical recordings show that excitatory (E) and inhibitory (I) drivings in the E-I balanced state are substantially larger than the overall input. We show that such a state arises naturally in fully adapting networks which are deterministic, autonomously active and not subject to stochastic external or internal drivings. Temporary imbalances between excitatory and inhibitory inputs lead to large but short-lived activity bursts that stabilize irregular dynamics. We simulate autonomous networks of rate-encoding neurons for which all synaptic weights are plastic and subject to a Hebbian plasticity rule, the flux rule, that can be derived from the stationarity principle of statistical learning. Moreover, the average firing rate is regulated individually via a standard homeostatic adaption of the bias of each neuron's input-output non-linear function. Additionally, networks with and without short-term plasticity are considered. E-I balance may arise only when the mean excitatory and inhibitory weights are themselves balanced, modulo the overall activity level. We show that synaptic weight balance, which has been considered hitherto as given, naturally arises in autonomous neural networks when the here considered self-limiting Hebbian synaptic plasticity rule is continuously active.

Vesicular zinc promotes presynaptic and inhibits postsynaptic long term potentiation of mossy fiber-CA3 synapse

PubMed Central

Pan, Enhui; Zhang, Xiao-an; Huang, Zhen; Krezel, Artur; Zhao, Min; Tin-berg, Christine E.; Lippard, Stephen J.; McNamara, James O.

2011-01-01

The presence of zinc in glutamatergic synaptic vesicles of excitatory neurons of mammalian cerebral cortex suggests that zinc might regulate plasticity of synapses formed by these neurons. Long term potentiation (LTP) is a form of synaptic plasticity that may underlie learning and memory. We tested the hypothesis that zinc within vesicles of mossy fibers (mf) contributes to mf-LTP, a classical form of presynaptic LTP. We synthesized an extracellular zinc chelator with selectivity and kinetic properties suitable for study of the large transient of zinc in the synaptic cleft induced by mf stimulation. We found that vesicular zinc is required for presynaptic mf-LTP. Unexpectedly, vesicular zinc also inhibits a novel form of postsynaptic mf-LTP. Because the mf-CA3 synapse provides a major source of excitatory input to the hippocampus, regulating its efficacy by these dual actions of vesicular zinc is critical to proper function of hippocampal circuitry in health and disease. PMID:21943607

Dendritic excitability modulates dendritic information processing in a purkinje cell model.

PubMed

Coop, Allan D; Cornelis, Hugo; Santamaria, Fidel

2010-01-01

Using an electrophysiological compartmental model of a Purkinje cell we quantified the contribution of individual active dendritic currents to processing of synaptic activity from granule cells. We used mutual information as a measure to quantify the information from the total excitatory input current (I(Glu)) encoded in each dendritic current. In this context, each active current was considered an information channel. Our analyses showed that most of the information was encoded by the calcium (I(CaP)) and calcium activated potassium (I(Kc)) currents. Mutual information between I(Glu) and I(CaP) and I(Kc) was sensitive to different levels of excitatory and inhibitory synaptic activity that, at the same time, resulted in the same firing rate at the soma. Since dendritic excitability could be a mechanism to regulate information processing in neurons we quantified the changes in mutual information between I(Glu) and all Purkinje cell currents as a function of the density of dendritic Ca (g(CaP)) and Kca (g(Kc)) conductances. We extended our analysis to determine the window of temporal integration of I(Glu) by I(CaP) and I(Kc) as a function of channel density and synaptic activity. The window of information integration has a stronger dependence on increasing values of g(Kc) than on g(CaP), but at high levels of synaptic stimulation information integration is reduced to a few milliseconds. Overall, our results show that different dendritic conductances differentially encode synaptic activity and that dendritic excitability and the level of synaptic activity regulate the flow of information in dendrites.

Glucose Rapidly Induces Different Forms of Excitatory Synaptic Plasticity in Hypothalamic POMC Neurons

PubMed Central

Hu, Jun; Jiang, Lin; Low, Malcolm J.; Rui, Liangyou

2014-01-01

Hypothalamic POMC neurons are required for glucose and energy homeostasis. POMC neurons have a wide synaptic connection with neurons both within and outside the hypothalamus, and their activity is controlled by a balance between excitatory and inhibitory synaptic inputs. Brain glucose-sensing plays an essential role in the maintenance of normal body weight and metabolism; however, the effect of glucose on synaptic transmission in POMC neurons is largely unknown. Here we identified three types of POMC neurons (EPSC(+), EPSC(−), and EPSC(+/−)) based on their glucose-regulated spontaneous excitatory postsynaptic currents (sEPSCs), using whole-cell patch-clamp recordings. Lowering extracellular glucose decreased the frequency of sEPSCs in EPSC(+) neurons, but increased it in EPSC(−) neurons. Unlike EPSC(+) and EPSC(−) neurons, EPSC(+/−) neurons displayed a bi-phasic sEPSC response to glucoprivation. In the first phase of glucoprivation, both the frequency and the amplitude of sEPSCs decreased, whereas in the second phase, they increased progressively to the levels above the baseline values. Accordingly, lowering glucose exerted a bi-phasic effect on spontaneous action potentials in EPSC(+/−) neurons. Glucoprivation decreased firing rates in the first phase, but increased them in the second phase. These data indicate that glucose induces distinct excitatory synaptic plasticity in different subpopulations of POMC neurons. This synaptic remodeling is likely to regulate the sensitivity of the melanocortin system to neuronal and hormonal signals. PMID:25127258

Complex-learning Induced Modifications in Synaptic Inhibition: Mechanisms and Functional Significance.

PubMed

Reuveni, Iris; Lin, Longnian; Barkai, Edi

2018-06-15

Following training in a difficult olfactory-discrimination (OD) task rats acquire the capability to perform the task easily, with little effort. This new acquired skill, of 'learning how to learn' is termed 'rule learning'. At the single-cell level, rule learning is manifested in long-term enhancement of intrinsic neuronal excitability of piriform cortex (PC) pyramidal neurons, and in excitatory synaptic connections between these neurons to maintain cortical stability, such long-lasting increase in excitability must be accompanied by paralleled increase in inhibitory processes that would prevent hyper-excitable activation. In this review we describe the cellular and molecular mechanisms underlying complex-learning-induced long-lasting modifications in GABA A -receptors and GABA B -receptor-mediated synaptic inhibition. Subsequently we discuss how such modifications support the induction and preservation of long-term memories in the in the mammalian brain. Based on experimental results, computational analysis and modeling, we propose that rule learning is maintained by doubling the strength of synaptic inputs, excitatory as well as inhibitory, in a sub-group of neurons. This enhanced synaptic transmission, which occurs in all (or almost all) synaptic inputs onto these neurons, activates specific stored memories. At the molecular level, such rule-learning-relevant synaptic strengthening is mediated by doubling the conductance of synaptic channels, but not their numbers. This post synaptic process is controlled by a whole-cell mechanism via particular second messenger systems. This whole-cell mechanism enables memory amplification when required and memory extinction when not relevant. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

Dopamine loss alters the hippocampus-nucleus accumbens synaptic transmission in the Tg2576 mouse model of Alzheimer's disease.

PubMed

Cordella, Alberto; Krashia, Paraskevi; Nobili, Annalisa; Pignataro, Annabella; La Barbera, Livia; Viscomi, Maria Teresa; Valzania, Alessandro; Keller, Flavio; Ammassari-Teule, Martine; Mercuri, Nicola Biagio; Berretta, Nicola; D'Amelio, Marcello

2018-08-01

The functional loop involving the ventral tegmental area (VTA), dorsal hippocampus and nucleus accumbens (NAc) plays a pivotal role in the formation of spatial memory and persistent memory traces. In particular, the dopaminergic innervation from the VTA to the hippocampus is critical for hippocampal-related memory function and alterations in the midbrain dopaminergic system are frequently reported in Alzheimer's disease (AD), contributing to age-related decline in memory and non-cognitive functions. However, much less is known about the hippocampus-NAc connectivity in AD. Here, we evaluated the functioning of the hippocampus-to-NAc core connectivity in the Tg2576 mouse model of AD that shows a selective and progressive degeneration of VTA dopaminergic neurons. We show that reduced dopaminergic innervation in the Tg2576 hippocampus results in reduced synaptic plasticity and excitability of dorsal subiculum pyramidal neurons. Importantly, the glutamatergic transmission from the hippocampus to the NAc core is also impaired. Chemogenetic depolarisation of Tg2576 subicular pyramidal neurons with an excitatory Designer Receptor Exclusively Activated by Designer Drugs, or systemic administration of the DA precursor levodopa, can both rescue the deficits in Tg2576 mice. Our data suggest that the dopaminergic signalling in the hippocampus is essential for the proper functioning of the hippocampus-NAc excitatory synaptic transmission. Copyright © 2018 Elsevier Inc. All rights reserved.

Nothing can be coincidence: synaptic inhibition and plasticity in the cerebellar nuclei

PubMed Central

Pugh, Jason R.; Raman, Indira M.

2009-01-01

Many cerebellar neurons fire spontaneously, generating 10–100 action potentials per second even without synaptic input. This high basal activity correlates with information-coding mechanisms that differ from those of cells that are quiescent until excited synaptically. For example, in the deep cerebellar nuclei, Hebbian patterns of coincident synaptic excitation and postsynaptic firing fail to induce long-term increases in the strength of excitatory inputs. Instead, excitatory synaptic currents are potentiated by combinations of inhibition and excitation that resemble the activity of Purkinje and mossy fiber afferents that is predicted to occur during cerebellar associative learning tasks. Such results indicate that circuits with intrinsically active neurons have rules for information transfer and storage that distinguish them from other brain regions. PMID:19178955

A new efficient method for synaptic vesicle quantification reveals differences between medial prefrontal cortex perforated and nonperforated synapses.

PubMed

Nava, Nicoletta; Chen, Fenghua; Wegener, Gregers; Popoli, Maurizio; Nyengaard, Jens Randel

2014-02-01

Communication between neurons is mediated by the release of neurotransmitter-containing vesicles from presynaptic terminals. Quantitative characterization of synaptic vesicles can be highly valuable for understanding mechanisms underlying synaptic function and plasticity. We performed a quantitative ultrastructural analysis of cortical excitatory synapses by mean of a new, efficient method, as an alternative to three-dimensional (3D) reconstruction. Based on a hierarchical sampling strategy and unequivocal identification of the region of interest, serial sections from excitatory synapses of medial prefrontal cortex (mPFC) of six Sprague-Dawley rats were acquired with a transmission electron microscope. Unbiased estimates of total 3D volume of synaptic terminals were obtained through the Cavalieri estimator, and adequate correction factors for vesicle profile number estimation were applied for final vesicle quantification. Our analysis was based on 79 excitatory synapses, nonperforated (NPSs) and perforated (PSs) subtypes. We found that total number of docked and reserve-pool vesicles in PSs significantly exceeded that in NPSs (by, respectively, 77% and 78%). These differences were found to be related to changes in size between the two subtypes (active zone area by 86%; bouton volume by 105%) rather than to postsynaptic density shape. Positive significant correlations were found between number of docked and reserve-pool vesicles, active zone area and docked vesicles, and bouton volume and reserve pool vesicles. Our method confirmed the large size of mPFC PSs and a linear correlation between presynaptic features of typical hippocampal synapses. Moreover, a greater number of docked vesicles in PSs may promote a high synaptic strength of these synapses. Copyright © 2013 Wiley Periodicals, Inc.

Cdk5-dependent phosphorylation of liprinα1 mediates neuronal activity-dependent synapse development

PubMed Central

Huang, Huiqian; Lin, Xiaochen; Liang, Zhuoyi; Zhao, Teng; Du, Shengwang; Loy, Michael M. T.; Lai, Kwok-On; Fu, Amy K. Y.

2017-01-01

The experience-dependent modulation of brain circuitry depends on dynamic changes in synaptic connections that are guided by neuronal activity. In particular, postsynaptic maturation requires changes in dendritic spine morphology, the targeting of postsynaptic proteins, and the insertion of synaptic neurotransmitter receptors. Thus, it is critical to understand how neuronal activity controls postsynaptic maturation. Here we report that the scaffold protein liprinα1 and its phosphorylation by cyclin-dependent kinase 5 (Cdk5) are critical for the maturation of excitatory synapses through regulation of the synaptic localization of the major postsynaptic organizer postsynaptic density (PSD)-95. Whereas Cdk5 phosphorylates liprinα1 at Thr701, this phosphorylation decreases in neurons in response to neuronal activity. Blockade of liprinα1 phosphorylation enhances the structural and functional maturation of excitatory synapses. Nanoscale superresolution imaging reveals that inhibition of liprinα1 phosphorylation increases the colocalization of liprinα1 with PSD-95. Furthermore, disruption of liprinα1 phosphorylation by a small interfering peptide, siLIP, promotes the synaptic localization of PSD-95 and enhances synaptic strength in vivo. Our findings collectively demonstrate that the Cdk5-dependent phosphorylation of liprinα1 is important for the postsynaptic organization during activity-dependent synapse development. PMID:28760951

Synaptic Impairment in Layer 1 of the Prefrontal Cortex Induced by Repeated Stress During Adolescence is Reversed in Adulthood

PubMed Central

Negrón-Oyarzo, Ignacio; Dagnino-Subiabre, Alexies; Muñoz Carvajal, Pablo

2015-01-01

Chronic stress is a risk factor for the development of psychiatric disorders, some of which involve dysfunction of the prefrontal cortex (PFC). There is a higher prevalence of these chronic stress-related psychiatric disorders during adolescence, when the PFC has not yet fully matured. In the present work we studied the effect of repeated stress during adolescence on synaptic function in the PFC in adolescence and adulthood. To this end, adolescent Sprague-Dawley rats were subjected to seven consecutive days of restraint stress. Afterward, both synaptic transmission and short- and long-term synaptic plasticity were evaluated in layer 1 of medial-PFC (mPFC) slices from adolescent and adult rats. We found that repeated stress significantly reduced the amplitude of evoked field excitatory post-synaptic potential (fEPSP) in the mPFC. Isolation of excitatory transmission reveled that lower-amplitude fEPSPs were associated with a reduction in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated transmission. We also found that repeated stress significantly decreased long-term depression (LTD). Interestingly, AMPA/kainate receptor-mediated transmission and LTD were recovered in adult animals that experienced a three-week stress-free recovery period. The data indicates that the changes in synaptic transmission and plasticity in the mPFC induced by repeated stress during adolescence are reversed in adulthood after a stress-free period. PMID:26617490

Synaptic Impairment in Layer 1 of the Prefrontal Cortex Induced by Repeated Stress During Adolescence is Reversed in Adulthood.

PubMed

Negrón-Oyarzo, Ignacio; Dagnino-Subiabre, Alexies; Muñoz Carvajal, Pablo

2015-01-01

Chronic stress is a risk factor for the development of psychiatric disorders, some of which involve dysfunction of the prefrontal cortex (PFC). There is a higher prevalence of these chronic stress-related psychiatric disorders during adolescence, when the PFC has not yet fully matured. In the present work we studied the effect of repeated stress during adolescence on synaptic function in the PFC in adolescence and adulthood. To this end, adolescent Sprague-Dawley rats were subjected to seven consecutive days of restraint stress. Afterward, both synaptic transmission and short- and long-term synaptic plasticity were evaluated in layer 1 of medial-PFC (mPFC) slices from adolescent and adult rats. We found that repeated stress significantly reduced the amplitude of evoked field excitatory post-synaptic potential (fEPSP) in the mPFC. Isolation of excitatory transmission reveled that lower-amplitude fEPSPs were associated with a reduction in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated transmission. We also found that repeated stress significantly decreased long-term depression (LTD). Interestingly, AMPA/kainate receptor-mediated transmission and LTD were recovered in adult animals that experienced a three-week stress-free recovery period. The data indicates that the changes in synaptic transmission and plasticity in the mPFC induced by repeated stress during adolescence are reversed in adulthood after a stress-free period.

Ketone bodies do not directly alter excitatory or inhibitory hippocampal synaptic transmission.

PubMed

Thio, L L; Wong, M; Yamada, K A

2000-01-25

To determine the effect of the ketone bodies beta-hydroxybutyrate (betaHB) and acetoacetate (AA) on excitatory and inhibitory neurotransmission in the mammalian CNS. The ketogenic diet is presumed to be an effective anticonvulsant regimen for some children with medically intractable seizures. However, its mechanism of action remains a mystery. According to one hypothesis, ketone bodies have anticonvulsant properties. The authors examined the effect of betaHB and AA on excitatory and inhibitory synaptic transmission in rat hippocampal-entorhinal cortex slices and cultured hippocampal neurons. In cultured neurons, their effect was also directly assayed on postsynaptic receptor properties. Finally, their ability to prevent spontaneous seizures was determined in a hippocampal-entorhinal cortex slice model. betaHB and AA did not alter synaptic transmission in these models. The anticonvulsant properties of the ketogenic diet do not result from a direct effect of ketone bodies on the primary voltage and ligand gated ion channels mediating excitatory or inhibitory neurotransmission in the hippocampus.

In vivo activation of Wnt signaling pathway enhances cognitive function of adult mice and reverses cognitive deficits in an Alzheimer's disease model.

PubMed

Vargas, Jessica Y; Fuenzalida, Marco; Inestrosa, Nibaldo C

2014-02-05

The role of the Wnt signaling pathway during synaptic development has been well established. In the adult brain, different components of Wnt signaling are expressed, but little is known about its role in mature synapses. Emerging in vitro studies have implicated Wnt signaling in synaptic plasticity. Furthermore, activation of Wnt signaling has shown to protect against amyloid-β-induced synaptic impairment. The present study provides the first evidence that in vivo activation of Wnt signaling improves episodic memory, increases excitatory synaptic transmission, and enhances long-term potentiation in adult wild-type mice. Moreover, the activation of Wnt signaling also rescues memory loss and improves synaptic dysfunction in APP/PS1-transgenic mice that model the amyloid pathology of Alzheimer's diseases. These findings indicate that Wnt signaling modulates cognitive function in the adult brain and could be a novel promising target for Alzheimer's disease therapy.

Cell-specific gain modulation by synaptically released zinc in cortical circuits of audition.

PubMed

Anderson, Charles T; Kumar, Manoj; Xiong, Shanshan; Tzounopoulos, Thanos

2017-09-09

In many excitatory synapses, mobile zinc is found within glutamatergic vesicles and is coreleased with glutamate. Ex vivo studies established that synaptically released (synaptic) zinc inhibits excitatory neurotransmission at lower frequencies of synaptic activity but enhances steady state synaptic responses during higher frequencies of activity. However, it remains unknown how synaptic zinc affects neuronal processing in vivo. Here, we imaged the sound-evoked neuronal activity of the primary auditory cortex in awake mice. We discovered that synaptic zinc enhanced the gain of sound-evoked responses in CaMKII-expressing principal neurons, but it reduced the gain of parvalbumin- and somatostatin-expressing interneurons. This modulation was sound intensity-dependent and, in part, NMDA receptor-independent. By establishing a previously unknown link between synaptic zinc and gain control of auditory cortical processing, our findings advance understanding about cortical synaptic mechanisms and create a new framework for approaching and interpreting the role of the auditory cortex in sound processing.

Structural Basis of Arc Binding to Synaptic Proteins: Implications for Cognitive Disease

DOE PAGES

Zhang, Wenchi; Wu, Jing; Ward, Matthew D.; ...

2015-04-09

Arc is a cellular immediate-early gene (IEG) that functions at excitatory synapses and is required for learning and memory. Here we report crystal structures of Arc subdomains that form a bi-lobar architecture remarkably similar to the capsid domain of human immunodeficiency virus (HIV) gag protein. Analysis indicates Arc originated from the Ty3/Gypsy retrotransposon family and was “domesticated” in higher vertebrates for synaptic functions. The Arc N-terminal lobe evolved a unique hydrophobic pocket that mediates intermolecular binding with synaptic proteins as resolved in complexes with TARPγ2 (Stargazin) and CaMKII peptides and is essential for Arc’s synaptic function. A consensus sequence formore » Arc binding identifies several additional partners that include genes implicated in schizophrenia. Arc N-lobe binding is inhibited by small chemicals suggesting Arc’s synaptic action may be druggable. Finally, these studies reveal the remarkable evolutionary origin of Arc and provide a structural basis for understanding Arc’s contribution to neural plasticity and disease.« less

Structural Basis of Arc Binding to Synaptic Proteins: Implications for Cognitive Disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Wenchi; Wu, Jing; Ward, Matthew D.

Arc is a cellular immediate-early gene (IEG) that functions at excitatory synapses and is required for learning and memory. Here we report crystal structures of Arc subdomains that form a bi-lobar architecture remarkably similar to the capsid domain of human immunodeficiency virus (HIV) gag protein. Analysis indicates Arc originated from the Ty3/Gypsy retrotransposon family and was “domesticated” in higher vertebrates for synaptic functions. The Arc N-terminal lobe evolved a unique hydrophobic pocket that mediates intermolecular binding with synaptic proteins as resolved in complexes with TARPγ2 (Stargazin) and CaMKII peptides and is essential for Arc’s synaptic function. A consensus sequence formore » Arc binding identifies several additional partners that include genes implicated in schizophrenia. Arc N-lobe binding is inhibited by small chemicals suggesting Arc’s synaptic action may be druggable. Finally, these studies reveal the remarkable evolutionary origin of Arc and provide a structural basis for understanding Arc’s contribution to neural plasticity and disease.« less

Structural Basis of Arc Binding to Synaptic Proteins: Implications for Cognitive Disease

PubMed Central

Zhang, Wenchi; Wu, Jing; Ward, Matthew D.; Yang, Sunggu; Chuang, Yang-An; Xiao, Meifang; Li, Ruojing; Leahy, Daniel J.; Worley, Paul F.

2015-01-01

SUMMARY Arc is a cellular immediate early gene (IEG) that functions at excitatory synapses and is required for learning and memory. We report crystal structures of Arc subdomains that form a bi-lobar architecture remarkably similar to the capsid domain of human immunodeficiency virus (HIV) gag protein. Analysis indicates Arc originated from the Ty3/Gypsy retrotransposon family and was “domesticated” in higher vertebrates for synaptic functions. The Arc N-terminal lobe evolved a unique hydrophobic pocket that mediates intermolecular binding with synaptic proteins as resolved in complexes with TARPγ2 (Stargazin) and CaMKII peptides, and is essential for Arc’s synaptic function. A consensus sequence for Arc binding identifies several additional partners that include genes implicated in schizophrenia. Arc N-lobe binding is inhibited by small chemicals suggesting Arc’s synaptic action may be druggable. These studies reveal the remarkable evolutionary origin of Arc and provide a structural basis for understanding Arc’s contribution to neural plasticity and disease. PMID:25864631

Reduced sensory synaptic excitation impairs motor neuron function via Kv2.1 in spinal muscular atrophy.

PubMed

Fletcher, Emily V; Simon, Christian M; Pagiazitis, John G; Chalif, Joshua I; Vukojicic, Aleksandra; Drobac, Estelle; Wang, Xiaojian; Mentis, George Z

2017-07-01

Behavioral deficits in neurodegenerative diseases are often attributed to the selective dysfunction of vulnerable neurons via cell-autonomous mechanisms. Although vulnerable neurons are embedded in neuronal circuits, the contributions of their synaptic partners to disease process are largely unknown. Here we show that, in a mouse model of spinal muscular atrophy (SMA), a reduction in proprioceptive synaptic drive leads to motor neuron dysfunction and motor behavior impairments. In SMA mice or after the blockade of proprioceptive synaptic transmission, we observed a decrease in the motor neuron firing that could be explained by the reduction in the expression of the potassium channel Kv2.1 at the surface of motor neurons. Chronically increasing neuronal activity pharmacologically in vivo led to a normalization of Kv2.1 expression and an improvement in motor function. Our results demonstrate a key role of excitatory synaptic drive in shaping the function of motor neurons during development and the contribution of its disruption to a neurodegenerative disease.

Reduced sensory synaptic excitation impairs motor neuron function via Kv2.1 in spinal muscular atrophy

PubMed Central

Fletcher, Emily V.; Simon, Christian M.; Pagiazitis, John G.; Chalif, Joshua I.; Vukojicic, Aleksandra; Drobac, Estelle; Wang, Xiaojian; Mentis, George Z.

2017-01-01

Behavioral deficits in neurodegenerative diseases are often attributed to the selective dysfunction of vulnerable neurons via cell-autonomous mechanisms. Although vulnerable neurons are embedded in neuronal circuits, the contribution of their synaptic partners to the disease process is largely unknown. Here, we show that in a mouse model of spinal muscular atrophy (SMA), a reduction in proprioceptive synaptic drive leads to motor neuron dysfunction and motor behavior impairments. In SMA mice or after the blockade of proprioceptive synaptic transmission we observed a decrease in the motor neuron firing which could be explained by the reduction in the expression of the potassium channel Kv2.1 at the surface of motor neurons. Increasing neuronal activity pharmacologically by chronic exposure in vivo led to a normalization of Kv2.1 expression and an improvement in motor function. Our results demonstrate a key role of excitatory synaptic drive in shaping the function of motor neurons during development and the contribution of its disruption to a neurodegenerative disease. PMID:28504671

Organization and dynamics of the actin cytoskeleton during dendritic spine morphological remodeling.

PubMed

Chazeau, Anaël; Giannone, Grégory

2016-08-01

In the central nervous system, most excitatory post-synapses are small subcellular structures called dendritic spines. Their structure and morphological remodeling are tightly coupled to changes in synaptic transmission. The F-actin cytoskeleton is the main driving force of dendritic spine remodeling and sustains synaptic plasticity. It is therefore essential to understand how changes in synaptic transmission can regulate the organization and dynamics of actin binding proteins (ABPs). In this review, we will provide a detailed description of the organization and dynamics of F-actin and ABPs in dendritic spines and will discuss the current models explaining how the actin cytoskeleton sustains both structural and functional synaptic plasticity.

Astrocytes refine cortical connectivity at dendritic spines

PubMed Central

Risher, W Christopher; Patel, Sagar; Kim, Il Hwan; Uezu, Akiyoshi; Bhagat, Srishti; Wilton, Daniel K; Pilaz, Louis-Jan; Singh Alvarado, Jonnathan; Calhan, Osman Y; Silver, Debra L; Stevens, Beth; Calakos, Nicole; Soderling, Scott H; Eroglu, Cagla

2014-01-01

During cortical synaptic development, thalamic axons must establish synaptic connections despite the presence of the more abundant intracortical projections. How thalamocortical synapses are formed and maintained in this competitive environment is unknown. Here, we show that astrocyte-secreted protein hevin is required for normal thalamocortical synaptic connectivity in the mouse cortex. Absence of hevin results in a profound, long-lasting reduction in thalamocortical synapses accompanied by a transient increase in intracortical excitatory connections. Three-dimensional reconstructions of cortical neurons from serial section electron microscopy (ssEM) revealed that, during early postnatal development, dendritic spines often receive multiple excitatory inputs. Immuno-EM and confocal analyses revealed that majority of the spines with multiple excitatory contacts (SMECs) receive simultaneous thalamic and cortical inputs. Proportion of SMECs diminishes as the brain develops, but SMECs remain abundant in Hevin-null mice. These findings reveal that, through secretion of hevin, astrocytes control an important developmental synaptic refinement process at dendritic spines. DOI: http://dx.doi.org/10.7554/eLife.04047.001 PMID:25517933

Excitatory and inhibitory synaptic connectivity to layer V fast-spiking interneurons in the freeze lesion model of cortical microgyria

PubMed Central

Jin, Xiaoming; Jiang, Kewen

2014-01-01

A variety of major developmental cortical malformations are closely associated with clinically intractable epilepsy. Pathophysiological aspects of one such disorder, human polymicrogyria, can be modeled by making neocortical freeze lesions (FL) in neonatal rodents, resulting in the formation of microgyri. Previous studies showed enhanced excitatory and inhibitory synaptic transmission and connectivity in cortical layer V pyramidal neurons in the paramicrogyral cortex. In young adult transgenic mice that express green fluorescent protein (GFP) specifically in parvalbumin positive fast-spiking (FS) interneurons, we used laser scanning photostimulation (LSPS) of caged glutamate to map excitatory and inhibitory synaptic connectivity onto FS interneurons in layer V of paramicrogyral cortex in control and FL groups. The proportion of uncaging sites from which excitatory postsynaptic currents (EPSCs) could be evoked (hotspot ratio) increased slightly but significantly in FS cells of the FL vs. control cortex, while the mean amplitude of LSPS-evoked EPSCs at hotspots did not change. In contrast, the hotspot ratio of inhibitory postsynaptic currents (IPSCs) was significantly decreased in FS neurons of the FL cortex. These alterations in synaptic inputs onto FS interneurons may result in an enhanced inhibitory output. We conclude that alterations in synaptic connectivity to cortical layer V FS interneurons do not contribute to hyperexcitability of the FL model. Instead, the enhanced inhibitory output from these neurons may partially offset an earlier demonstrated increase in synaptic excitation of pyramidal cells and thereby maintain a relative balance between excitation and inhibition in the affected cortical circuitry. PMID:24990567

Excitatory Post-Synaptic Potential Mimicked in Indium-Zinc-Oxide Synaptic Transistors Gated by Methyl Cellulose Solid Electrolyte

PubMed Central

Guo, Liqiang; Wen, Juan; Ding, Jianning; Wan, Changjin; Cheng, Guanggui

2016-01-01

The excitatory postsynaptic potential (EPSP) of biological synapses is mimicked in indium-zinc-oxide synaptic transistors gated by methyl cellulose solid electrolyte. These synaptic transistors show excellent electrical performance at an operating voltage of 0.8 V, Ion/off ratio of 2.5 × 106, and mobility of 38.4 cm2/Vs. After this device is connected to a resistance of 4 MΩ in series, it exhibits excellent characteristics as an inverter. A threshold potential of 0.3 V is achieved by changing the gate pulse amplitude, width, or number, which is analogous to biological EPSP. PMID:27924838

Synaptic inhibition and γ-aminobutyric acid in the mammalian central nervous system

PubMed Central

OBATA, Kunihiko

2013-01-01

Signal transmission through synapses connecting two neurons is mediated by release of neurotransmitter from the presynaptic axon terminals and activation of its receptor at the postsynaptic neurons. γ-Aminobutyric acid (GABA), non-protein amino acid formed by decarboxylation of glutamic acid, is a principal neurotransmitter at inhibitory synapses of vertebrate and invertebrate nervous system. On one hand glutamic acid serves as a principal excitatory neurotransmitter. This article reviews GABA researches on; (1) synaptic inhibition by membrane hyperpolarization, (2) exclusive localization in inhibitory neurons, (3) release from inhibitory neurons, (4) excitatory action at developmental stage, (5) phenotype of GABA-deficient mouse produced by gene-targeting, (6) developmental adjustment of neural network and (7) neurological/psychiatric disorder. In the end, GABA functions in simple nervous system and plants, and non-amino acid neurotransmitters were supplemented. PMID:23574805

Rapid disinhibition by adjustment of PV intrinsic excitability during whisker map plasticity in mouse S1.

PubMed

Gainey, Melanie A; Aman, Joseph W; Feldman, Daniel E

2018-04-20

Rapid plasticity of layer (L) 2/3 inhibitory circuits is an early step in sensory cortical map plasticity, but its cellular basis is unclear. We show that, in mice of either sex, 1 day whisker deprivation drives rapid loss of L4-evoked feedforward inhibition and more modest loss of feedforward excitation in L2/3 pyramidal (PYR) cells, increasing E-I conductance ratio. Rapid disinhibition was due to reduced L4-evoked spiking by L2/3 parvalbumin (PV) interneurons, caused by reduced PV intrinsic excitability. This included elevated PV spike threshold, associated with an increase in low-threshold, voltage activated delayed rectifier (presumed Kv1) and A-type potassium currents. Excitatory synaptic input and unitary inhibitory output of PV cells were unaffected. Functionally, the loss of feedforward inhibition and excitation were precisely coordinated in L2/3 PYR cells, so that peak feedforward synaptic depolarization remained stable. Thus, rapid plasticity of PV intrinsic excitability offsets early weakening of excitatory circuits to homeostatically stabilize synaptic potentials in PYR cells of sensory cortex. SIGNIFICANCE STATEMENT Inhibitory circuits in cerebral cortex are highly plastic, but the cellular mechanisms and functional importance of this plasticity are incompletely understood. We show that brief (1-day) sensory deprivation rapidly weakens parvalbumin (PV) inhibitory circuits by reducing the intrinsic excitability of PV neurons. This involved a rapid increase in voltage-gated potassium conductances that control near-threshold spiking excitability. Functionally, the loss of PV-mediated feedforward inhibition in L2/3 pyramidal cells was precisely balanced with the separate loss of feedforward excitation, resulting in a net homeostatic stabilization of synaptic potentials. Thus, rapid plasticity of PV intrinsic excitability implements network-level homeostasis to stabilize synaptic potentials in sensory cortex. Copyright © 2018 the authors.

Cell autonomous regulation of hippocampal circuitry via Aph1b-γ-secretase/neuregulin 1 signalling

PubMed Central

Fazzari, Pietro; Snellinx, An; Sabanov, Victor; Ahmed, Tariq; Serneels, Lutgarde; Gartner, Annette; Shariati, S Ali M; Balschun, Detlef; De Strooper, Bart

2014-01-01

Neuregulin 1 (NRG1) and the γ-secretase subunit APH1B have been previously implicated as genetic risk factors for schizophrenia and schizophrenia relevant deficits have been observed in rodent models with loss of function mutations in either gene. Here we show that the Aph1b-γ-secretase is selectively involved in Nrg1 intracellular signalling. We found that Aph1b-deficient mice display a decrease in excitatory synaptic markers. Electrophysiological recordings show that Aph1b is required for excitatory synaptic transmission and plasticity. Furthermore, gain and loss of function and genetic rescue experiments indicate that Nrg1 intracellular signalling promotes dendritic spine formation downstream of Aph1b-γ-secretase in vitro and in vivo. In conclusion, our study sheds light on the physiological role of Aph1b-γ-secretase in brain and provides a new mechanistic perspective on the relevance of NRG1 processing in schizophrenia. DOI: http://dx.doi.org/10.7554/eLife.02196.001 PMID:24891237

Mechanism and treatment for the learning and memory deficits associated with mouse models of Noonan syndrome

PubMed Central

Lee, Yong-Seok; Ehninger, Dan; Zhou, Miou; Oh, Jun-Young; Kang, Minkyung; Kwak, Chuljung; Ryu, Hyun-Hee; Butz, Delana; Araki, Toshiyuki; Cai, Ying; Balaji, J.; Sano, Yoshitake; Nam, Christine I.; Kim, Hyong Kyu; Kaang, Bong-Kiun; Burger, Corinna; Neel, Benjamin G.; Silva, Alcino J.

2015-01-01

In Noonan Syndrome (NS) 30% to 50% of subjects show cognitive deficits of unknown etiology and with no known treatment. Here, we report that knock-in mice expressing either of two NS-associated Ptpn11 mutations show hippocampal-dependent spatial learning impairments and deficits in hippocampal long-term potentiation (LTP). In addition, viral overexpression of the PTPN11D61G in adult hippocampus results in increased baseline excitatory synaptic function, deficits in LTP and spatial learning, which can all be reversed by a MEK inhibitor. Furthermore, brief treatment with lovastatin reduces Ras-Erk activation in the brain, and normalizes the LTP and learning deficits in adult Ptpn11D61G/+ mice. Our results demonstrate that increased basal Erk activity and corresponding baseline increases in excitatory synaptic function are responsible for the LTP impairments and, consequently, the learning deficits in mouse models of NS. These data also suggest that lovastatin or MEK inhibitors may be useful for treating the cognitive deficits in NS. PMID:25383899

Activity-dependent dendritic spine neck changes are correlated with synaptic strength

PubMed Central

Araya, Roberto; Vogels, Tim P.; Yuste, Rafael

2014-01-01

Most excitatory inputs in the mammalian brain are made on dendritic spines, rather than on dendritic shafts. Spines compartmentalize calcium, and this biochemical isolation can underlie input-specific synaptic plasticity, providing a raison d’etre for spines. However, recent results indicate that the spine can experience a membrane potential different from that in the parent dendrite, as though the spine neck electrically isolated the spine. Here we use two-photon calcium imaging of mouse neocortical pyramidal neurons to analyze the correlation between the morphologies of spines activated under minimal synaptic stimulation and the excitatory postsynaptic potentials they generate. We find that excitatory postsynaptic potential amplitudes are inversely correlated with spine neck lengths. Furthermore, a spike timing-dependent plasticity protocol, in which two-photon glutamate uncaging over a spine is paired with postsynaptic spikes, produces rapid shrinkage of the spine neck and concomitant increases in the amplitude of the evoked spine potentials. Using numerical simulations, we explore the parameter regimes for the spine neck resistance and synaptic conductance changes necessary to explain our observations. Our data, directly correlating synaptic and morphological plasticity, imply that long-necked spines have small or negligible somatic voltage contributions, but that, upon synaptic stimulation paired with postsynaptic activity, they can shorten their necks and increase synaptic efficacy, thus changing the input/output gain of pyramidal neurons. PMID:24982196

The immunoglobulin family member dendrite arborization and synapse maturation 1 (Dasm1) controls excitatory synapse maturation

PubMed Central

Shi, Song-Hai; Cheng, Tong; Jan, Lily Yeh; Jan, Yuh-Nung

2004-01-01

In the developing mammalian brain, a large fraction of excitatory synapses initially contain only N-methyl-d-aspartate receptor and thus are “silent” at the resting membrane potential. As development progresses, synapses acquire α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA-Rs). Although this maturation of excitatory synapses has been well characterized, the molecular basis for this developmental change is not known. Here, we report that dendrite arborization and synapse maturation 1 (Dasm1), an Ig superfamily member, controls excitatory synapse maturation. Dasm1 is localized at the excitatory synapses. Suppression of Dasm1 expression by using RNA interference or expression of dominant negative deletion mutants of Dasm1 in hippocampal neurons at late developmental stage specifically impairs AMPA-R-mediated, but not N-methyl-d-aspartate receptor-mediated, synaptic transmission. The ability of Dasm1 to regulate synaptic AMPA-Rs requires its intracellular C-terminal PDZ domain-binding motif, which interacts with two synaptic PDZ domain-containing proteins involved in spine/synapse maturation, Shank and S-SCAM. Moreover, expression of dominant negative deletion mutants of Dasm1 leads to more immature silent synapses. These results suggest that Dasm1, as a transmembrane molecule, likely provides a link to bridge extracellular signals and intracellular signaling complexes in controlling excitatory synapse maturation. PMID:15340156

Extensive excitatory network interactions shape temporal processing of communication signals in a model sensory system.

PubMed

Ma, Xiaofeng; Kohashi, Tsunehiko; Carlson, Bruce A

2013-07-01

Many sensory brain regions are characterized by extensive local network interactions. However, we know relatively little about the contribution of this microcircuitry to sensory coding. Detailed analyses of neuronal microcircuitry are usually performed in vitro, whereas sensory processing is typically studied by recording from individual neurons in vivo. The electrosensory pathway of mormyrid fish provides a unique opportunity to link in vitro studies of synaptic physiology with in vivo studies of sensory processing. These fish communicate by actively varying the intervals between pulses of electricity. Within the midbrain posterior exterolateral nucleus (ELp), the temporal filtering of afferent spike trains establishes interval tuning by single neurons. We characterized pairwise neuronal connectivity among ELp neurons with dual whole cell recording in an in vitro whole brain preparation. We found a densely connected network in which single neurons influenced the responses of other neurons throughout the network. Similarly tuned neurons were more likely to share an excitatory synaptic connection than differently tuned neurons, and synaptic connections between similarly tuned neurons were stronger than connections between differently tuned neurons. We propose a general model for excitatory network interactions in which strong excitatory connections both reinforce and adjust tuning and weak excitatory connections make smaller modifications to tuning. The diversity of interval tuning observed among this population of neurons can be explained, in part, by each individual neuron receiving a different complement of local excitatory inputs.

Glutamate-Bound NMDARs Arising from In Vivo-like Network Activity Extend Spatio-temporal Integration in a L5 Cortical Pyramidal Cell Model

PubMed Central

Farinella, Matteo; Ruedt, Daniel T.; Gleeson, Padraig; Lanore, Frederic; Silver, R. Angus

2014-01-01

In vivo, cortical pyramidal cells are bombarded by asynchronous synaptic input arising from ongoing network activity. However, little is known about how such ‘background’ synaptic input interacts with nonlinear dendritic mechanisms. We have modified an existing model of a layer 5 (L5) pyramidal cell to explore how dendritic integration in the apical dendritic tuft could be altered by the levels of network activity observed in vivo. Here we show that asynchronous background excitatory input increases neuronal gain and extends both temporal and spatial integration of stimulus-evoked synaptic input onto the dendritic tuft. Addition of fast and slow inhibitory synaptic conductances, with properties similar to those from dendritic targeting interneurons, that provided a ‘balanced’ background configuration, partially counteracted these effects, suggesting that inhibition can tune spatio-temporal integration in the tuft. Excitatory background input lowered the threshold for NMDA receptor-mediated dendritic spikes, extended their duration and increased the probability of additional regenerative events occurring in neighbouring branches. These effects were also observed in a passive model where all the non-synaptic voltage-gated conductances were removed. Our results show that glutamate-bound NMDA receptors arising from ongoing network activity can provide a powerful spatially distributed nonlinear dendritic conductance. This may enable L5 pyramidal cells to change their integrative properties as a function of local network activity, potentially allowing both clustered and spatially distributed synaptic inputs to be integrated over extended timescales. PMID:24763087

Zinc transporter-1 concentrates at the postsynaptic density of hippocampal synapses.

PubMed

Sindreu, Carlos; Bayés, Álex; Altafaj, Xavier; Pérez-Clausell, Jeús

2014-03-07

Zinc concentrates at excitatory synapses, both at the postsynaptic density and in a subset of glutamatergic boutons. Zinc can modulate synaptic plasticity, memory formation and nociception by regulating transmitter receptors and signal transduction pathways. Also, intracellular zinc accumulation is a hallmark of degenerating neurons in several neurological disorders. To date, no single zinc extrusion mechanism has been directly localized to synapses. Based on the presence of a canonical PDZ I motif in the Zinc Transporter-1 protein (ZnT1), we hypothesized that ZnT1 may be targeted to synaptic compartments for local control of cytosolic zinc. Using our previously developed protocol for the co-localization of reactive zinc and synaptic proteins, we further asked if ZnT1 expression correlates with presynaptic zinc content in individual synapses. Here we demonstrate that ZnT1 is a plasma membrane protein that is enriched in dendritic spines and in biochemically isolated synaptic membranes. Hippocampal CA1 synapses labelled by postembedding immunogold showed over a 5-fold increase in ZnT1 concentration at synaptic junctions compared with extrasynaptic membranes. Subsynaptic analysis revealed a peak ZnT1 density on the postsynaptic side of the synapse, < 10 nm away from the postsynaptic membrane. ZnT1 was found in the vast majority of excitatory synapses regardless of the presence of vesicular zinc in presynaptic boutons. Our study has identified ZnT1 as a novel postsynaptic density protein, and it may help elucidate the role of zinc homeostasis in synaptic function and disease.

Anterograde Jelly belly ligand to Alk receptor signaling at developing synapses is regulated by Mind the gap.

PubMed

Rohrbough, Jeffrey; Broadie, Kendal

2010-10-01

Bidirectional trans-synaptic signals induce synaptogenesis and regulate subsequent synaptic maturation. Presynaptically secreted Mind the gap (Mtg) molds the synaptic cleft extracellular matrix, leading us to hypothesize that Mtg functions to generate the intercellular environment required for efficient signaling. We show in Drosophila that secreted Jelly belly (Jeb) and its receptor tyrosine kinase Anaplastic lymphoma kinase (Alk) are localized to developing synapses. Jeb localizes to punctate aggregates in central synaptic neuropil and neuromuscular junction (NMJ) presynaptic terminals. Secreted Jeb and Mtg accumulate and colocalize extracellularly in surrounding synaptic boutons. Alk concentrates in postsynaptic domains, consistent with an anterograde, trans-synaptic Jeb-Alk signaling pathway at developing synapses. Jeb synaptic expression is increased in Alk mutants, consistent with a requirement for Alk receptor function in Jeb uptake. In mtg null mutants, Alk NMJ synaptic levels are reduced and Jeb expression is dramatically increased. NMJ synapse morphology and molecular assembly appear largely normal in jeb and Alk mutants, but larvae exhibit greatly reduced movement, suggesting impaired functional synaptic development. jeb mutant movement is significantly rescued by neuronal Jeb expression. jeb and Alk mutants display normal NMJ postsynaptic responses, but a near loss of patterned, activity-dependent NMJ transmission driven by central excitatory output. We conclude that Jeb-Alk expression and anterograde trans-synaptic signaling are modulated by Mtg and play a key role in establishing functional synaptic connectivity in the developing motor circuit.

Carbamazepine and oxcarbazepine, but not eslicarbazepine, enhance excitatory synaptic transmission onto hippocampal CA1 pyramidal cells through an antagonist action at adenosine A1 receptors.

PubMed

Booker, Sam A; Pires, Nuno; Cobb, Stuart; Soares-da-Silva, Patrício; Vida, Imre

2015-06-01

This study assessed the anticonvulsant and seizure generation effects of carbamazepine (CBZ), oxcarbazepine (OXC) and eslicarbazepine (S-Lic) in wild-type mice. Electrophysiological recordings were made to discriminate potential cellular and synaptic mechanisms underlying anti- and pro-epileptic actions. The anticonvulsant and pro-convulsant effects were evaluated in the MES, the 6-Hz and the Irwin tests. Whole-cell patch-clamp recordings were used to investigate the effects on fast excitatory and inhibitory synaptic transmission in hippocampal area CA1. The safety window for CBZ, OXC and eslicarbazepine (ED50 value against the MES test and the dose that produces grade 5 convulsions in all mice), was 6.3, 6.0 and 12.5, respectively. At high concentrations the three drugs reduced synaptic transmission. CBZ and OXC enhanced excitatory postsynaptic currents (EPSCs) at low, therapeutically-relevant concentrations. These effects were associated with no change in inhibitory postsynaptic currents (IPSCs) resulting in altered balance between excitation and inhibition. S-Lic had no effect on EPSC or IPSC amplitudes over the same concentration range. The CBZ mediated enhancement of EPSCs was blocked by DPCPX, a selective antagonist, and occluded by CCPA, a selective agonist of the adenosine A1 receptor. Furthermore, reduction of endogenous adenosine by application of the enzyme adenosine deaminase also abolished the CBZ- and OXC-induced increase of EPSCs, indicating that the two drugs act as antagonists at native adenosine receptors. In conclusion, CBZ and OXC possess pro-epileptic actions at clinically-relevant concentrations through the enhancement of excitatory synaptic transmission. S-Lic by comparison has no such effect on synaptic transmission, explaining its lack of seizure exacerbation. Copyright © 2015 Elsevier Ltd. All rights reserved.

Oxytocin mediates early experience-dependent cross-modal plasticity in the sensory cortices.

PubMed

Zheng, Jing-Jing; Li, Shu-Jing; Zhang, Xiao-Di; Miao, Wan-Ying; Zhang, Dinghong; Yao, Haishan; Yu, Xiang

2014-03-01

Sensory experience is critical to development and plasticity of neural circuits. Here we report a new form of plasticity in neonatal mice, where early sensory experience cross-modally regulates development of all sensory cortices via oxytocin signaling. Unimodal sensory deprivation from birth through whisker deprivation or dark rearing reduced excitatory synaptic transmission in the correspondent sensory cortex and cross-modally in other sensory cortices. Sensory experience regulated synthesis and secretion of the neuropeptide oxytocin as well as its level in the cortex. Both in vivo oxytocin injection and increased sensory experience elevated excitatory synaptic transmission in multiple sensory cortices and significantly rescued the effects of sensory deprivation. Together, these results identify a new function for oxytocin in promoting cross-modal, experience-dependent cortical development. This link between sensory experience and oxytocin is particularly relevant to autism, where hypersensitivity or hyposensitivity to sensory inputs is prevalent and oxytocin is a hotly debated potential therapy.

Autism-linked neuroligin-3 R451C mutation differentially alters hippocampal and cortical synaptic function.

PubMed

Etherton, Mark; Földy, Csaba; Sharma, Manu; Tabuchi, Katsuhiko; Liu, Xinran; Shamloo, Mehrdad; Malenka, Robert C; Südhof, Thomas C

2011-08-16

Multiple independent mutations in neuroligin genes were identified in patients with familial autism, including the R451C substitution in neuroligin-3 (NL3). Previous studies showed that NL3(R451C) knock-in mice exhibited modestly impaired social behaviors, enhanced water maze learning abilities, and increased synaptic inhibition in the somatosensory cortex, and they suggested that the behavioral changes in these mice may be caused by a general shift of synaptic transmission to inhibition. Here, we confirm that NL3(R451C) mutant mice behaviorally exhibit social interaction deficits and electrophysiologically display increased synaptic inhibition in the somatosensory cortex. Unexpectedly, however, we find that the NL3(R451C) mutation produced a strikingly different phenotype in the hippocampus. Specifically, in the hippocampal CA1 region, the NL3(R451C) mutation caused an ∼1.5-fold increase in AMPA receptor-mediated excitatory synaptic transmission, dramatically altered the kinetics of NMDA receptor-mediated synaptic responses, induced an approximately twofold up-regulation of NMDA receptors containing NR2B subunits, and enhanced long-term potentiation almost twofold. NL3 KO mice did not exhibit any of these changes. Quantitative light microscopy and EM revealed that the NL3(R451C) mutation increased dendritic branching and altered the structure of synapses in the stratum radiatum of the hippocampus. Thus, in NL3(R451C) mutant mice, a single point mutation in a synaptic cell adhesion molecule causes context-dependent changes in synaptic transmission; these changes are consistent with the broad impact of this mutation on murine and human behaviors, suggesting that NL3 controls excitatory and inhibitory synapse properties in a region- and circuit-specific manner.

Age-Dependent Glutamate Induction of Synaptic Plasticity in Cultured Hippocampal Neurons

ERIC Educational Resources Information Center

Ivenshitz, Miriam; Segal, Menahem; Sapoznik, Stav

2006-01-01

A common denominator for the induction of morphological and functional plasticity in cultured hippocampal neurons involves the activation of excitatory synapses. We now demonstrate massive morphological plasticity in mature cultured hippocampal neurons caused by a brief exposure to glutamate. This plasticity involves a slow, 70%-80% increase in…

Separate Functional Properties of NMDARs Regulate Distinct Aspects of Spatial Cognition

ERIC Educational Resources Information Center

Sanders, Erin M.; Nyarko-Odoom, Akua O.; Zhao, Kevin; Nguyen, Michael; Liao, Hong Hong Liao; Keith, Matthew; Pyon, Jane; Kozma, Alyssa; Sanyal, Mohima; McHail, Daniel G.; Dumas, Theodore C.

2018-01-01

N-methyl-D-aspartate receptors (NMDARs) at excitatory synapses are central to activity-dependent synaptic plasticity and learning and memory. NMDARs act as ionotropic and metabotropic receptors by elevating postsynaptic calcium concentrations and by direct intracellular protein signaling. In the forebrain, these properties are controlled largely…

Presynaptic LRP4 promotes synapse number and function of excitatory CNS neurons

PubMed Central

Mosca, Timothy J; Luginbuhl, David J; Wang, Irving E; Luo, Liqun

2017-01-01

Precise coordination of synaptic connections ensures proper information flow within circuits. The activity of presynaptic organizing molecules signaling to downstream pathways is essential for such coordination, though such entities remain incompletely known. We show that LRP4, a conserved transmembrane protein known for its postsynaptic roles, functions presynaptically as an organizing molecule. In the Drosophila brain, LRP4 localizes to the nerve terminals at or near active zones. Loss of presynaptic LRP4 reduces excitatory (not inhibitory) synapse number, impairs active zone architecture, and abolishes olfactory attraction - the latter of which can be suppressed by reducing presynaptic GABAB receptors. LRP4 overexpression increases synapse number in excitatory and inhibitory neurons, suggesting an instructive role and a common downstream synapse addition pathway. Mechanistically, LRP4 functions via the conserved kinase SRPK79D to ensure normal synapse number and behavior. This highlights a presynaptic function for LRP4, enabling deeper understanding of how synapse organization is coordinated. DOI: http://dx.doi.org/10.7554/eLife.27347.001 PMID:28606304

pH modulation of glial glutamate transporters regulates synaptic transmission in the nucleus of the solitary tract

PubMed Central

McCrimmon, Donald R.; Martina, Marco

2013-01-01

The nucleus of the solitary tract (NTS) is the major site for termination of visceral sensory afferents contributing to homeostatic regulation of, for example, arterial pressure, gastric motility, and breathing. Whereas much is known about how different neuronal populations influence these functions, information about the role of glia remains scant. In this article, we propose that glia may contribute to NTS functions by modulating excitatory neurotransmission. We found that acidification (pH 7.0) depolarizes NTS glia by inhibiting K+-selective membrane currents. NTS glia also showed functional expression of voltage-sensitive glutamate transporters, suggesting that extracellular acidification regulates synaptic transmission by compromising glial glutamate uptake. To test this hypothesis, we evoked glutamatergic slow excitatory potentials (SEPs) in NTS neurons with repetitive stimulation (20 pulses at 10 Hz) of the solitary tract. This SEP depends on accumulation of glutamate following repetitive stimulation, since it was potentiated by blocking glutamate uptake with dl-threo-β-benzyloxyaspartic acid (TBOA) or a glia-specific glutamate transport blocker, dihydrokainate (DHK). Importantly, extracellular acidification (pH 7.0) also potentiated the SEP. This effect appeared to be mediated through a depolarization-induced inhibition of glial transporter activity, because it was occluded by TBOA and DHK. In agreement, pH 7.0 did not directly alter d-aspartate-induced responses in NTS glia or properties of presynaptic glutamate release. Thus acidification-dependent regulation of glial function affects synaptic transmission within the NTS. These results suggest that glia play a modulatory role in the NTS by integrating local tissue signals (such as pH) with synaptic inputs from peripheral afferents. PMID:23615553

Novel IL1RAPL1 mutations associated with intellectual disability impair synaptogenesis.

PubMed

Ramos-Brossier, Mariana; Montani, Caterina; Lebrun, Nicolas; Gritti, Laura; Martin, Christelle; Seminatore-Nole, Christine; Toussaint, Aurelie; Moreno, Sarah; Poirier, Karine; Dorseuil, Olivier; Chelly, Jamel; Hackett, Anna; Gecz, Jozef; Bieth, Eric; Faudet, Anne; Heron, Delphine; Frank Kooy, R; Loeys, Bart; Humeau, Yann; Sala, Carlo; Billuart, Pierre

2015-02-15

Mutations in interleukin-1 receptor accessory protein like 1 (IL1RAPL1) gene have been associated with non-syndromic intellectual disability (ID) and autism spectrum disorder. This protein interacts with synaptic partners like PSD-95 and PTPδ, regulating the formation and function of excitatory synapses. The aim of this work was to characterize the synaptic consequences of three IL1RAPL1 mutations, two novel causing the deletion of exon 6 (Δex6) and one point mutation (C31R), identified in patients with ID. Using immunofluorescence and electrophysiological recordings, we examined the effects of IL1RAPL1 mutant over-expression on synapse formation and function in cultured rodent hippocampal neurons. Δex6 but not C31R mutation leads to IL1RAPL1 protein instability and mislocalization within dendrites. Analysis of different markers of excitatory synapses and sEPSC recording revealed that both mutants fail to induce pre- and post-synaptic differentiation, contrary to WT IL1RAPL1 protein. Cell aggregation and immunoprecipitation assays in HEK293 cells showed a reduction of the interaction between IL1RAPL1 mutants and PTPδ that could explain the observed synaptogenic defect in neurons. However, these mutants do not affect all cellular signaling because their over-expression still activates JNK pathway. We conclude that both mutations described in this study lead to a partial loss of function of the IL1RAPL1 protein through different mechanisms. Our work highlights the important function of the trans-synaptic PTPδ/IL1RAPL1 interaction in synaptogenesis and as such in ID in the patients. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Active integration of glutamatergic input to the inferior olive generates bidirectional postsynaptic potentials

PubMed Central

Garden, Derek L. F.; Rinaldi, Arianna

2016-01-01

Key points We establish experimental preparations for optogenetic investigation of glutamatergic input to the inferior olive.Neurones in the principal olivary nucleus receive monosynaptic extra‐somatic glutamatergic input from the neocortex.Glutamatergic inputs to neurones in the inferior olive generate bidirectional postsynaptic potentials (PSPs), with a fast excitatory component followed by a slower inhibitory component.Small conductance calcium‐activated potassium (SK) channels are required for the slow inhibitory component of glutamatergic PSPs and oppose temporal summation of inputs at intervals ≤ 20 ms.Active integration of synaptic input within the inferior olive may play a central role in control of olivo‐cerebellar climbing fibre signals. Abstract The inferior olive plays a critical role in motor coordination and learning by integrating diverse afferent signals to generate climbing fibre inputs to the cerebellar cortex. While it is well established that climbing fibre signals are important for motor coordination, the mechanisms by which neurones in the inferior olive integrate synaptic inputs and the roles of particular ion channels are unclear. Here, we test the hypothesis that neurones in the inferior olive actively integrate glutamatergic synaptic inputs. We demonstrate that optogenetically activated long‐range synaptic inputs to the inferior olive, including projections from the motor cortex, generate rapid excitatory potentials followed by slower inhibitory potentials. Synaptic projections from the motor cortex preferentially target the principal olivary nucleus. We show that inhibitory and excitatory components of the bidirectional synaptic potentials are dependent upon AMPA (GluA) receptors, are GABAA independent, and originate from the same presynaptic axons. Consistent with models that predict active integration of synaptic inputs by inferior olive neurones, we find that the inhibitory component is reduced by blocking large conductance calcium‐activated potassium channels with iberiotoxin, and is abolished by blocking small conductance calcium‐activated potassium channels with apamin. Summation of excitatory components of synaptic responses to inputs at intervals ≤ 20 ms is increased by apamin, suggesting a role for the inhibitory component of glutamatergic responses in temporal integration. Our results indicate that neurones in the inferior olive implement novel rules for synaptic integration and suggest new principles for the contribution of inferior olive neurones to coordinated motor behaviours. PMID:27767209

Enhanced excitatory input to melanin concentrating hormone neurons during developmental period of high food intake is mediated by GABA.

PubMed

Li, Ying; van den Pol, Anthony N

2009-12-02

In contrast to the local axons of GABA neurons of the cortex and hippocampus, lateral hypothalamic neurons containing melanin concentrating hormone (MCH) and GABA send long axons throughout the brain and play key roles in energy homeostasis and mental status. In adults, MCH neurons maintain a hyperpolarized membrane potential and most of the synaptic input is inhibitory. In contrast, we found that developing MCH neurons received substantially more excitatory synaptic input. Based on gramicidin-perforated patch recordings in hypothalamic slices from MCH-green fluorescent protein transgenic mice, we found that GABA was the primary excitatory synaptic transmitter in embryonic and neonatal ages up to postnatal day 10. Surprisingly, glutamate assumed only a minor excitatory role, if any. GABA plays a complex role in developing MCH neurons, with its actions conditionally dependent on a number of factors. GABA depolarization could lead to an increase in spikes either independently or in summation with other depolarizing stimuli, or alternately, depending on the relative timing of other depolarizing events, could lead to shunting inhibition. The developmental shift from depolarizing to hyperpolarizing occurred later in the dendrites than in the cell body. Early GABA depolarization was based on a Cl(-)-dependent inward current. An interesting secondary depolarization in mature neurons that followed an initial hyperpolarization was based on a bicarbonate mechanism. Thus during the early developmental period when food consumption is high, MCH neurons are more depolarized than in the adult, and an increased level of excitatory synaptic input to these orexigenic cells is mediated by GABA.

Enhanced excitatory input to MCH neurons during developmental period of high food intake is mediated by GABA

PubMed Central

Li, Ying; van den Pol, Anthony N.

2010-01-01

In contrast to the local axons of GABA neurons of the cortex and hippocampus, lateral hypothalamic neurons containing melanin concentrating hormone (MCH) and GABA send long axons throughout the brain and play key roles in energy homeostasis and mental status. In adults, MCH neurons maintain a hyperpolarized membrane potential and most of the synaptic input is inhibitory. In contrast, we found that developing MCH neurons received substantially more excitatory synaptic input. Based on gramicidicin-perforated patch recordings in hypothalamic slices from MCH-GFP transgenic mice, we found that GABA was the primary excitatory synaptic transmitter in embryonic and neonatal ages up to postnatal day 10. Surprisingly, glutamate assumed only a minor excitatory role, if any. GABA plays a complex role in developing MCH neurons, with its actions conditionally dependent on a number of factors. GABA depolarization could lead to an increase in spikes either independently or in summation with other depolarizing stimuli, or alternately, depending on the relative timing of other depolarizing events, could lead to shunting inhibition. The developmental shift from depolarizing to hyperpolarizing occurred later in the dendrites than in the cell body. Early GABA depolarization was based on a Cl− dependent inward current. An interesting secondary depolarization in mature neurons that followed an initial hyperpolarization was based on a bicarbonate mechanism. Thus during the early developmental period when food consumption is high, MCH neurons are more depolarized than in the adult, and an increased level of excitatory synaptic input to these orexigenic cells is mediated by GABA. PMID:19955372

Synapsin- and Actin-Dependent Frequency Enhancement in Mouse Hippocampal Mossy Fiber Synapses

PubMed Central

Owe, Simen G.; Jensen, Vidar; Evergren, Emma; Ruiz, Arnaud; Shupliakov, Oleg; Kullmann, Dimitri M.; Storm-Mathisen, Jon; Walaas, S. Ivar; Hvalby, Øivind

2009-01-01

The synapsin proteins have different roles in excitatory and inhibitory synaptic terminals. We demonstrate a differential role between types of excitatory terminals. Structural and functional aspects of the hippocampal mossy fiber (MF) synapses were studied in wild-type (WT) mice and in synapsin double-knockout mice (DKO). A severe reduction in the number of synaptic vesicles situated more than 100 nm away from the presynaptic membrane active zone was found in the synapsin DKO animals. The ultrastructural level gave concomitant reduction in F-actin immunoreactivity observed at the periactive endocytic zone of the MF terminals. Frequency facilitation was normal in synapsin DKO mice at low firing rates (∼0.1 Hz) but was impaired at firing rates within the physiological range (∼2 Hz). Synapses made by associational/commissural fibers showed comparatively small frequency facilitation at the same frequencies. Synapsin-dependent facilitation in MF synapses of WT mice was attenuated by blocking F-actin polymerization with cytochalasin B in hippocampal slices. Synapsin III, selectively seen in MF synapses, is enriched specifically in the area adjacent to the synaptic cleft. This may underlie the ability of synapsin III to promote synaptic depression, contributing to the reduced frequency facilitation observed in the absence of synapsins I and II. PMID:18550596

Enhanced astroglial Ca2+ signaling increases excitatory synaptic strength in the epileptic brain.

PubMed

Álvarez-Ferradas, Carla; Morales, Juan Carlos; Wellmann, Mario; Nualart, Francisco; Roncagliolo, Manuel; Fuenzalida, Marco; Bonansco, Christian

2015-09-01

The fine-tuning of synaptic transmission by astrocyte signaling is crucial to CNS physiology. However, how exactly astroglial excitability and gliotransmission are affected in several neuropathologies, including epilepsy, remains unclear. Here, using a chronic model of temporal lobe epilepsy (TLE) in rats, we found that astrocytes from astrogliotic hippocampal slices displayed an augmented incidence of TTX-insensitive spontaneous slow Ca(2+) transients (STs), suggesting a hyperexcitable pattern of astroglial activity. As a consequence, elevated glutamate-mediated gliotransmission, observed as increased slow inward current (SICs) frequency, up-regulates the probability of neurotransmitter release in CA3-CA1 synapses. Selective blockade of spontaneous astroglial Ca(2+) elevations as well as the inhibition of purinergic P2Y1 or mGluR5 receptors relieves the abnormal enhancement of synaptic strength. Moreover, mGluR5 blockade eliminates any synaptic effects induced by P2Y1R inhibition alone, suggesting that the Pr modulation via mGluR occurs downstream of P2Y1R-mediated Ca(2+)-dependent glutamate release from astrocyte. Our findings show that elevated Ca(2+)-dependent glutamate gliotransmission from hyperexcitable astrocytes up-regulates excitatory neurotransmission in epileptic hippocampus, suggesting that gliotransmission should be considered as a novel functional key in a broad spectrum of neuropathological conditions. © 2015 Wiley Periodicals, Inc.

NMDA receptor as a newly identified member of the metabotropic glutamate receptor family: clinical implications for neurodegenerative diseases.

PubMed

Chung, ChiHye

2013-08-01

Recent reports have proposed a novel function for the N-methyl-D-aspartate (NMDA) receptor (NMDAR), a well-known excitatory, ionotropic receptor. A series of observations employing pharmacological techniques has proposed that upon ligand binding, this ionotropic receptor can actually function via signaling cascades independent of traditional ionotropic action. Moreover, the "metabotropic" action of NMDARs is suggested to mediate a form of synaptic plasticity, namely long-term synaptic depression (LTD), which shares cellular mechanisms with the synaptic deficits observed in Alzheimer's disease. Given that a growing body of clinical and preclinical evidence strongly recommends NMDAR antagonists for their therapeutic potentials and advantages in a variety of diseases, further investigation into their molecular and cellular mechanisms is required to better understand the "metabotropic" action of NMDARs.

Hyperactivity of newborn Pten knock-out neurons results from increased excitatory synaptic drive.

PubMed

Williams, Michael R; DeSpenza, Tyrone; Li, Meijie; Gulledge, Allan T; Luikart, Bryan W

2015-01-21

Developing neurons must regulate morphology, intrinsic excitability, and synaptogenesis to form neural circuits. When these processes go awry, disorders, including autism spectrum disorder (ASD) or epilepsy, may result. The phosphatase Pten is mutated in some patients having ASD and seizures, suggesting that its mutation disrupts neurological function in part through increasing neuronal activity. Supporting this idea, neuronal knock-out of Pten in mice can cause macrocephaly, behavioral changes similar to ASD, and seizures. However, the mechanisms through which excitability is enhanced following Pten depletion are unclear. Previous studies have separately shown that Pten-depleted neurons can drive seizures, receive elevated excitatory synaptic input, and have abnormal dendrites. We therefore tested the hypothesis that developing Pten-depleted neurons are hyperactive due to increased excitatory synaptogenesis using electrophysiology, calcium imaging, morphological analyses, and modeling. This was accomplished by coinjecting retroviruses to either "birthdate" or birthdate and knock-out Pten in granule neurons of the murine neonatal dentate gyrus. We found that Pten knock-out neurons, despite a rapid onset of hypertrophy, were more active in vivo. Pten knock-out neurons fired at more hyperpolarized membrane potentials, displayed greater peak spike rates, and were more sensitive to depolarizing synaptic input. The increased sensitivity of Pten knock-out neurons was due, in part, to a higher density of synapses located more proximal to the soma. We determined that increased synaptic drive was sufficient to drive hypertrophic Pten knock-out neurons beyond their altered action potential threshold. Thus, our work contributes a developmental mechanism for the increased activity of Pten-depleted neurons. Copyright © 2015 the authors 0270-6474/15/350943-17$15.00/0.

Transmission to interneurons is via slow excitatory synaptic potentials mediated by P2Y(1) receptors during descending inhibition in guinea-pig ileum.

PubMed

Thornton, Peter D J; Gwynne, Rachel M; McMillan, Darren J; Bornstein, Joel C

2013-01-01

The nature of synaptic transmission at functionally distinct synapses in intestinal reflex pathways has not been fully identified. In this study, we investigated whether transmission between interneurons in the descending inhibitory pathway is mediated by a purine acting at P2Y receptors to produce slow excitatory synaptic potentials (EPSPs). Myenteric neurons from guinea-pig ileum in vitro were impaled with intracellular microelectrodes. Responses to distension 15 mm oral to the recording site, in a separately perfused stimulation chamber and to electrical stimulation of local nerve trunks were recorded. A subset of neurons, previously identified as nitric oxide synthase immunoreactive descending interneurons, responded to both stimuli with slow EPSPs that were reversibly abolished by a high concentration of PPADS (30 μM, P2 receptor antagonist). When added to the central chamber of a three chambered organ bath, PPADS concentration-dependently depressed transmission through that chamber of descending inhibitory reflexes, measured as inhibitory junction potentials in the circular muscle of the anal chamber. Reflexes evoked by distension in the central chamber were unaffected. A similar depression of transmission was seen when the specific P2Y(1) receptor antagonist MRS 2179 (10 μM) was in the central chamber. Blocking either nicotinic receptors (hexamethonium 200 μM) or 5-HT(3) receptors (granisetron 1 μM) together with P2 receptors had no greater effect than blocking P2 receptors alone. Slow EPSPs mediated by P2Y(1) receptors, play a primary role in transmission between descending interneurons of the inhibitory reflexes in the guinea-pig ileum. This is the first demonstration for a primary role of excitatory metabotropic receptors in physiological transmission at a functionally identified synapse.

Synaptic and intrinsic activation of GABAergic neurons in the cardiorespiratory brainstem network.

PubMed

Frank, Julie G; Mendelowitz, David

2012-01-01

GABAergic pathways in the brainstem play an essential role in respiratory rhythmogenesis and interactions between the respiratory and cardiovascular neuronal control networks. However, little is known about the identity and function of these GABAergic inhibitory neurons and what determines their activity. In this study we have identified a population of GABAergic neurons in the ventrolateral medulla that receive increased excitatory post-synaptic potentials during inspiration, but also have spontaneous firing in the absence of synaptic input. Using transgenic mice that express GFP under the control of the Gad1 (GAD67) gene promoter, we determined that this population of GABAergic neurons is in close apposition to cardioinhibitory parasympathetic cardiac neurons in the nucleus ambiguus (NA). These neurons fire in synchronization with inspiratory activity. Although they receive excitatory glutamatergic synaptic inputs during inspiration, this excitatory neurotransmission was not altered by blocking nicotinic receptors, and many of these GABAergic neurons continue to fire after synaptic blockade. The spontaneous firing in these GABAergic neurons was not altered by the voltage-gated calcium channel blocker cadmium chloride that blocks both neurotransmission to these neurons and voltage-gated Ca(2+) currents, but spontaneous firing was diminished by riluzole, demonstrating a role of persistent sodium channels in the spontaneous firing in these cardiorespiratory GABAergic neurons that possess a pacemaker phenotype. The spontaneously firing GABAergic neurons identified in this study that increase their activity during inspiration would support respiratory rhythm generation if they acted primarily to inhibit post-inspiratory neurons and thereby release inspiration neurons to increase their activity. This population of inspiratory-modulated GABAergic neurons could also play a role in inhibiting neurons that are most active during expiration and provide a framework for respiratory sinus arrhythmia as there is an increase in heart rate during inspiration that occurs via inhibition of premotor parasympathetic cardioinhibitory neurons in the NA during inspiration.

Modulation of NMDA Receptor Properties and Synaptic Transmission by the NR3A Subunit in Mouse Hippocampal and Cerebrocortical Neurons

PubMed Central

Tong, Gary; Takahashi, Hiroto; Tu, Shichun; Shin, Yeonsook; Talantova, Maria; Zago, Wagner; Xia, Peng; Nie, Zhiguo; Goetz, Thomas; Zhang, Dongxian; Lipton, Stuart A.; Nakanishi, Nobuki

2015-01-01

Expression of the NR3A subunit with NR1/NR2 in Xenopus oocytes or mammalian cell lines leads to a reduction in N-methyl-D-aspartate (NMDA)-induced currents and decreased Mg2+ sensitivity and Ca2+ permeability compared with NR1/NR2 receptors. Consistent with these findings, neurons from NR3A knockout (KO) mice exhibit enhanced NMDA-induced currents. Recombinant NR3A can also form excitatory glycine receptors with NR1 in the absence of NR2. However, the effects of NR3A on channel properties in neurons and synaptic transmission have not been fully elucidated. To study physiological roles of NR3A subunits, we generated NR3A transgenic (Tg) mice. Cultured NR3A Tg neurons exhibited two populations of NMDA receptor (NMDAR) channels, reduced Mg2+ sensitivity, and decreased Ca2+ permeability in response to NMDA/glycine, but glycine alone did not elicit excitatory currents. In addition, NMDAR-mediated excitatory postsynaptic currents (EPSCs) in NR3A Tg hippocampal slices showed reduced Mg2+ sensitivity, consistent with the notion that NR3A subunits incorporated into synaptic NMDARs. To study the function of endogenous NR3A subunits, we compared NMDAR-mediated EPSCs in NR3A KO and WT control mice. In NR3A KO mice, the ratio of the amplitudes of the NMDAR-mediated component to α-amino-3-hydroxy-5-methyl-4-isox-azolepropionic acid receptor-mediated component of the EPSC was significantly larger than that seen in WT littermates. This result suggests that NR3A subunits contributed to the NMDAR-mediated component of the EPSC in WT mice. Taken together, these results show that NR3A subunits contribute to NMDAR responses from both synaptic and extra-synaptic receptors, likely composed of NR1, NR2, and NR3 subunits. PMID:18003876

Thalamic reticular cells firing modes and its dependency on the frequency and amplitude ranges of the current stimulus.

PubMed

Hernandez, Oscar; Hernandez, Lilibeth; Vera, David; Santander, Alcides; Zurek, Eduardo

2015-01-01

The neurons of the Thalamic Reticular Nucleus (TRNn) respond to inputs in two activity modes called burst and tonic firing and both can be observed in different physiological states. The functional states of the thalamus depend in part on the properties of synaptic transmission between the TRNn and the thalamocortical and corticothalamic neurons. A dendrite can receive inhibitory and excitatory postsynaptic potentials. The novelties presented in this paper can be summarized as follows: First, it shows, through a computational simulation, that the burst and tonic firings observed in the TRNn soma could be explained as a product of random synaptic inputs on the distal dendrites, the tonic firings are generated by random excitatory stimuli, and the burst firings are generated by two different types of stimuli: inhibitory random stimuli, and a combination of inhibitory (from TRNn) and excitatory (from corticothalamic and thalamocortical neurons) random stimuli; second, according to in vivo recordings, we have found that the burst observed in the TRNn soma has graduate properties that are proportional to the stimuli frequency; and third, a novel method for showing in a quantitative manner the accelerando-decelerando pattern is proposed.

Ethanol exposure during the third trimester equivalent does not affect GABAA or AMPA receptor-mediated spontaneous synaptic transmission in rat CA3 pyramidal neurons.

PubMed

Baculis, Brian Charles; Valenzuela, Carlos Fernando

2015-12-02

Ethanol exposure during the rodent equivalent to the 3(rd) trimester of human pregnancy (i.e., first 1-2 weeks of neonatal life) has been shown to produce structural and functional alterations in the CA3 hippocampal sub-region, which is involved in associative memory. Synaptic plasticity mechanisms dependent on retrograde release of brain-derived neurotrophic factor (BDNF) driven by activation of L-type voltage-gated Ca(2+) channels (L-VGCCs) are thought to play a role in stabilization of both GABAergic and glutamatergic synapses in CA3 pyramidal neurons. We previously showed that ethanol exposure during the first week of life blocks BDNF/L-VGCC-dependent long-term potentiation of GABAA receptor-mediated synaptic transmission in these neurons. Here, we tested whether this effect is associated with lasting alterations in GABAergic and glutamatergic transmission. Rats were exposed to air or ethanol for 3 h/day between postnatal days three and five in vapor inhalation chambers, a paradigm that produces peak serum ethanol levels near 0.3 g/dl. Whole-cell patch-clamp electrophysiological recordings of spontaneous inhibitory and excitatory postsynaptic currents (sIPSCs and sEPSCs, respectively) were obtained from CA3 pyramidal neurons in coronal brain slices prepared at postnatal days 13-17. Ethanol exposure did not significantly affect the frequency, amplitude, rise-time and half-width of either sIPSCs or sEPSCs. We show that an ethanol exposure paradigm known to inhibit synaptic plasticity mechanisms that may participate in the stabilization of GABAergic and glutamatergic synapses in CA3 pyramidal neurons does not produce lasting functional alterations in these synapses, suggesting that compensatory mechanisms restored the balance of excitatory and inhibitory synaptic transmission.

Rapid Neocortical Dynamics: Cellular and Network Mechanisms

PubMed Central

Haider, Bilal; McCormick, David A.

2011-01-01

The highly interconnected local and large-scale networks of the neocortical sheet rapidly and dynamically modulate their functional connectivity according to behavioral demands. This basic operating principle of the neocortex is mediated by the continuously changing flow of excitatory and inhibitory synaptic barrages that not only control participation of neurons in networks but also define the networks themselves. The rapid control of neuronal responsiveness via synaptic bombardment is a fundamental property of cortical dynamics that may provide the basis of diverse behaviors, including sensory perception, motor integration, working memory, and attention. PMID:19409263

Voltage Gated Calcium Channel Activation by Backpropagating Action Potentials Downregulates NMDAR Function.

PubMed

Theis, Anne-Kathrin; Rózsa, Balázs; Katona, Gergely; Schmitz, Dietmar; Johenning, Friedrich W

2018-01-01

The majority of excitatory synapses are located on dendritic spines of cortical glutamatergic neurons. In spines, compartmentalized Ca 2+ signals transduce electrical activity into specific long-term biochemical and structural changes. Action potentials (APs) propagate back into the dendritic tree and activate voltage gated Ca 2+ channels (VGCCs). For spines, this global mode of spine Ca 2+ signaling is a direct biochemical feedback of suprathreshold neuronal activity. We previously demonstrated that backpropagating action potentials (bAPs) result in long-term enhancement of spine VGCCs. This activity-dependent VGCC plasticity results in a large interspine variability of VGCC Ca 2+ influx. Here, we investigate how spine VGCCs affect glutamatergic synaptic transmission. We combined electrophysiology, two-photon Ca 2+ imaging and two-photon glutamate uncaging in acute brain slices from rats. T- and R-type VGCCs were the dominant depolarization-associated Ca 2+ conductances in dendritic spines of excitatory layer 2 neurons and do not affect synaptic excitatory postsynaptic potentials (EPSPs) measured at the soma. Using two-photon glutamate uncaging, we compared the properties of glutamatergic synapses of single spines that express different levels of VGCCs. While VGCCs contributed to EPSP mediated Ca 2+ influx, the amount of EPSP mediated Ca 2+ influx is not determined by spine VGCC expression. On a longer timescale, the activation of VGCCs by bAP bursts results in downregulation of spine NMDAR function.

The influence of single bursts vs. single spikes at excitatory dendrodendritic synapses

PubMed Central

Masurkar, Arjun V.; Chen, Wei R.

2015-01-01

The synchronization of neuronal activity is thought to enhance information processing. There is much evidence supporting rhythmically bursting external tufted cells (ETCs) of the rodent olfactory bulb glomeruli coordinating the activation of glomerular interneurons and mitral cells via dendrodendritic excitation. However, as bursting has variable significance at axodendritic cortical synapses, it is not clear if ETC bursting imparts a specific functional advantage over the preliminary spike in dendrodendritic synaptic networks. To answer this question, we investigated the influence of single ETC bursts and spikes with the in-vitro rat olfactory bulb preparation at different levels of processing, via calcium imaging of presynaptic ETC dendrites, dual electrical recording of ETC–interneuron synaptic pairs, and multicellular calcium imaging of ETC-induced population activity. Our findings supported single ETC bursts, vs. single spikes, driving robust presynaptic calcium signaling, which in turn was associated with profound extension of the initial monosynaptic spike-driven dendrodendritic excitatory postsynaptic potential. This extension could be driven by either the spike-dependent or spike-independent components of the burst. At the population level, burst-induced excitation was more widespread and reliable compared with single spikes. This further supports the ETC network, in part due to a functional advantage of bursting at excitatory dendrodendritic synapses, coordinating synchronous activity at behaviorally relevant frequencies related to odor processing in vivo. PMID:22277089

Contributions of diverse excitatory and inhibitory neurons to recurrent network activity in cerebral cortex.

PubMed

Neske, Garrett T; Patrick, Saundra L; Connors, Barry W

2015-01-21

The recurrent synaptic architecture of neocortex allows for self-generated network activity. One form of such activity is the Up state, in which neurons transiently receive barrages of excitatory and inhibitory synaptic inputs that depolarize many neurons to spike threshold before returning to a relatively quiescent Down state. The extent to which different cell types participate in Up states is still unclear. Inhibitory interneurons have particularly diverse intrinsic properties and synaptic connections with the local network, suggesting that different interneurons might play different roles in activated network states. We have studied the firing, subthreshold behavior, and synaptic conductances of identified cell types during Up and Down states in layers 5 and 2/3 in mouse barrel cortex in vitro. We recorded from pyramidal cells and interneurons expressing parvalbumin (PV), somatostatin (SOM), vasoactive intestinal peptide (VIP), or neuropeptide Y. PV cells were the most active interneuron subtype during the Up state, yet the other subtypes also received substantial synaptic conductances and often generated spikes. In all cell types except PV cells, the beginning of the Up state was dominated by synaptic inhibition, which decreased thereafter; excitation was more persistent, suggesting that inhibition is not the dominant force in terminating Up states. Compared with barrel cortex, SOM and VIP cells were much less active in entorhinal cortex during Up states. Our results provide a measure of functional connectivity of various neuron types in barrel cortex and suggest differential roles for interneuron types in the generation and control of persistent network activity. Copyright © 2015 the authors 0270-6474/15/351089-17$15.00/0.

Zinc transporter-1 concentrates at the postsynaptic density of hippocampal synapses

PubMed Central

2014-01-01

Background Zinc concentrates at excitatory synapses, both at the postsynaptic density and in a subset of glutamatergic boutons. Zinc can modulate synaptic plasticity, memory formation and nociception by regulating transmitter receptors and signal transduction pathways. Also, intracellular zinc accumulation is a hallmark of degenerating neurons in several neurological disorders. To date, no single zinc extrusion mechanism has been directly localized to synapses. Based on the presence of a canonical PDZ I motif in the Zinc Transporter-1 protein (ZnT1), we hypothesized that ZnT1 may be targeted to synaptic compartments for local control of cytosolic zinc. Using our previously developed protocol for the co-localization of reactive zinc and synaptic proteins, we further asked if ZnT1 expression correlates with presynaptic zinc content in individual synapses. Findings Here we demonstrate that ZnT1 is a plasma membrane protein that is enriched in dendritic spines and in biochemically isolated synaptic membranes. Hippocampal CA1 synapses labelled by postembedding immunogold showed over a 5-fold increase in ZnT1 concentration at synaptic junctions compared with extrasynaptic membranes. Subsynaptic analysis revealed a peak ZnT1 density on the postsynaptic side of the synapse, < 10 nm away from the postsynaptic membrane. ZnT1 was found in the vast majority of excitatory synapses regardless of the presence of vesicular zinc in presynaptic boutons. Conclusions Our study has identified ZnT1 as a novel postsynaptic density protein, and it may help elucidate the role of zinc homeostasis in synaptic function and disease. PMID:24602382

Unsupervised discrimination of patterns in spiking neural networks with excitatory and inhibitory synaptic plasticity

PubMed Central

Srinivasa, Narayan; Cho, Youngkwan

2014-01-01

A spiking neural network model is described for learning to discriminate among spatial patterns in an unsupervised manner. The network anatomy consists of source neurons that are activated by external inputs, a reservoir that resembles a generic cortical layer with an excitatory-inhibitory (EI) network and a sink layer of neurons for readout. Synaptic plasticity in the form of STDP is imposed on all the excitatory and inhibitory synapses at all times. While long-term excitatory STDP enables sparse and efficient learning of the salient features in inputs, inhibitory STDP enables this learning to be stable by establishing a balance between excitatory and inhibitory currents at each neuron in the network. The synaptic weights between source and reservoir neurons form a basis set for the input patterns. The neural trajectories generated in the reservoir due to input stimulation and lateral connections between reservoir neurons can be readout by the sink layer neurons. This activity is used for adaptation of synapses between reservoir and sink layer neurons. A new measure called the discriminability index (DI) is introduced to compute if the network can discriminate between old patterns already presented in an initial training session. The DI is also used to compute if the network adapts to new patterns without losing its ability to discriminate among old patterns. The final outcome is that the network is able to correctly discriminate between all patterns—both old and new. This result holds as long as inhibitory synapses employ STDP to continuously enable current balance in the network. The results suggest a possible direction for future investigation into how spiking neural networks could address the stability-plasticity question despite having continuous synaptic plasticity. PMID:25566045

Unsupervised discrimination of patterns in spiking neural networks with excitatory and inhibitory synaptic plasticity.

PubMed

Srinivasa, Narayan; Cho, Youngkwan

2014-01-01

A spiking neural network model is described for learning to discriminate among spatial patterns in an unsupervised manner. The network anatomy consists of source neurons that are activated by external inputs, a reservoir that resembles a generic cortical layer with an excitatory-inhibitory (EI) network and a sink layer of neurons for readout. Synaptic plasticity in the form of STDP is imposed on all the excitatory and inhibitory synapses at all times. While long-term excitatory STDP enables sparse and efficient learning of the salient features in inputs, inhibitory STDP enables this learning to be stable by establishing a balance between excitatory and inhibitory currents at each neuron in the network. The synaptic weights between source and reservoir neurons form a basis set for the input patterns. The neural trajectories generated in the reservoir due to input stimulation and lateral connections between reservoir neurons can be readout by the sink layer neurons. This activity is used for adaptation of synapses between reservoir and sink layer neurons. A new measure called the discriminability index (DI) is introduced to compute if the network can discriminate between old patterns already presented in an initial training session. The DI is also used to compute if the network adapts to new patterns without losing its ability to discriminate among old patterns. The final outcome is that the network is able to correctly discriminate between all patterns-both old and new. This result holds as long as inhibitory synapses employ STDP to continuously enable current balance in the network. The results suggest a possible direction for future investigation into how spiking neural networks could address the stability-plasticity question despite having continuous synaptic plasticity.

Homeostatic scaling of vesicular glutamate and GABA transporter expression in rat neocortical circuits.

PubMed

De Gois, Stéphanie; Schäfer, Martin K-H; Defamie, Norah; Chen, Chu; Ricci, Anthony; Weihe, Eberhard; Varoqui, Hélène; Erickson, Jeffrey D

2005-08-03

Homeostatic control of pyramidal neuron firing rate involves a functional balance of feedforward excitation and feedback inhibition in neocortical circuits. Here, we reveal a dynamic scaling in vesicular excitatory (vesicular glutamate transporters VGLUT1 and VGLUT2) and inhibitory (vesicular inhibitory amino acid transporter VIAAT) transporter mRNA and synaptic protein expression in rat neocortical neuronal cultures, using a well established in vitro protocol to induce homeostatic plasticity. During the second and third week of synaptic differentiation, the predominant vesicular transporters expressed in neocortical neurons, VGLUT1 and VIAAT, are both dramatically upregulated. In mature cultures, VGLUT1 and VIAAT exhibit bidirectional and opposite regulation by prolonged activity changes. Endogenous coregulation during development and homeostatic scaling of the expression of the transporters in functionally differentiated cultures may serve to control vesicular glutamate and GABA filling and adjust functional presynaptic excitatory/inhibitory balance. Unexpectedly, hyperexcitation in differentiated cultures triggers a striking increase in VGLUT2 mRNA and synaptic protein, whereas decreased excitation reduces levels. VGLUT2 mRNA and protein are expressed in subsets of VGLUT1-encoded neocortical neurons that we identify in primary cultures and in neocortex in situ and in vivo. After prolonged hyperexcitation, downregulation of VGLUT1/synaptophysin intensity ratios at most synapses is observed, whereas a subset of VGLUT1-containing boutons selectively increase the expression of VGLUT2. Bidirectional and opposite regulation of VGLUT1 and VGLUT2 by activity may serve as positive or negative feedback regulators for cortical synaptic transmission. Intracortical VGLUT1/VGLUT2 coexpressing neurons have the capacity to independently modulate the level of expression of either transporter at discrete synapses and therefore may serve as a plastic interface between subcortical thalamic input (VGLUT2) and cortical output (VGLUT1) neurons.

Neuronal adenosine release, and not astrocytic ATP release, mediates feedback inhibition of excitatory activity

PubMed Central

Lovatt, Ditte; Xu, Qiwu; Liu, Wei; Takano, Takahiro; Smith, Nathan A.; Schnermann, Jurgen; Tieu, Kim; Nedergaard, Maiken

2012-01-01

Adenosine is a potent anticonvulsant acting on excitatory synapses through A1 receptors. Cellular release of ATP, and its subsequent extracellular enzymatic degradation to adenosine, could provide a powerful mechanism for astrocytes to control the activity of neural networks during high-intensity activity. Despite adenosine's importance, the cellular source of adenosine remains unclear. We report here that multiple enzymes degrade extracellular ATP in brain tissue, whereas only Nt5e degrades AMP to adenosine. However, endogenous A1 receptor activation during cortical seizures in vivo or heterosynaptic depression in situ is independent of Nt5e activity, and activation of astrocytic ATP release via Ca2+ photolysis does not trigger synaptic depression. In contrast, selective activation of postsynaptic CA1 neurons leads to release of adenosine and synaptic depression. This study shows that adenosine-mediated synaptic depression is not a consequence of astrocytic ATP release, but is instead an autonomic feedback mechanism that suppresses excitatory transmission during prolonged activity. PMID:22421436

Mu-opioid receptors modulate the stability of dendritic spines

PubMed Central

Liao, Dezhi; Lin, Hang; Law, Ping Yee; Loh, Horace H.

2005-01-01

Opioids classically regulate the excitability of neurons by suppressing synaptic GABA release from inhibitory neurons. Here, we report a role for opioids in modulating excitatory synaptic transmission. By activating ubiquitously clustered μ-opioid receptor (MOR) in excitatory synapses, morphine caused collapse of preexisting dendritic spines and decreased synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. Meanwhile, the opioid antagonist naloxone increased the density of spines. Chronic treatment with morphine decreased the density of dendritic spines even in the presence of Tetrodotoxin, a sodium channel blocker, indicating that the morphine's effect was not caused by altered activity in neural network through suppression of GABA release. The effect of morphine on dendritic spines was absent in transgenic mice lacking MORs and was blocked by CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-ThrNH2), a μ-receptor antagonist. These data together with others suggest that endogenous opioids and/or constitutive activity of MORs participate in maintaining normal morphology and function of spines, challenging the classical model of opioids. Abnormal alteration of spines may occur in drug addiction when opioid receptors are overactivated by exogenous opiates. PMID:15659552

NMDA Receptor as a Newly Identified Member of the Metabotropic Glutamate Receptor Family: Clinical Implications for Neurodegenerative Diseases

PubMed Central

Chung, ChiHye

2013-01-01

Recent reports have proposed a novel function for the N-methyl-d-aspartate (NMDA) receptor (NMDAR), a well-known excitatory, ionotropic receptor. A series of observations employing pharmacological techniques has proposed that upon ligand binding, this ionotropic receptor can actually function via signaling cascades independent of traditional ionotropic action. Moreover, the “metabotropic” action of NMDARs is suggested to mediate a form of synaptic plasticity, namely long-term synaptic depression (LTD), which shares cellular mechanisms with the synaptic deficits observed in Alzheimer’s disease. Given that a growing body of clinical and preclinical evidence strongly recommends NMDAR antagonists for their therapeutic potentials and advantages in a variety of diseases, further investigation into their molecular and cellular mechanisms is required to better understand the “metabotropic” action of NMDARs. PMID:23740429

Excitatory Amino Acids as Transmitters in the Brain

DTIC Science & Technology

1989-04-30

Amino Acids as Transmitters in the Brain 12 PERSONAL AUTHOR(S) Cotman, C.W. 13a TYPE OF REPORT 1i3b TIME OYERED 14. DATE OF REPORT (Ye, Month, Day) 5s...necenearia i dentf by block number) FIEL.D GROUP SBGOP Excitatory receptors, excitatory amino acids , excitotoxicit N-methyl-D-aspartate, kainate...mediated by excitatory amino acids and their receptors. These receptors participate in both standard synaptic transmission as well as higher order

Emergent Spatial Patterns of Excitatory and Inhibitory Synaptic Strengths Drive Somatotopic Representational Discontinuities and their Plasticity in a Computational Model of Primary Sensory Cortical Area 3b

PubMed Central

Grajski, Kamil A.

2016-01-01

Mechanisms underlying the emergence and plasticity of representational discontinuities in the mammalian primary somatosensory cortical representation of the hand are investigated in a computational model. The model consists of an input lattice organized as a three-digit hand forward-connected to a lattice of cortical columns each of which contains a paired excitatory and inhibitory cell. Excitatory and inhibitory synaptic plasticity of feedforward and lateral connection weights is implemented as a simple covariance rule and competitive normalization. Receptive field properties are computed independently for excitatory and inhibitory cells and compared within and across columns. Within digit representational zones intracolumnar excitatory and inhibitory receptive field extents are concentric, single-digit, small, and unimodal. Exclusively in representational boundary-adjacent zones, intracolumnar excitatory and inhibitory receptive field properties diverge: excitatory cell receptive fields are single-digit, small, and unimodal; and the paired inhibitory cell receptive fields are bimodal, double-digit, and large. In simulated syndactyly (webbed fingers), boundary-adjacent intracolumnar receptive field properties reorganize to within-representation type; divergent properties are reacquired following syndactyly release. This study generates testable hypotheses for assessment of cortical laminar-dependent receptive field properties and plasticity within and between cortical representational zones. For computational studies, present results suggest that concurrent excitatory and inhibitory plasticity may underlie novel emergent properties. PMID:27504086

Stabilization of memory States by stochastic facilitating synapses.

PubMed

Miller, Paul

2013-12-06

Bistability within a small neural circuit can arise through an appropriate strength of excitatory recurrent feedback. The stability of a state of neural activity, measured by the mean dwelling time before a noise-induced transition to another state, depends on the neural firing-rate curves, the net strength of excitatory feedback, the statistics of spike times, and increases exponentially with the number of equivalent neurons in the circuit. Here, we show that such stability is greatly enhanced by synaptic facilitation and reduced by synaptic depression. We take into account the alteration in times of synaptic vesicle release, by calculating distributions of inter-release intervals of a synapse, which differ from the distribution of its incoming interspike intervals when the synapse is dynamic. In particular, release intervals produced by a Poisson spike train have a coefficient of variation greater than one when synapses are probabilistic and facilitating, whereas the coefficient of variation is less than one when synapses are depressing. However, in spite of the increased variability in postsynaptic input produced by facilitating synapses, their dominant effect is reduced synaptic efficacy at low input rates compared to high rates, which increases the curvature of neural input-output functions, leading to wider regions of bistability in parameter space and enhanced lifetimes of memory states. Our results are based on analytic methods with approximate formulae and bolstered by simulations of both Poisson processes and of circuits of noisy spiking model neurons.

The up and down states of cortical networks

NASA Astrophysics Data System (ADS)

Ghorbani, Maryam; Levine, Alex J.; Mehta, Mayank; Bruinsma, Robijn

2011-03-01

The cortical networks show a collective activity of alternating active and silent states known as up and down states during slow wave sleep or anesthesia. The mechanism of this spontaneous activity as well as the anesthesia or sleep are still not clear. Here, using a mean field approach, we present a simple model to study the spontaneous activity of a homogenous cortical network of excitatory and inhibitory neurons that are recurrently connected. A key new ingredient in this model is that the activity-dependant synaptic depression is considered only for the excitatory neurons. We find depending on the strength of the synaptic depression and synaptic efficacies, the phase space contains strange attractors or stable fixed points at active or quiescent regimes. At the strange attractor phase, we can have oscillations similar to up and down states with flat and noisy up states. Moreover, we show that by increasing the synaptic efficacy corresponding to the connections between the excitatory neurons, the characteristics of the up and down states change in agreement with the changes that we observe in the intracellular recordings of the membrane potential from the entorhinal cortex by varying the depth of anesthesia. Thus, we propose that by measuring the value of this synaptic efficacy, one can quantify the depth of anesthesia which is clinically very important. These findings provide a simple, analytical understanding of the spontaneous cortical dynamics.

Parvalbumin interneuron mediated feedforward inhibition controls signal output in the deep layers of the perirhinal‐entorhinal cortex

PubMed Central

Willems, Janske G. P.; Wadman, Wytse J.

2018-01-01

Abstract The perirhinal (PER) and lateral entorhinal (LEC) cortex form an anatomical link between the neocortex and the hippocampus. However, neocortical activity is transmitted through the PER and LEC to the hippocampus with a low probability, suggesting the involvement of the inhibitory network. This study explored the role of interneuron mediated inhibition, activated by electrical stimulation in the agranular insular cortex (AiP), in the deep layers of the PER and LEC. Activated synaptic input by AiP stimulation rarely evoked action potentials in the PER‐LEC deep layer excitatory principal neurons, most probably because the evoked synaptic response consisted of a small excitatory and large inhibitory conductance. Furthermore, parvalbumin positive (PV) interneurons—a subset of interneurons projecting onto the axo‐somatic region of principal neurons—received synaptic input earlier than principal neurons, suggesting recruitment of feedforward inhibition. This synaptic input in PV interneurons evoked varying trains of action potentials, explaining the fast rising, long lasting synaptic inhibition received by deep layer principal neurons. Altogether, the excitatory input from the AiP onto deep layer principal neurons is overruled by strong feedforward inhibition. PV interneurons, with their fast, extensive stimulus‐evoked firing, are able to deliver this fast evoked inhibition in principal neurons. This indicates an essential role for PV interneurons in the gating mechanism of the PER‐LEC network. PMID:29341361

Polymer-electrolyte-gated nanowire synaptic transistors for neuromorphic applications

NASA Astrophysics Data System (ADS)

Zou, Can; Sun, Jia; Gou, Guangyang; Kong, Ling-An; Qian, Chuan; Dai, Guozhang; Yang, Junliang; Guo, Guang-hua

2017-09-01

Polymer-electrolytes are formed by dissolving a salt in polymer instead of water, the conducting mechanism involves the segmental motion-assisted diffusion of ion in the polymer matrix. Here, we report on the fabrication of tin oxide (SnO2) nanowire synaptic transistors using polymer-electrolyte gating. A thin layer of poly(ethylene oxide) and lithium perchlorate (PEO/LiClO4) was deposited on top of the devices, which was used to boost device performances. A voltage spike applied on the in-plane gate attracts ions toward the polymer-electrolyte/SnO2 nanowire interface and the ions are gradually returned after the pulse is removed, which can induce a dynamic excitatory postsynaptic current in the nanowire channel. The SnO2 synaptic transistors exhibit the behavior of short-term plasticity like the paired-pulse facilitation and self-adaptation, which is related to the electric double-effect regulation. In addition, the synaptic logic functions and the logical function transformation are also discussed. Such single SnO2 nanowire-based synaptic transistors are of great importance for future neuromorphic devices.

AMPA-receptor specific biogenesis complexes control synaptic transmission and intellectual ability

PubMed Central

Brechet, Aline; Buchert, Rebecca; Schwenk, Jochen; Boudkkazi, Sami; Zolles, Gerd; Siquier-Pernet, Karine; Schaber, Irene; Bildl, Wolfgang; Saadi, Abdelkrim; Bole-Feysot, Christine; Nitschke, Patrick; Reis, Andre; Sticht, Heinrich; Al-Sanna’a, Nouriya; Rolfs, Arndt; Kulik, Akos; Schulte, Uwe; Colleaux, Laurence; Abou Jamra, Rami; Fakler, Bernd

2017-01-01

AMPA-type glutamate receptors (AMPARs), key elements in excitatory neurotransmission in the brain, are macromolecular complexes whose properties and cellular functions are determined by the co-assembled constituents of their proteome. Here we identify AMPAR complexes that transiently form in the endoplasmic reticulum (ER) and lack the core-subunits typical for AMPARs in the plasma membrane. Central components of these ER AMPARs are the proteome constituents FRRS1l (C9orf4) and CPT1c that specifically and cooperatively bind to the pore-forming GluA1-4 proteins of AMPARs. Bi-allelic mutations in the human FRRS1L gene are shown to cause severe intellectual disability with cognitive impairment, speech delay and epileptic activity. Virus-directed deletion or overexpression of FRRS1l strongly impact synaptic transmission in adult rat brain by decreasing or increasing the number of AMPARs in synapses and extra-synaptic sites. Our results provide insight into the early biogenesis of AMPARs and demonstrate its pronounced impact on synaptic transmission and brain function. PMID:28675162

Functional regeneration of the ex-vivo reconstructed mesocorticolimbic dopaminergic system.

PubMed

Dossi, Elena; Heine, Claudia; Servettini, Ilenio; Gullo, Francesca; Sygnecka, Katja; Franke, Heike; Illes, Peter; Wanke, Enzo

2013-12-01

CNS reparative-medicine therapeutic strategies need answers on the putative recapitulation of the basic rules leading to mammalian CNS development. To achieve this aim, we focus on the regeneration of functional connections in the mesocorticolimbic dopaminergic system. We used organotypic slice cocultures of ventral tegmental area/substantia nigra (VTA/SN) and prefrontal cortex (PFC) on a multielectrode array (MEA) platform to record spikes and local field potentials. The spontaneously growing synaptically based bidirectional bursting activity was followed from 2 to 28 days in vitro (DIV). A statistical analysis of excitatory and inhibitory neurons properties of the physiological firing activity demonstrated a remarkable, exponentially increasing maturation with a time constant of about 5-7 DIV. Immunohistochemistry demonstrated that the ratio of excitatory/inhibitory neurons (3:1) was in line with the functional results obtained. Exemplary pharmacology suggested that GABAA receptors were able to exert phasic and tonic inhibition typical of an adulthood network. Moreover, dopamine D2 receptor inactivation was equally inhibitory both on the spontaneous neuronal activity recorded by MEA and on patch-clamp electrophysiology in PFC pyramidal neurons. These results demonstrate that axon growth cones reach synaptic targets up to full functionality and that organotypic cocultures of the VTA/SN-PFC perfectly model their newly born dopaminergic, glutamatergic and GABAergic neuronal circuitries.

A synaptic trek to autism.

PubMed

Bourgeron, Thomas

2009-04-01

Autism spectrum disorders (ASD) are diagnosed on the basis of three behavioral features namely deficits in social communication, absence or delay in language, and stereotypy. The susceptibility genes to ASD remain largely unknown, but two major pathways are emerging. Mutations in TSC1/TSC2, NF1, or PTEN activate the mTOR/PI3K pathway and lead to syndromic ASD with tuberous sclerosis, neurofibromatosis, or macrocephaly. Mutations in NLGN3/4, SHANK3, or NRXN1 alter synaptic function and lead to mental retardation, typical autism, or Asperger syndrome. The mTOR/PI3K pathway is associated with abnormal cellular/synaptic growth rate, whereas the NRXN-NLGN-SHANK pathway is associated with synaptogenesis and imbalance between excitatory and inhibitory currents. Taken together, these data strongly suggest that abnormal synaptic homeostasis represent a risk factor to ASD.

The maturational theory of brain development and cerebral excitability in the multifactorially inherited manic-depressive psychosis and schizophrenia.

PubMed

Saugstad, L F

1994-12-01

An association has been established between the multifactorially inherited rate of physical maturation and the final step in brain development, when some 40% of synapses are eliminated. This may imply that similarly to endocrine disease entities, we have cerebral disease entities at the extremes of the maturational rate continuum. The restriction of prepubertal pruning to excitatory synapses leaving the number of inhibitory ones fairly constant, implies changes in cerebral excitability as a function of rate of maturation (age at puberty). In early maturation there will be an excess in excitatory drive due to prematurely abridged pruning, which compounds a synchronization tendency inherent in excessive synaptic density. Lowering excitatory level with antiepileptics is hypothesized to be a logical treatment in this type of brain dysfunction. In late maturation, a deficit in excitatory drive due to failure to shut down the pruning process associated with a tendency to the breakdown of circuitry and desynchronization, adds to a similar adversity inherent in reduced synaptic density. Raising the excitatory level with convulsants is hypothesized to be the treatment for this type of CNS dysfunction. The maturational theory of Kraepelin's psychoses holds that they are naturally occurring contrasting chemical signaling disorders in the brain at the extremes of the maturational rate continuum: manic depressive psychosis is a disorder of the early maturer and comprises raised cerebral excitability and a raised density of synapses. This is successfully treated with anti-epileptics like sodium valproate and carbamazepin. Schizophrenia is a disorder in late maturation with reduced cerebral excitability and reduced synaptic density. This is accordingly treated with convulsants such as typical and atypical neuroleptics. However, the conventional effective treatments in both disorders act on inhibition only by either lowering or raising inhibitory level. While the neuroleptics drugs are superior anti-psychotics they nevertheless do not affect the deviation in cerebral excitability which would explain why they do not cure. Disturbed circadian rhythms which precede psychotic episodes in manic depressives accord with a primary dysfunction in the CNS, the suprachiasmatic nucleus of the hypothalamus via its direct input the glutamatergic retinohypothalamic tract. The residual deficits in schizophrenia accord with persistently disconnected circuitry and communication which is a consequence of reduced excitatory level and is manifested in insufficient motivation, a reduced drive associated hypofunction, and neuromuscular dysfunction.

The amygdala excitatory/inhibitory balance in a valproate-induced rat autism model.

PubMed

Lin, Hui-Ching; Gean, Po-Wu; Wang, Chao-Chuan; Chan, Yun-Han; Chen, Po See

2013-01-01

The amygdala is an important structure contributing to socio-emotional behavior. However, the role of the amygdala in autism remains inconclusive. In this study, we used the 28-35 days valproate (VPA)-induced rat model of autism to observe the autistic phenotypes and evaluate their synaptic characteristics in the lateral nucleus (LA) of the amygdala. The VPA-treated offspring demonstrated less social interaction, increased anxiety, enhanced fear learning and impaired fear memory extinction. Slice preparation and electrophysiological recordings of the amygdala showed significantly enhanced long-term potentiation (LTP) while stimulating the thalamic-amygdala pathway of the LA. In addition, the pair pulse facilitation (PPF) at 30- and 60-ms intervals decreased significantly. Whole-cell recordings of the LA pyramidal neurons showed an increased miniature excitatory postsynaptic current (EPSC) frequency and amplitude. The relative contributions of the AMPA receptor and NMDA receptor to the EPSCs did not differ significantly between groups. These results suggested that the enhancement of the presynaptic efficiency of excitatory synaptic transmission might be associated with hyperexcitibility and enhanced LTP in LA pyramidal neurons. Disruption of the synaptic excitatory/inhibitory (E/I) balance in the LA of VPA-treated rats might play certain roles in the development of behaviors in the rat that may be relevant to autism. Further experiments to demonstrate the direct link are warranted.

Cannabinoids suppress synaptic input to neurones of the rat dorsal motor nucleus of the vagus nerve

PubMed Central

Derbenev, Andrei V; Stuart, Thomas C; Smith, Bret N

2004-01-01

Cannabinoids bind central type 1 receptors (CB1R) and modify autonomic functions, including feeding and anti-emetic behaviours, when administered peripherally or into the dorsal vagal complex. Western blots and immunohistochemistry indicated the expression of CB1R in the rat dorsal vagal complex, and tissue polymerase chain reaction confirmed that CB1R message was made within the region. To identify a cellular substrate for the central autonomic effects of cannabinoids, whole-cell patch-clamp recordings were made in brainstem slices to determine the effects of CB1R activation on synaptic transmission to neurones of the dorsal motor nucleus of the vagus (DMV). A subset of these neurones was identified as gastric related after being labelled retrogradely from the stomach. The CB1R agonists WIN55,212-2 and anandamide decreased the frequency of spontaneous excitatory or inhibitory postsynaptic currents in a concentration-related fashion, an effect that persisted in the presence of tetrodotoxin. Paired pulse ratios of electrically evoked postsynaptic currents were also increased by WIN55,212-2. The effects of WIN55,212-2 were sensitive to the selective CB1R antagonist AM251. Cannabinoid agonist effects on synaptic input originating from neurones in the nucleus tractus solitarius (NTS) were determined by evoking activity in the NTS with local glutamate application. Excitatory and inhibitory synaptic inputs arising from the NTS were attenuated by WIN55,212-2. Our results indicate that cannabinoids inhibit transfer of synaptic information to the DMV, including that arising from the NTS, in part by acting at receptors located on presynaptic terminals contacting DMV neurones. Inhibition of synaptic input to DMV neurones is likely to contribute to the suppression of visceral motor responses by cannabinoids. PMID:15272041

Statistical mechanics of neocortical interactions. Derivation of short-term-memory capacity

NASA Astrophysics Data System (ADS)

Ingber, Lester

1984-06-01

A theory developed by the author to describe macroscopic neocortical interactions demonstrates that empirical values of chemical and electrical parameters of synaptic interactions establish several minima of the path-integral Lagrangian as a function of excitatory and inhibitory columnar firings. The number of possible minima, their time scales of hysteresis and probable reverberations, and their nearest-neighbor columnar interactions are all consistent with well-established empirical rules of human short-term memory. Thus, aspects of conscious experience are derived from neuronal firing patterns, using modern methods of nonlinear nonequilibrium statistical mechanics to develop realistic explicit synaptic interactions.

Mathematical modelling of non-stationary fluctuation analysis for studying channel properties of synaptic AMPA receptors

PubMed Central

Benke, Timothy A; Lüthi, Andreas; Palmer, Mary J; Wikström, Martin A; Anderson, William W; Isaac, John T R; Collingridge, Graham L

2001-01-01

The molecular properties of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors are an important factor determining excitatory synaptic transmission in the brain. Changes in the number (N) or single-channel conductance (γ) of functional AMPA receptors may underlie synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD). These parameters have been estimated using non-stationary fluctuation analysis (NSFA). The validity of NSFA for studying the channel properties of synaptic AMPA receptors was assessed using a cable model with dendritic spines and a microscopic kinetic description of AMPA receptors. Electrotonic, geometric and kinetic parameters were altered in order to determine their effects on estimates of the underlying γ. Estimates of γ were very sensitive to the access resistance of the recording (RA) and the mean open time of AMPA channels. Estimates of γ were less sensitive to the distance between the electrode and the synaptic site, the electrotonic properties of dendritic structures, recording electrode capacitance and background noise. Estimates of γ were insensitive to changes in spine morphology, synaptic glutamate concentration and the peak open probability (Po) of AMPA receptors. The results obtained using the model agree with biological data, obtained from 91 dendritic recordings from rat CA1 pyramidal cells. A correlation analysis showed that RA resulted in a slowing of the decay time constant of excitatory postsynaptic currents (EPSCs) by approximately 150 %, from an estimated value of 3.1 ms. RA also greatly attenuated the absolute estimate of γ by approximately 50-70 %. When other parameters remain constant, the model demonstrates that NSFA of dendritic recordings can readily discriminate between changes in γvs. changes in N or Po. Neither background noise nor asynchronous activation of multiple synapses prevented reliable discrimination between changes in γ and changes in either N or Po. The model (available online) can be used to predict how changes in the different properties of AMPA receptors may influence synaptic transmission and plasticity. PMID:11731574

Imbalanced pattern completion vs. separation in cognitive disease: network simulations of synaptic pathologies predict a personalized therapeutics strategy.

PubMed

Hanson, Jesse E; Madison, Daniel V

2010-08-13

Diverse Mouse genetic models of neurodevelopmental, neuropsychiatric, and neurodegenerative causes of impaired cognition exhibit at least four convergent points of synaptic malfunction: 1) Strength of long-term potentiation (LTP), 2) Strength of long-term depression (LTD), 3) Relative inhibition levels (Inhibition), and 4) Excitatory connectivity levels (Connectivity). To test the hypothesis that pathological increases or decreases in these synaptic properties could underlie imbalances at the level of basic neural network function, we explored each type of malfunction in a simulation of autoassociative memory. These network simulations revealed that one impact of impairments or excesses in each of these synaptic properties is to shift the trade-off between pattern separation and pattern completion performance during memory storage and recall. Each type of synaptic pathology either pushed the network balance towards intolerable error in pattern separation or intolerable error in pattern completion. Imbalances caused by pathological impairments or excesses in LTP, LTD, inhibition, or connectivity, could all be exacerbated, or rescued, by the simultaneous modulation of any of the other three synaptic properties. Because appropriate modulation of any of the synaptic properties could help re-balance network function, regardless of the origins of the imbalance, we propose a new strategy of personalized cognitive therapeutics guided by assay of pattern completion vs. pattern separation function. Simulated examples and testable predictions of this theorized approach to cognitive therapeutics are presented.

GluN2B-containing NMDA receptors blockade rescues bidirectional synaptic plasticity in the bed nucleus of the stria terminalis of cocaine self-administering rats.

PubMed

deBacker, Julian; Hawken, Emily R; Normandeau, Catherine P; Jones, Andrea A; Di Prospero, Cynthia; Mechefske, Elysia; Gardner Gregory, James; Hayton, Scott J; Dumont, Éric C

2015-01-01

Drugs of abuse have detrimental effects on homeostatic synaptic plasticity in the motivational brain network. Bidirectional plasticity at excitatory synapses helps keep neural circuits within a functional range to allow for behavioral flexibility. Therefore, impaired bidirectional plasticity of excitatory synapses may contribute to the behavioral hallmarks of addiction, yet this relationship remains unclear. Here we tracked excitatory synaptic strength in the oval bed nucleus of the stria terminalis (ovBNST) using whole-cell voltage-clamp recordings in brain slices from rats self-administering sucrose or cocaine. In the cocaine group, we measured both a persistent increase in AMPA to NMDA ratio (A:N) and slow decay time of NMDA currents throughout the self-administration period and after withdrawal from cocaine. In contrast, the sucrose group exhibited an early increase in A:N ratios (acquisition) that returned toward baseline values with continued self-administration (maintenance) and after withdrawal. The sucrose rats also displayed a decrease in NMDA current decay time with continued self-administration (maintenance), which normalized after withdrawal. Cocaine self-administering rats exhibited impairment in NMDA-dependent long-term depression (LTD) that could be rescued by GluN2B-containing NMDA receptor blockade. Sucrose self-administering rats demonstrated no impairment in NMDA-dependent LTD. During the maintenance period of self-administration, in vivo (daily intraperitoneally for 5 days) pharmacologic blockade of GluN2B-containing NMDA receptors did not reduce lever pressing for cocaine. However, in vivo GluN2B blockade did normalize A:N ratios in cocaine self-administrating rats, and dissociated the magnitude of ovBNST A:N ratios from drug-seeking behavior after protracted withdrawal. Altogether, our data demonstrate when and how bidirectional plasticity at ovBNST excitatory synapses becomes dysfunctional with cocaine self-administration and that NMDA-mediated potentiation of AMPA receptors in this region may be part of the neural circuits of drug relapse.

The influence of single bursts versus single spikes at excitatory dendrodendritic synapses.

PubMed

Masurkar, Arjun V; Chen, Wei R

2012-02-01

The synchronization of neuronal activity is thought to enhance information processing. There is much evidence supporting rhythmically bursting external tufted cells (ETCs) of the rodent olfactory bulb glomeruli coordinating the activation of glomerular interneurons and mitral cells via dendrodendritic excitation. However, as bursting has variable significance at axodendritic cortical synapses, it is not clear if ETC bursting imparts a specific functional advantage over the preliminary spike in dendrodendritic synaptic networks. To answer this question, we investigated the influence of single ETC bursts and spikes with the in vitro rat olfactory bulb preparation at different levels of processing, via calcium imaging of presynaptic ETC dendrites, dual electrical recording of ETC -interneuron synaptic pairs, and multicellular calcium imaging of ETC-induced population activity. Our findings supported single ETC bursts, versus single spikes, driving robust presynaptic calcium signaling, which in turn was associated with profound extension of the initial monosynaptic spike-driven dendrodendritic excitatory postsynaptic potential. This extension could be driven by either the spike-dependent or spike-independent components of the burst. At the population level, burst-induced excitation was more widespread and reliable compared with single spikes. This further supports the ETC network, in part due to a functional advantage of bursting at excitatory dendrodendritic synapses, coordinating synchronous activity at behaviorally relevant frequencies related to odor processing in vivo. © 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Short-term field stimulation mimics synaptic maturation of hippocampal synapses

PubMed Central

Bagley, Elena E; Westbrook, Gary L

2012-01-01

Many aspects of synaptic transmission are modified during development, reflecting not only the consequence of developmental programmes of gene expression, but also the effects of ongoing neural activity. We investigated the role of synaptic activity in the maturation of Schaffer collateral (SC)–CA1 synapses using sustained low frequency field stimulation of acute brain slices. Between postnatal days 4–6 and 14–16, mouse SC–CA1 synapses in naïve slices showed a developmental decrease in the probability of transmitter release (Pr) and an increase in the contribution of GluN2A (NR2A) subunits to the NMDA receptor-mediated excitatory postsynaptic current (EPSC). Surprisingly, these developmental changes could be mimicked by short term (4 h) in vitro synaptic activity in slices taken from postnatal days (PND) 4–6 mice. However, different activity levels were required to alter release probability compared to the NMDA receptor subunit composition. Spontaneous synaptic activity was sufficient to alter the NMDA receptor subunit composition, but sustained low-frequency field stimulation of the brain slice (0.1 Hz, 4 h) was necessary to reduce release probability, as assessed 1 h following the cessation of stimulation. The protein synthesis inhibitor anisomycin blocked the effect of field stimulation on release probability. These results indicate that features of mature excitatory synapses can be rapidly induced in immature neurons. The activity dependence of the Pr and NMDA receptor subunit composition serves as a sensitive indicator of prior neural activity, and provides dual mechanisms for homeostatic control of excitatory synaptic efficacy. PMID:22351628

Short-term field stimulation mimics synaptic maturation of hippocampal synapses.

PubMed

Bagley, Elena E; Westbrook, Gary L

2012-04-01

Many aspects of synaptic transmission are modified during development, reflecting not only the consequence of developmental programmes of gene expression, but also the effects of ongoing neural activity. We investigated the role of synaptic activity in the maturation of Schaffer collateral (SC)-CA1 synapses using sustained low frequency field stimulation of acute brain slices. Between postnatal days 4-6 and 14-16, mouse SC-CA1 synapses in naïve slices showed a developmental decrease in the probability of transmitter release (P(r)) and an increase in the contribution of GluN2A (NR2A) subunits to the NMDA receptor-mediated excitatory postsynaptic current (EPSC). Surprisingly, these developmental changes could be mimicked by short term (4 h) in vitro synaptic activity in slices taken from postnatal days (PND) 4-6 mice. However, different activity levels were required to alter release probability compared to the NMDA receptor subunit composition. Spontaneous synaptic activity was sufficient to alter the NMDA receptor subunit composition, but sustained low-frequency field stimulation of the brain slice (0.1 Hz, 4 h) was necessary to reduce release probability, as assessed 1 h following the cessation of stimulation. The protein synthesis inhibitor anisomycin blocked the effect of field stimulation on release probability. These results indicate that features of mature excitatory synapses can be rapidly induced in immature neurons. The activity dependence of the P(r) and NMDA receptor subunit composition serves as a sensitive indicator of prior neural activity, and provides dual mechanisms for homeostatic control of excitatory synaptic efficacy.

Top-Down Modulation on Perceptual Decision with Balanced Inhibition through Feedforward and Feedback Inhibitory Neurons

PubMed Central

Wang, Cheng-Te; Lee, Chung-Ting; Wang, Xiao-Jing; Lo, Chung-Chuan

2013-01-01

Recent physiological studies have shown that neurons in various regions of the central nervous systems continuously receive noisy excitatory and inhibitory synaptic inputs in a balanced and covaried fashion. While this balanced synaptic input (BSI) is typically described in terms of maintaining the stability of neural circuits, a number of experimental and theoretical studies have suggested that BSI plays a proactive role in brain functions such as top-down modulation for executive control. Two issues have remained unclear in this picture. First, given the noisy nature of neuronal activities in neural circuits, how do the modulatory effects change if the top-down control implements BSI with different ratios between inhibition and excitation? Second, how is a top-down BSI realized via only excitatory long-range projections in the neocortex? To address the first issue, we systematically tested how the inhibition/excitation ratio affects the accuracy and reaction times of a spiking neural circuit model of perceptual decision. We defined an energy function to characterize the network dynamics, and found that different ratios modulate the energy function of the circuit differently and form two distinct functional modes. To address the second issue, we tested BSI with long-distance projection to inhibitory neurons that are either feedforward or feedback, depending on whether these inhibitory neurons do or do not receive inputs from local excitatory cells, respectively. We found that BSI occurs in both cases. Furthermore, when relying on feedback inhibitory neurons, through the recurrent interactions inside the circuit, BSI dynamically and automatically speeds up the decision by gradually reducing its inhibitory component in the course of a trial when a decision process takes too long. PMID:23626812

Top-down modulation on perceptual decision with balanced inhibition through feedforward and feedback inhibitory neurons.

PubMed

Wang, Cheng-Te; Lee, Chung-Ting; Wang, Xiao-Jing; Lo, Chung-Chuan

2013-01-01

Recent physiological studies have shown that neurons in various regions of the central nervous systems continuously receive noisy excitatory and inhibitory synaptic inputs in a balanced and covaried fashion. While this balanced synaptic input (BSI) is typically described in terms of maintaining the stability of neural circuits, a number of experimental and theoretical studies have suggested that BSI plays a proactive role in brain functions such as top-down modulation for executive control. Two issues have remained unclear in this picture. First, given the noisy nature of neuronal activities in neural circuits, how do the modulatory effects change if the top-down control implements BSI with different ratios between inhibition and excitation? Second, how is a top-down BSI realized via only excitatory long-range projections in the neocortex? To address the first issue, we systematically tested how the inhibition/excitation ratio affects the accuracy and reaction times of a spiking neural circuit model of perceptual decision. We defined an energy function to characterize the network dynamics, and found that different ratios modulate the energy function of the circuit differently and form two distinct functional modes. To address the second issue, we tested BSI with long-distance projection to inhibitory neurons that are either feedforward or feedback, depending on whether these inhibitory neurons do or do not receive inputs from local excitatory cells, respectively. We found that BSI occurs in both cases. Furthermore, when relying on feedback inhibitory neurons, through the recurrent interactions inside the circuit, BSI dynamically and automatically speeds up the decision by gradually reducing its inhibitory component in the course of a trial when a decision process takes too long.

Synaptic reorganization of inhibitory hilar interneuron circuitry after traumatic brain injury in mice

PubMed Central

Hunt, Robert F.; Scheff, Stephen W.; Smith, Bret N.

2011-01-01

Functional plasticity of synaptic networks in the dentate gyrus has been implicated in the development of posttraumatic epilepsy and in cognitive dysfunction after traumatic brain injury, but little is known about potentially pathogenic changes in inhibitory circuits. We examined synaptic inhibition of dentate granule cells and excitability of surviving GABAergic hilar interneurons 8–13 weeks after cortical contusion brain injury in transgenic mice that express enhanced green fluorescent protein in a subpopulation of inhibitory neurons. Whole-cell voltage-clamp recordings in granule cells revealed a reduction in spontaneous and miniature IPSC frequency after head injury; no concurrent change in paired-pulse ratio was found in granule cells after paired electrical stimulation of the hilus. Despite reduced inhibitory input to granule cells, action potential and EPSC frequencies were increased in hilar GABA neurons from slices ipsilateral to the injury, versus those from control or contralateral slices. Further, increased excitatory synaptic activity was detected in hilar GABA neurons ipsilateral to the injury after glutamate photostimulation of either the granule cell or CA3 pyramidal cell layers. Together, these findings suggest that excitatory drive to surviving hilar GABA neurons is enhanced by convergent input from both pyramidal and granule cells, but synaptic inhibition of granule cells is not fully restored after injury. This rewiring of circuitry regulating hilar inhibitory neurons may reflect an important compensatory mechanism, but it may also contribute to network destabilization by increasing the relative impact of surviving individual interneurons in controlling granule cell excitability in the posttraumatic dentate gyrus. PMID:21543618

Electrical Advantages of Dendritic Spines

PubMed Central

Gulledge, Allan T.; Carnevale, Nicholas T.; Stuart, Greg J.

2012-01-01

Many neurons receive excitatory glutamatergic input almost exclusively onto dendritic spines. In the absence of spines, the amplitudes and kinetics of excitatory postsynaptic potentials (EPSPs) at the site of synaptic input are highly variable and depend on dendritic location. We hypothesized that dendritic spines standardize the local geometry at the site of synaptic input, thereby reducing location-dependent variability of local EPSP properties. We tested this hypothesis using computational models of simplified and morphologically realistic spiny neurons that allow direct comparison of EPSPs generated on spine heads with EPSPs generated on dendritic shafts at the same dendritic locations. In all morphologies tested, spines greatly reduced location-dependent variability of local EPSP amplitude and kinetics, while having minimal impact on EPSPs measured at the soma. Spine-dependent standardization of local EPSP properties persisted across a range of physiologically relevant spine neck resistances, and in models with variable neck resistances. By reducing the variability of local EPSPs, spines standardized synaptic activation of NMDA receptors and voltage-gated calcium channels. Furthermore, spines enhanced activation of NMDA receptors and facilitated the generation of NMDA spikes and axonal action potentials in response to synaptic input. Finally, we show that dynamic regulation of spine neck geometry can preserve local EPSP properties following plasticity-driven changes in synaptic strength, but is inefficient in modifying the amplitude of EPSPs in other cellular compartments. These observations suggest that one function of dendritic spines is to standardize local EPSP properties throughout the dendritic tree, thereby allowing neurons to use similar voltage-sensitive postsynaptic mechanisms at all dendritic locations. PMID:22532875

Estimates of the location of L-type Ca2+ channels in motoneurons of different sizes: a computational study.

PubMed

Grande, Giovanbattista; Bui, Tuan V; Rose, P Ken

2007-06-01

In the presence of monoamines, L-type Ca(2+) channels on the dendrites of motoneurons contribute to persistent inward currents (PICs) that can amplify synaptic inputs two- to sixfold. However, the exact location of the L-type Ca(2+) channels is controversial, and the importance of the location as a means of regulating the input-output properties of motoneurons is unknown. In this study, we used a computational strategy developed previously to estimate the dendritic location of the L-type Ca(2+) channels and test the hypothesis that the location of L-type Ca(2+) channels varies as a function of motoneuron size. Compartmental models were constructed based on dendritic trees of five motoneurons that ranged in size from small to large. These models were constrained by known differences in PIC activation reported for low- and high-conductance motoneurons and the relationship between somatic PIC threshold and the presence or absence of tonic excitatory or inhibitory synaptic activity. Our simulations suggest that L-type Ca(2+) channels are concentrated in hotspots whose distance from the soma increases with the size of the dendritic tree. Moving the hotspots away from these sites (e.g., using the hotspot locations from large motoneurons on intermediate-sized motoneurons) fails to replicate the shifts in PIC threshold that occur experimentally during tonic excitatory or inhibitory synaptic activity. In models equipped with a size-dependent distribution of L-type Ca(2+) channels, the amplification of synaptic current by PICs depends on motoneuron size and the location of the synaptic input on the dendritic tree.

Excitatory Synaptic Drive and Feedforward Inhibition in the Hippocampal CA3 Circuit Are Regulated by SynCAM 1.

PubMed

Park, Kellie A; Ribic, Adema; Laage Gaupp, Fabian M; Coman, Daniel; Huang, Yuegao; Dulla, Chris G; Hyder, Fahmeed; Biederer, Thomas

2016-07-13

Select adhesion proteins control the development of synapses and modulate their structural and functional properties. Despite these important roles, the extent to which different synapse-organizing mechanisms act across brain regions to establish connectivity and regulate network properties is incompletely understood. Further, their functional roles in different neuronal populations remain to be defined. Here, we applied diffusion tensor imaging (DTI), a modality of magnetic resonance imaging (MRI), to map connectivity changes in knock-out (KO) mice lacking the synaptogenic cell adhesion protein SynCAM 1. This identified reduced fractional anisotropy in the hippocampal CA3 area in absence of SynCAM 1. In agreement, mossy fiber refinement in CA3 was impaired in SynCAM 1 KO mice. Mossy fibers make excitatory inputs onto postsynaptic specializations of CA3 pyramidal neurons termed thorny excrescences and these structures were smaller in the absence of SynCAM 1. However, the most prevalent targets of mossy fibers are GABAergic interneurons and SynCAM 1 loss unexpectedly reduced the number of excitatory terminals onto parvalbumin (PV)-positive interneurons in CA3. SynCAM 1 KO mice additionally exhibited lower postsynaptic GluA1 expression in these PV-positive interneurons. These synaptic imbalances in SynCAM 1 KO mice resulted in CA3 disinhibition, in agreement with reduced feedforward inhibition in this network in the absence of SynCAM 1-dependent excitatory drive onto interneurons. In turn, mice lacking SynCAM 1 were impaired in memory tasks involving CA3. Our results support that SynCAM 1 modulates excitatory mossy fiber inputs onto both interneurons and principal neurons in the hippocampal CA3 area to balance network excitability. This study advances our understanding of synapse-organizing mechanisms on two levels. First, the data support that synaptogenic proteins guide connectivity and can function in distinct brain regions even if they are expressed broadly. Second, the results demonstrate that a synaptogenic process that controls excitatory inputs to both pyramidal neurons and interneurons can balance excitation and inhibition. Specifically, the study reveals that hippocampal CA3 connectivity is modulated by the synapse-organizing adhesion protein SynCAM 1 and identifies a novel, SynCAM 1-dependent mechanism that controls excitatory inputs onto parvalbumin-positive interneurons. This enables SynCAM 1 to regulate feedforward inhibition and set network excitability. Further, we show that diffusion tensor imaging is sensitive to these cellular refinements affecting neuronal connectivity. Copyright © 2016 the authors 0270-6474/16/367465-12$15.00/0.

Excitatory amino acid transmitters in epilepsy.

PubMed

Meldrum, B S

1991-01-01

For the majority of human epilepsy syndromes, the molecular and cellular basis for the epileptic activity remains largely conjectural. The principal hypotheses currently concern: defects in membrane ionic conductances or transport mechanisms; defects in gamma-aminobutyric acid (GABA)-mediated inhibitory processes; and enhanced or abnormal excitatory synaptic action. Substantial evidence exists in humans and animals for acquired abnormalities in excitatory amino acid neurotransmission that may participate in the abnormal patterns of neuronal discharge, and this could provide the morphological basis for a recurrent excitatory pathway sustaining seizure discharges in temporal lobe epilepsy. In practice, two approaches appear significant in the suppression of seizures. One is to act postsynaptically on receptors to decrease the excitation induced by glutamate, and the other is to decrease synaptic release of glutamate and aspartate. Agents acting upon adenosine or GABAB receptors decrease glutamate release in vitro but do not have significant anticonvulsant activity, probably because of their predominant actions at other sites. Lamotrigine blocks stimulated release of glutamate and shows anticonvulsant activity in a wide range of animal models.

Norepinephrine versus Dopamine and their Interaction in Modulating Synaptic Function in the Prefrontal Cortex

PubMed Central

Xing, Bo; Li, Yan-Chun; Gao, Wen-Jun

2016-01-01

Among the neuromodulators that regulate prefrontal cortical circuit function, the catecholamine transmitters norepinephrine (NE) and dopamine (DA) stand out as powerful players in working memory and attention. Perturbation of either NE or DA signaling is implicated in the pathogenesis of several neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), schizophrenia, and drug addiction. Although the precise mechanisms employed by NE and DA to cooperatively control prefrontal functions are not fully understood, emerging research indicates that both transmitters regulate electrical and biochemical aspects of neuronal function by modulating convergent ionic and synaptic signaling in the prefrontal cortex (PFC). This review summarizes previous studies that investigated the effects of both NE and DA on excitatory and inhibitory transmissions in the prefrontal cortical circuitry. Specifically, we focus on the functional interaction between NE and DA in prefrontal cortical local circuitry, synaptic integration, signaling pathways, and receptor properties. Although it is clear that both NE and DA innervate the PFC extensively and modulate synaptic function by activating distinctly different receptor subtypes and signaling pathways, it remains unclear how these two systems coordinate their actions to optimize PFC function for appropriate behavior. Throughout this review, we provide perspectives and highlight several critical topics for future studies. PMID:26790349

Cadherin-13, a risk gene for ADHD and comorbid disorders, impacts GABAergic function in hippocampus and cognition.

PubMed

Rivero, O; Selten, M M; Sich, S; Popp, S; Bacmeister, L; Amendola, E; Negwer, M; Schubert, D; Proft, F; Kiser, D; Schmitt, A G; Gross, C; Kolk, S M; Strekalova, T; van den Hove, D; Resink, T J; Nadif Kasri, N; Lesch, K P

2015-10-13

Cadherin-13 (CDH13), a unique glycosylphosphatidylinositol-anchored member of the cadherin family of cell adhesion molecules, has been identified as a risk gene for attention-deficit/hyperactivity disorder (ADHD) and various comorbid neurodevelopmental and psychiatric conditions, including depression, substance abuse, autism spectrum disorder and violent behavior, while the mechanism whereby CDH13 dysfunction influences pathogenesis of neuropsychiatric disorders remains elusive. Here we explored the potential role of CDH13 in the inhibitory modulation of brain activity by investigating synaptic function of GABAergic interneurons. Cellular and subcellular distribution of CDH13 was analyzed in the murine hippocampus and a mouse model with a targeted inactivation of Cdh13 was generated to evaluate how CDH13 modulates synaptic activity of hippocampal interneurons and behavioral domains related to psychopathologic (endo)phenotypes. We show that CDH13 expression in the cornu ammonis (CA) region of the hippocampus is confined to distinct classes of interneurons. Specifically, CDH13 is expressed by numerous parvalbumin and somatostatin-expressing interneurons located in the stratum oriens, where it localizes to both the soma and the presynaptic compartment. Cdh13(-/-) mice show an increase in basal inhibitory, but not excitatory, synaptic transmission in CA1 pyramidal neurons. Associated with these alterations in hippocampal function, Cdh13(-/-) mice display deficits in learning and memory. Taken together, our results indicate that CDH13 is a negative regulator of inhibitory synapses in the hippocampus, and provide insights into how CDH13 dysfunction may contribute to the excitatory/inhibitory imbalance observed in neurodevelopmental disorders, such as ADHD and autism.

Efficient Coding and Energy Efficiency Are Promoted by Balanced Excitatory and Inhibitory Synaptic Currents in Neuronal Network

PubMed Central

Yu, Lianchun; Shen, Zhou; Wang, Chen; Yu, Yuguo

2018-01-01

Selective pressure may drive neural systems to process as much information as possible with the lowest energy cost. Recent experiment evidence revealed that the ratio between synaptic excitation and inhibition (E/I) in local cortex is generally maintained at a certain value which may influence the efficiency of energy consumption and information transmission of neural networks. To understand this issue deeply, we constructed a typical recurrent Hodgkin-Huxley network model and studied the general principles that governs the relationship among the E/I synaptic current ratio, the energy cost and total amount of information transmission. We observed in such a network that there exists an optimal E/I synaptic current ratio in the network by which the information transmission achieves the maximum with relatively low energy cost. The coding energy efficiency which is defined as the mutual information divided by the energy cost, achieved the maximum with the balanced synaptic current. Although background noise degrades information transmission and imposes an additional energy cost, we find an optimal noise intensity that yields the largest information transmission and energy efficiency at this optimal E/I synaptic transmission ratio. The maximization of energy efficiency also requires a certain part of energy cost associated with spontaneous spiking and synaptic activities. We further proved this finding with analytical solution based on the response function of bistable neurons, and demonstrated that optimal net synaptic currents are capable of maximizing both the mutual information and energy efficiency. These results revealed that the development of E/I synaptic current balance could lead a cortical network to operate at a highly efficient information transmission rate at a relatively low energy cost. The generality of neuronal models and the recurrent network configuration used here suggest that the existence of an optimal E/I cell ratio for highly efficient energy costs and information maximization is a potential principle for cortical circuit networks. Summary We conducted numerical simulations and mathematical analysis to examine the energy efficiency of neural information transmission in a recurrent network as a function of the ratio of excitatory and inhibitory synaptic connections. We obtained a general solution showing that there exists an optimal E/I synaptic ratio in a recurrent network at which the information transmission as well as the energy efficiency of this network achieves a global maximum. These results reflect general mechanisms for sensory coding processes, which may give insight into the energy efficiency of neural communication and coding. PMID:29773979

Efficient Coding and Energy Efficiency Are Promoted by Balanced Excitatory and Inhibitory Synaptic Currents in Neuronal Network.

PubMed

Yu, Lianchun; Shen, Zhou; Wang, Chen; Yu, Yuguo

2018-01-01

Selective pressure may drive neural systems to process as much information as possible with the lowest energy cost. Recent experiment evidence revealed that the ratio between synaptic excitation and inhibition (E/I) in local cortex is generally maintained at a certain value which may influence the efficiency of energy consumption and information transmission of neural networks. To understand this issue deeply, we constructed a typical recurrent Hodgkin-Huxley network model and studied the general principles that governs the relationship among the E/I synaptic current ratio, the energy cost and total amount of information transmission. We observed in such a network that there exists an optimal E/I synaptic current ratio in the network by which the information transmission achieves the maximum with relatively low energy cost. The coding energy efficiency which is defined as the mutual information divided by the energy cost, achieved the maximum with the balanced synaptic current. Although background noise degrades information transmission and imposes an additional energy cost, we find an optimal noise intensity that yields the largest information transmission and energy efficiency at this optimal E/I synaptic transmission ratio. The maximization of energy efficiency also requires a certain part of energy cost associated with spontaneous spiking and synaptic activities. We further proved this finding with analytical solution based on the response function of bistable neurons, and demonstrated that optimal net synaptic currents are capable of maximizing both the mutual information and energy efficiency. These results revealed that the development of E/I synaptic current balance could lead a cortical network to operate at a highly efficient information transmission rate at a relatively low energy cost. The generality of neuronal models and the recurrent network configuration used here suggest that the existence of an optimal E/I cell ratio for highly efficient energy costs and information maximization is a potential principle for cortical circuit networks. We conducted numerical simulations and mathematical analysis to examine the energy efficiency of neural information transmission in a recurrent network as a function of the ratio of excitatory and inhibitory synaptic connections. We obtained a general solution showing that there exists an optimal E/I synaptic ratio in a recurrent network at which the information transmission as well as the energy efficiency of this network achieves a global maximum. These results reflect general mechanisms for sensory coding processes, which may give insight into the energy efficiency of neural communication and coding.

Cell Class-Dependent Intracortical Connectivity and Output Dynamics of Layer 6 Projection Neurons of the Rat Primary Visual Cortex.

PubMed

Cotel, Florence; Fletcher, Lee N; Kalita-de Croft, Simon; Apergis-Schoute, John; Williams, Stephen R

2018-07-01

Neocortical information processing is powerfully influenced by the activity of layer 6 projection neurons through control of local intracortical and subcortical circuitry. Morphologically distinct classes of layer 6 projection neuron have been identified in the mammalian visual cortex, which exhibit contrasting receptive field properties, but little information is available on their functional specificity. To address this we combined anatomical tracing techniques with high-resolution patch-clamp recording to identify morphological and functional distinct classes of layer 6 projection neurons in the rat primary visual cortex, which innervated separable subcortical territories. Multisite whole-cell recordings in brain slices revealed that corticoclaustral and corticothalamic layer 6 projection neurons exhibited similar somatically recorded electrophysiological properties. These classes of layer 6 projection neurons were sparsely and reciprocally synaptically interconnected, but could be differentiated by cell-class, but not target-cell-dependent rules of use-dependent depression and facilitation of unitary excitatory synaptic output. Corticoclaustral and corticothalamic layer 6 projection neurons were differentially innervated by columnar excitatory circuitry, with corticoclaustral, but not corticothalamic, neurons powerfully driven by layer 4 pyramidal neurons, and long-range pathways conveyed in neocortical layer 1. Our results therefore reveal projection target-specific, functionally distinct, streams of layer 6 output in the rodent neocortex.

Structure-Function Relationship of Transporters in the Glutamate-Glutamine Cycle of the Central Nervous System.

PubMed

Hayashi, Mariko Kato

2018-04-12

Many kinds of transporters contribute to glutamatergic excitatory synaptic transmission. Glutamate is loaded into synaptic vesicles by vesicular glutamate transporters to be released from presynaptic terminals. After synaptic vesicle release, glutamate is taken up by neurons or astrocytes to terminate the signal and to prepare for the next signal. Glutamate transporters on the plasma membrane are responsible for transporting glutamate from extracellular fluid to cytoplasm. Glutamate taken up by astrocyte is converted to glutamine by glutamine synthetase and transported back to neurons through glutamine transporters on the plasma membranes of the astrocytes and then on neurons. Glutamine is converted back to glutamate by glutaminase in the neuronal cytoplasm and then loaded into synaptic vesicles again. Here, the structures of glutamate transporters and glutamine transporters, their conformational changes, and how they use electrochemical gradients of various ions for substrate transport are summarized. Pharmacological regulations of these transporters are also discussed.

Autism-like behaviours and enhanced memory formation and synaptic plasticity in Lrfn2/SALM1-deficient mice.

PubMed

Morimura, Naoko; Yasuda, Hiroki; Yamaguchi, Kazuhiko; Katayama, Kei-Ichi; Hatayama, Minoru; Tomioka, Naoko H; Odagawa, Maya; Kamiya, Akiko; Iwayama, Yoshimi; Maekawa, Motoko; Nakamura, Kazuhiko; Matsuzaki, Hideo; Tsujii, Masatsugu; Yamada, Kazuyuki; Yoshikawa, Takeo; Aruga, Jun

2017-06-12

Lrfn2/SALM1 is a PSD-95-interacting synapse adhesion molecule, and human LRFN2 is associated with learning disabilities. However its role in higher brain function and underlying mechanisms remain unknown. Here, we show that Lrfn2 knockout mice exhibit autism-like behavioural abnormalities, including social withdrawal, decreased vocal communications, increased stereotyped activities and prepulse inhibition deficits, together with enhanced learning and memory. In the hippocampus, the levels of synaptic PSD-95 and GluA1 are decreased. The synapses are structurally and functionally immature with spindle shaped spines, smaller postsynaptic densities, reduced AMPA/NMDA ratio, and enhanced LTP. In vitro experiments reveal that synaptic surface expression of AMPAR depends on the direct interaction between Lrfn2 and PSD-95. Furthermore, we detect functionally defective LRFN2 missense mutations in autism and schizophrenia patients. Together, these findings indicate that Lrfn2/LRFN2 serve as core components of excitatory synapse maturation and maintenance, and their dysfunction causes immature/silent synapses with pathophysiological state.

Autism-Associated Insertion Mutation (InsG) of Shank3 Exon 21 Causes Impaired Synaptic Transmission and Behavioral Deficits

PubMed Central

Speed, Haley E.; Kouser, Mehreen; Xuan, Zhong; Reimers, Jeremy M.; Ochoa, Christine F.; Gupta, Natasha; Liu, Shunan

2015-01-01

SHANK3 (also known as PROSAP2) is a postsynaptic scaffolding protein at excitatory synapses in which mutations and deletions have been implicated in patients with idiopathic autism, Phelan–McDermid (aka 22q13 microdeletion) syndrome, and other neuropsychiatric disorders. In this study, we have created a novel mouse model of human autism caused by the insertion of a single guanine nucleotide into exon 21 (Shank3G). The resulting frameshift causes a premature STOP codon and loss of major higher molecular weight Shank3 isoforms at the synapse. Shank3G/G mice exhibit deficits in hippocampus-dependent spatial learning, impaired motor coordination, altered response to novelty, and sensory processing deficits. At the cellular level, Shank3G/G mice also exhibit impaired hippocampal excitatory transmission and plasticity as well as changes in baseline NMDA receptor-mediated synaptic responses. This work identifies clear alterations in synaptic function and behavior in a novel, genetically accurate mouse model of autism mimicking an autism-associated insertion mutation. Furthermore, these findings lay the foundation for future studies aimed to validate and study region-selective and temporally selective genetic reversal studies in the Shank3G/G mouse that was engineered with such future experiments in mind. PMID:26134648

Distributed Cerebellar Motor Learning: A Spike-Timing-Dependent Plasticity Model

PubMed Central

Luque, Niceto R.; Garrido, Jesús A.; Naveros, Francisco; Carrillo, Richard R.; D'Angelo, Egidio; Ros, Eduardo

2016-01-01

Deep cerebellar nuclei neurons receive both inhibitory (GABAergic) synaptic currents from Purkinje cells (within the cerebellar cortex) and excitatory (glutamatergic) synaptic currents from mossy fibers. Those two deep cerebellar nucleus inputs are thought to be also adaptive, embedding interesting properties in the framework of accurate movements. We show that distributed spike-timing-dependent plasticity mechanisms (STDP) located at different cerebellar sites (parallel fibers to Purkinje cells, mossy fibers to deep cerebellar nucleus cells, and Purkinje cells to deep cerebellar nucleus cells) in close-loop simulations provide an explanation for the complex learning properties of the cerebellum in motor learning. Concretely, we propose a new mechanistic cerebellar spiking model. In this new model, deep cerebellar nuclei embed a dual functionality: deep cerebellar nuclei acting as a gain adaptation mechanism and as a facilitator for the slow memory consolidation at mossy fibers to deep cerebellar nucleus synapses. Equipping the cerebellum with excitatory (e-STDP) and inhibitory (i-STDP) mechanisms at deep cerebellar nuclei afferents allows the accommodation of synaptic memories that were formed at parallel fibers to Purkinje cells synapses and then transferred to mossy fibers to deep cerebellar nucleus synapses. These adaptive mechanisms also contribute to modulate the deep-cerebellar-nucleus-output firing rate (output gain modulation toward optimizing its working range). PMID:26973504

Emergence of small-world structure in networks of spiking neurons through STDP plasticity.

PubMed

Basalyga, Gleb; Gleiser, Pablo M; Wennekers, Thomas

2011-01-01

In this work, we use a complex network approach to investigate how a neural network structure changes under synaptic plasticity. In particular, we consider a network of conductance-based, single-compartment integrate-and-fire excitatory and inhibitory neurons. Initially the neurons are connected randomly with uniformly distributed synaptic weights. The weights of excitatory connections can be strengthened or weakened during spiking activity by the mechanism known as spike-timing-dependent plasticity (STDP). We extract a binary directed connection matrix by thresholding the weights of the excitatory connections at every simulation step and calculate its major topological characteristics such as the network clustering coefficient, characteristic path length and small-world index. We numerically demonstrate that, under certain conditions, a nontrivial small-world structure can emerge from a random initial network subject to STDP learning.

Frequency tuning of synaptic inhibition underlying duration-tuned neurons in the mammalian inferior colliculus

PubMed Central

Valdizón-Rodríguez, Roberto

2017-01-01

Inhibition plays an important role in creating the temporal response properties of duration-tuned neurons (DTNs) in the mammalian inferior colliculus (IC). Neurophysiological and computational studies indicate that duration selectivity in the IC is created through the convergence of excitatory and inhibitory synaptic inputs offset in time. We used paired-tone stimulation and extracellular recording to measure the frequency tuning of the inhibition acting on DTNs in the IC of the big brown bat (Eptesicus fuscus). We stimulated DTNs with pairs of tones differing in duration, onset time, and frequency. The onset time of a short, best-duration (BD), probe tone set to the best excitatory frequency (BEF) was varied relative to the onset of a longer-duration, nonexcitatory (NE) tone whose frequency was varied. When the NE tone frequency was near or within the cell’s excitatory bandwidth (eBW), BD tone-evoked spikes were suppressed by an onset-evoked inhibition. The onset of the spike suppression was independent of stimulus frequency, but both the offset and duration of the suppression decreased as the NE tone frequency departed from the BEF. We measured the inhibitory frequency response area, best inhibitory frequency (BIF), and inhibitory bandwidth (iBW) of each cell. We found that the BIF closely matched the BEF, but the iBW was broader and usually overlapped the eBW measured from the same cell. These data suggest that temporal selectivity of midbrain DTNs is created and preserved by having cells receive an onset-evoked, constant-latency, broadband inhibition that largely overlaps the cell’s excitatory receptive field. We conclude by discussing possible neural sources of the inhibition. NEW & NOTEWORTHY Duration-tuned neurons (DTNs) arise from temporally offset excitatory and inhibitory synaptic inputs. We used single-unit recording and paired-tone stimulation to measure the spectral tuning of the inhibitory inputs to DTNs. The onset of inhibition was independent of stimulus frequency; the offset and duration of inhibition systematically decreased as the stimulus departed from the cell’s best excitatory frequency. Best inhibitory frequencies matched best excitatory frequencies; however, inhibitory bandwidths were more broadly tuned than excitatory bandwidths. PMID:28100657

Regulation of AMPA receptors by phosphorylation.

PubMed

Carvalho, A L; Duarte, C B; Carvalho, A P

2000-10-01

The AMPA receptors for glutamate are oligomeric structures that mediate fast excitatory responses in the central nervous system. Phosphorylation of AMPA receptors is an important mechanism for short-term modulation of their function, and is thought to play an important role in synaptic plasticity in different brain regions. Recent studies have shown that phosphorylation of AMPA receptors by cAMP-dependent protein kinase (PKA) and Ca2+- and calmodulin-dependent protein kinase II (CaMKII) potentiates their activity, but phosphorylation of the receptor subunits may also affect their interaction with intracellular proteins, and their expression at the plasma membrane. Phosphorylation of AMPA receptor subunits has also been investigated in relation to processes of synaptic plasticity. This review focuses on recent advances in understanding the molecular mechanisms of regulation of AMPA receptors, and their implications in synaptic plasticity.

Delayed and Temporally Imprecise Neurotransmission in Reorganizing Cortical Microcircuits

PubMed Central

Barnes, Samuel J.; Cheetham, Claire E.; Liu, Yan; Bennett, Sophie H.; Albieri, Giorgia; Jorstad, Anne A.; Knott, Graham W.

2015-01-01

Synaptic neurotransmission is modified at cortical connections throughout life. Varying the amplitude of the postsynaptic response is one mechanism that generates flexible signaling in neural circuits. The timing of the synaptic response may also play a role. Here, we investigated whether weakening and loss of an entire connection between excitatory cortical neurons was foreshadowed in the timing of the postsynaptic response. We made electrophysiological recordings in rat primary somatosensory cortex that was undergoing experience-dependent loss of complete local excitatory connections. The synaptic latency of pyramid–pyramid connections, which typically comprise multiple synapses, was longer and more variable. Connection strength and latency were not correlated. Instead, prolonged latency was more closely related to progression of connection loss. The action potential waveform and axonal conduction velocity were unaffected, suggesting that the altered timing of neurotransmission was attributable to a synaptic mechanism. Modeling studies indicated that increasing the latency and jitter at a subset of synapses reduced the number of action potentials fired by a postsynaptic neuron. We propose that prolonged synaptic latency and diminished temporal precision of neurotransmission are hallmarks of impending loss of a cortical connection. PMID:26085628

Adrenoceptor-Mediated Post- and Pre-Synaptic Regulations of the Reticulospinal Neurons in Rat Caudal Pontine Reticular Nucleus.

PubMed

Yang, Nian; Qiao, Qi-Cheng; Liu, Yu-Hui; Zhang, Ji-Qiang; Hu, Zhi-An; Zhang, Jun

2016-12-01

The central noradrenergic system participates in diverse nervous functions. Nevertheless, our knowledge of the action of adrenoceptors in motor regulation is still lacking. Intriguingly, reticulospinal neurons in the caudal pontine reticular nucleus (PnC) receive fairly dense noradrenergic innervation and play an important role in motor control. Here, after demonstrating the expression of α1- and α2-adrenoceptors in the PnC, we found that noradrenaline elicited a post-synaptic effect (inward or outward whole-cell current at -70 mV holding) on PnC reticulospinal neurons. The α1- and α2-adrenoceptors were co-expressed in individual PnC reticulospinal neurons to mediate an inward and an outward current component at -70 mV holding, respectively, which, when superposed, produced the overall post-synaptic effects of noradrenaline (NA). More importantly, the activation of post-synaptic α1- or α2-adrenoceptors indeed exerted opposing modulations (excitation vs. inhibition) on the firing activities of individual PnC reticulospinal neurons. Furthermore, the activation and inhibition of the Na + -permeable non-selective cationic conductance (NSCC) were demonstrated to be coupled to α1- and α2-adrenoceptors, respectively. Additionally, the activation of α2-adrenoceptors activated K + conductance. Pre-synaptically, the α2-adrenoceptors were expressed to attenuate the miniature excitatory postsynaptic current (mEPSC) in PnC reticulospinal neurons, but not to affect the miniature inhibitory postsynaptic current (mIPSC). Consistently, the evoked EPSC in PnC reticulospinal neurons was suppressed after the activation of pre-synaptic α2-adrenoceptors. Thus, the excitatory input and post-synaptic dynamics of PnC reticulospinal neurons are indeed intricately modulated by the activation of α1- and α2-adrenoceptors, through which motor control may be regulated in an adaptive manner by the central noradrenergic system.

When is an Inhibitory Synapse Effective?

NASA Astrophysics Data System (ADS)

Qian, Ning; Sejnowski, Terrence J.

1990-10-01

Interactions between excitatory and inhibitory synaptic inputs on dendrites determine the level of activity in neurons. Models based on the cable equation predict that silent shunting inhibition can strongly veto the effect of an excitatory input. The cable model assumes that ionic concentrations do not change during the electrical activity, which may not be a valid assumption, especially for small structures such as dendritic spines. We present here an analysis and computer simulations to show that for large Cl^- conductance changes, the more general Nernst-Planck electrodiffusion model predicts that shunting inhibition on spines should be much less effective than that predicted by the cable model. This is a consequence of the large changes in the intracellular ionic concentration of Cl^- that can occur in small structures, which would alter the reversal potential and reduce the driving force for Cl^-. Shunting inhibition should therefore not be effective on spines, but it could be significantly more effective on the dendritic shaft at the base of the spine. In contrast to shunting inhibition, hyperpolarizing synaptic inhibition mediated by K^+ currents can be very effective in reducing the excitatory synaptic potentials on the same spine if the excitatory conductance change is less than 10 nS. We predict that if the inhibitory synapses found on cortical spines are to be effective, then they should be mediated by K^+ through GABA_B receptors.

Network and neuronal membrane properties in hybrid networks reciprocally regulate selectivity to rapid thalamocortical inputs.

PubMed

Pesavento, Michael J; Pinto, David J

2012-11-01

Rapidly changing environments require rapid processing from sensory inputs. Varying deflection velocities of a rodent's primary facial vibrissa cause varying temporal neuronal activity profiles within the ventral posteromedial thalamic nucleus. Local neuron populations in a single somatosensory layer 4 barrel transform sparsely coded input into a spike count based on the input's temporal profile. We investigate this transformation by creating a barrel-like hybrid network with whole cell recordings of in vitro neurons from a cortical slice preparation, embedding the biological neuron in the simulated network by presenting virtual synaptic conductances via a conductance clamp. Utilizing the hybrid network, we examine the reciprocal network properties (local excitatory and inhibitory synaptic convergence) and neuronal membrane properties (input resistance) by altering the barrel population response to diverse thalamic input. In the presence of local network input, neurons are more selective to thalamic input timing; this arises from strong feedforward inhibition. Strongly inhibitory (damping) network regimes are more selective to timing and less selective to the magnitude of input but require stronger initial input. Input selectivity relies heavily on the different membrane properties of excitatory and inhibitory neurons. When inhibitory and excitatory neurons had identical membrane properties, the sensitivity of in vitro neurons to temporal vs. magnitude features of input was substantially reduced. Increasing the mean leak conductance of the inhibitory cells decreased the network's temporal sensitivity, whereas increasing excitatory leak conductance enhanced magnitude sensitivity. Local network synapses are essential in shaping thalamic input, and differing membrane properties of functional classes reciprocally modulate this effect.

An autism-associated point mutation in the neuroligin cytoplasmic tail selectively impairs AMPA receptor-mediated synaptic transmission in hippocampus.

PubMed

Etherton, Mark R; Tabuchi, Katsuhiko; Sharma, Manu; Ko, Jaewon; Südhof, Thomas C

2011-06-03

Neuroligins are evolutionarily conserved postsynaptic cell-adhesion molecules that function, at least in part, by forming trans-synaptic complexes with presynaptic neurexins. Different neuroligin isoforms perform diverse functions and exhibit distinct intracellular localizations, but contain similar cytoplasmic sequences whose role remains largely unknown. Here, we analysed the effect of a single amino-acid substitution (R704C) that targets a conserved arginine residue in the cytoplasmic sequence of all neuroligins, and that was associated with autism in neuroligin-4. We introduced the R704C mutation into mouse neuroligin-3 by homologous recombination, and examined its effect on synapses in vitro and in vivo. Electrophysiological and morphological studies revealed that the neuroligin-3 R704C mutation did not significantly alter synapse formation, but dramatically impaired synapse function. Specifically, the R704C mutation caused a major and selective decrease in AMPA receptor-mediated synaptic transmission in pyramidal neurons of the hippocampus, without similarly changing NMDA or GABA receptor-mediated synaptic transmission, and without detectably altering presynaptic neurotransmitter release. Our results suggest that the cytoplasmic tail of neuroligin-3 has a central role in synaptic transmission by modulating the recruitment of AMPA receptors to postsynaptic sites at excitatory synapses.

Hypothalamic modulation of the arterial chemoreceptor reflex in the anaesthetized cat: role of the nucleus tractus solitarii.

PubMed Central

Silva-Carvalho, L; Dawid-Milner, M S; Goldsmith, G E; Spyer, K M

1995-01-01

1. There is evidence in the literature of a mutual facilitatory interaction between the arterial chemoreceptor reflex and the alerting stage of the defence reaction, particularly in relation to the patterning of cardiorespiratory activity. The present study has been designed to test the hypothesis that a portion of this interaction involves synaptic interactions within the nucleus tractus solitarii (NTS). 2. The study has involved an analysis of the effective interactions between the stimulation of the arterial chemoreceptors and the hypothalamic defence area (HDA) on the activity of NTS neurones recorded in anaesthetized, paralysed and artificially ventilated cats. 3. A group of eighteen NTS neurones was classified as chemosensitive, on the basis of displaying EPSPs on sinus nerve stimulation (SN) and their failure to show an excitatory response to baroreceptor stimulation. Thirteen of these neurones displayed pronounced excitatory responses to chemoreceptor stimulation. In sixteen of these neurones HDA stimulation elicited an EPSP; in four of these sixteen neurones this early EPSP was followed by an IPSP. In the remaining two (of 18) neurones HDA stimulation provoked no obvious synaptic response but facilitated the efficacy of both chemoreceptor inputs and SN stimulation. 4. Neurones shown to receive convergent inputs from the arterial chemoreceptors (and SN stimulation) and HDA, often displayed excitatory responses to stimulation of other peripheral inputs. Vagally evoked EPSPs were observed in nine neurones, SLN-evoked responses in seven neurones and aortic nerve-evoked EPSPs in three neurones. 5. The organization of these synaptic interactions is discussed and these data are used to explain the pattern of interaction between chemoreceptor, baroreceptor and HDA inputs within the NTS. Conclusions are drawn regarding the functional role of different classes of NTS neurone, based on the findings in this and the accompanying two papers. PMID:8544136

Chronic nicotine treatment differentially modifies acute nicotine and alcohol actions on GABA(A) and glutamate receptors in hippocampal brain slices.

PubMed

Proctor, William R; Dobelis, Peter; Moritz, Anna T; Wu, Peter H

2011-03-01

Tobacco and alcohol are often co-abused producing interactive effects in the brain. Although nicotine enhances memory while ethanol impairs it, variable cognitive changes have been reported from concomitant use. This study was designed to determine how nicotine and alcohol interact at synaptic sites to modulate neuronal processes. Acute effects of nicotine, ethanol, and both drugs on synaptic excitatory glutamatergic and inhibitory GABAergic transmission were measured using whole-cell recording in hippocampal CA1 pyramidal neurons from brain slices of mice on control or nicotine-containing diets. Acute nicotine (50 nM) enhanced both GABAergic and glutamatergic synaptic transmission; potentiated GABA(A) receptor currents via activation of α7* and α4β2* nAChRs, and increased N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor currents through α7* receptors. While ethanol (80 mM) also increased GABA(A) currents, it inhibited NMDA currents. Although ethanol had no effect on AMPA currents, it blocked nicotine-induced increases in NMDA and AMPA currents. Following chronic nicotine treatment, acute nicotine or ethanol did not affect NMDA currents, while the effects of GABAergic responses were not altered. Acute ethanol ingestion selectively attenuated nicotine enhancement of excitatory glutamatergic NMDA and AMPA receptor function, suggesting an overall reduction in excitatory output from the hippocampus. It also indicated that ethanol could decrease the beneficial effects of nicotine on memory performance. In addition, chronic nicotine treatment produced tolerance to the effects of nicotine and cross-tolerance to the effects of ethanol on glutamatergic activity, leading to a potential increase in the use of these drugs. British Journal of Pharmacology © 2011 The British Pharmacological Society. No claim to original US government works.

Presynaptic Regulation of Leptin in a Defined Lateral Hypothalamus-Ventral Tegmental Area Neurocircuitry Depends on Energy State.

PubMed

Liu, Jing-Jing; Bello, Nicholas T; Pang, Zhiping P

2017-12-06

Synaptic transmission controls brain activity and behaviors, including food intake. Leptin, an adipocyte-derived hormone, acts on neurons located in the lateral hypothalamic area (LHA) to maintain energy homeostasis and regulate food intake behavior. The specific synaptic mechanisms, cell types, and neural projections mediating this effect remain unclear. In male mice, using pathway-specific retrograde tracing, whole-cell patch-clamp recordings and post hoc cell type identification, we found that leptin reduces excitatory synaptic strength onto both melanin-concentrating hormone- and orexin-expressing neurons projecting from the LHA to the ventral tegmental area (VTA), which may affect dopamine signaling and motivation for feeding. A presynaptic mechanism mediated by distinct intracellular signaling mechanisms may account for this regulation by leptin. The regulatory effects of leptin depend on intact leptin receptor signaling. Interestingly, the synaptic regulatory function of leptin in the LHA-to-VTA neuronal pathway is highly sensitive to energy states: both energy deficiency (acute fasting) and excessive energy storage (high-fat diet-induced obesity) blunt the effect of leptin. These data revealed that leptin may regulate synaptic transmission in the LHA-to-VTA neurocircuitry in an inverted "U-shape" fashion dependent on plasma glucose levels and related to metabolic states. SIGNIFICANCE STATEMENT The lateral hypothalamic area (LHA) to ventral tegmental area (VTA) projection is an important neural pathway involved in balancing whole-body energy states and reward. We found that the excitatory synaptic inputs to both orexin- and melanin-concentrating hormone expressing LHA neurons projecting to the VTA were suppressed by leptin, a peptide hormone derived from adipocytes that signals peripheral energy status to the brain. Interestingly, energy states seem to affect how leptin regulates synaptic transmission since both the depletion of energy induced by acute food deprivation and excessive storage of energy by high-fat diet feeding dampen the suppressive effect of leptin on synaptic transmission. Together, these data show that leptin regulates synaptic transmission and might be important for maintaining energy homeostasis. Copyright © 2017 the authors 0270-6474/17/3711854-13$15.00/0.

A Realistic Neural Mass Model of the Cortex with Laminar-Specific Connections and Synaptic Plasticity – Evaluation with Auditory Habituation

PubMed Central

Wang, Peng; Knösche, Thomas R.

2013-01-01

In this work we propose a biologically realistic local cortical circuit model (LCCM), based on neural masses, that incorporates important aspects of the functional organization of the brain that have not been covered by previous models: (1) activity dependent plasticity of excitatory synaptic couplings via depleting and recycling of neurotransmitters and (2) realistic inter-laminar dynamics via laminar-specific distribution of and connections between neural populations. The potential of the LCCM was demonstrated by accounting for the process of auditory habituation. The model parameters were specified using Bayesian inference. It was found that: (1) besides the major serial excitatory information pathway (layer 4 to layer 2/3 to layer 5/6), there exists a parallel “short-cut” pathway (layer 4 to layer 5/6), (2) the excitatory signal flow from the pyramidal cells to the inhibitory interneurons seems to be more intra-laminar while, in contrast, the inhibitory signal flow from inhibitory interneurons to the pyramidal cells seems to be both intra- and inter-laminar, and (3) the habituation rates of the connections are unsymmetrical: forward connections (from layer 4 to layer 2/3) are more strongly habituated than backward connections (from Layer 5/6 to layer 4). Our evaluation demonstrates that the novel features of the LCCM are of crucial importance for mechanistic explanations of brain function. The incorporation of these features into a mass model makes them applicable to modeling based on macroscopic data (like EEG or MEG), which are usually available in human experiments. Our LCCM is therefore a valuable building block for future realistic models of human cognitive function. PMID:24205009

Actions of (-)-baclofen on rat dorsal horn neurons.

PubMed

Kangrga, I; Jiang, M C; Randić, M

1991-10-25

The actions of a gamma-aminobutyric acid B (GABAB) agonist, (-)-baclofen, on the electrophysiological properties of neurons and synaptic transmission in the spinal dorsal horn (laminae I-IV) were examined by using intracellular recordings in spinal cord slice from young rats. In addition, the effects of baclofen on the dorsal root stimulation-evoked outflow of glutamate and aspartate from the spinal dorsal horn were examined by using high performance liquid chromatography (HPLC) with flourimetric detection. Superfusion of baclofen (5 nM to 10 microM) hyperpolarized, in a stereoselective and bicuculline-insensitive manner, the majority (86%) of tested neurons. The hyperpolarization was associated with a decrease in membrane resistance and persisted in a nominally zero-Ca2+, 10 mM Mg(2+)- or a TTX-containing solution. Our findings indicate that the hyperpolarizing effect of baclofen is probably due to an increase in conductance to potassium ions. Baclofen decreased the direct excitability of dorsal horn neurons, enhanced accommodation of spike discharge, and reduced the duration of Ca(2+)-dependent action potentials. Baclofen depressed, or blocked, excitatory postsynaptic potentials evoked by electrical stimulation of the dorsal roots. Spontaneously occurring synaptic potentials were also reversibly depressed by baclofen. Whereas baclofen did not produce any consistent change in the rate of the basal outflow of glutamate and aspartate, the stimulation-evoked release of the amino acids was blocked. The present results suggest that baclofen, by activating GABAB receptors, may modulate spinal afferent processing in the superficial dorsal horn by at least two mechanisms: (1) baclofen depresses excitatory synaptic transmission primarily by a presynaptic mechanism involving a decrease in the release of excitatory amino acids, and (2) at higher concentrations, the hyperpolarization and increased membrane conductance may contribute to the depressant effect of baclofen on excitatory synaptic transmission in the rat spinal dorsal horn.

Aniracetam reduces glutamate receptor desensitization and slows the decay of fast excitatory synaptic currents in the hippocampus.

PubMed Central

Isaacson, J S; Nicoll, R A

1991-01-01

Aniracetam is a nootropic drug that has been shown to selectively enhance quisqualate receptor-mediated responses in Xenopus oocytes injected with brain mRNA and in hippocampal pyramidal cells [Ito, I., Tanabe, S., Kohda, A. & Sugiyama, H. (1990) J. Physiol. (London) 424, 533-544]. We have used patch clamp recording techniques in hippocampal slices to elucidate the mechanism for this selective action. We find that aniracetam enhances glutamate-evoked currents in whole-cell recordings and, in outside-out patches, strongly reduces glutamate receptor desensitization. In addition, aniracetam selectively prolongs the time course and increases the peak amplitude of fast synaptic currents. These findings indicate that aniracetam slows the kinetics of fast synaptic transmission and are consistent with the proposal [Trussell, L. O. & Fischbach, G. D. (1989) Neuron 3, 209-218; Tang, C.-M., Dichter, M. & Morad, M. (1989) Science 243, 1474-1477] that receptor desensitization governs the strength of fast excitatory synaptic transmission in the brain. PMID:1660156

Aniracetam reduces glutamate receptor desensitization and slows the decay of fast excitatory synaptic currents in the hippocampus.

PubMed

Isaacson, J S; Nicoll, R A

1991-12-01

Aniracetam is a nootropic drug that has been shown to selectively enhance quisqualate receptor-mediated responses in Xenopus oocytes injected with brain mRNA and in hippocampal pyramidal cells [Ito, I., Tanabe, S., Kohda, A. & Sugiyama, H. (1990) J. Physiol. (London) 424, 533-544]. We have used patch clamp recording techniques in hippocampal slices to elucidate the mechanism for this selective action. We find that aniracetam enhances glutamate-evoked currents in whole-cell recordings and, in outside-out patches, strongly reduces glutamate receptor desensitization. In addition, aniracetam selectively prolongs the time course and increases the peak amplitude of fast synaptic currents. These findings indicate that aniracetam slows the kinetics of fast synaptic transmission and are consistent with the proposal [Trussell, L. O. & Fischbach, G. D. (1989) Neuron 3, 209-218; Tang, C.-M., Dichter, M. & Morad, M. (1989) Science 243, 1474-1477] that receptor desensitization governs the strength of fast excitatory synaptic transmission in the brain.

Slack KNa Channels Influence Dorsal Horn Synapses and Nociceptive Behavior.

PubMed

Evely, Katherine M; Pryce, Kerri D; Bausch, Anne E; Lukowski, Robert; Ruth, Peter; Haj-Dahmane, Samir; Bhattacharjee, Arin

2017-01-01

The sodium-activated potassium channel Slack (Kcnt1, Slo2.2) is highly expressed in dorsal root ganglion neurons where it regulates neuronal firing. Several studies have implicated the Slack channel in pain processing, but the precise mechanism or the levels within the sensory pathway where channels are involved remain unclear. Here, we furthered the behavioral characterization of Slack channel knockout mice and for the first time examined the role of Slack channels in the superficial, pain-processing lamina of the dorsal horn. We performed whole-cell recordings from spinal cord slices to examine the intrinsic and synaptic properties of putative inhibitory and excitatory lamina II interneurons. Slack channel deletion altered intrinsic properties and synaptic drive to favor an overall enhanced excitatory tone. We measured the amplitudes and paired pulse ratio of paired excitatory post-synaptic currents at primary afferent synapses evoked by electrical stimulation of the dorsal root entry zone. We found a substantial decrease in the paired pulse ratio at synapses in Slack deleted neurons compared to wildtype, indicating increased presynaptic release from primary afferents. Corroborating these data, plantar test showed Slack knockout mice have an enhanced nociceptive responsiveness to localized thermal stimuli compared to wildtype mice. Our findings suggest that Slack channels regulate synaptic transmission within the spinal cord dorsal horn and by doing so establishes the threshold for thermal nociception.

Comparison of the dynamics of neural interactions between current-based and conductance-based integrate-and-fire recurrent networks

PubMed Central

Cavallari, Stefano; Panzeri, Stefano; Mazzoni, Alberto

2014-01-01

Models of networks of Leaky Integrate-and-Fire (LIF) neurons are a widely used tool for theoretical investigations of brain function. These models have been used both with current- and conductance-based synapses. However, the differences in the dynamics expressed by these two approaches have been so far mainly studied at the single neuron level. To investigate how these synaptic models affect network activity, we compared the single neuron and neural population dynamics of conductance-based networks (COBNs) and current-based networks (CUBNs) of LIF neurons. These networks were endowed with sparse excitatory and inhibitory recurrent connections, and were tested in conditions including both low- and high-conductance states. We developed a novel procedure to obtain comparable networks by properly tuning the synaptic parameters not shared by the models. The so defined comparable networks displayed an excellent and robust match of first order statistics (average single neuron firing rates and average frequency spectrum of network activity). However, these comparable networks showed profound differences in the second order statistics of neural population interactions and in the modulation of these properties by external inputs. The correlation between inhibitory and excitatory synaptic currents and the cross-neuron correlation between synaptic inputs, membrane potentials and spike trains were stronger and more stimulus-modulated in the COBN. Because of these properties, the spike train correlation carried more information about the strength of the input in the COBN, although the firing rates were equally informative in both network models. Moreover, the network activity of COBN showed stronger synchronization in the gamma band, and spectral information about the input higher and spread over a broader range of frequencies. These results suggest that the second order statistics of network dynamics depend strongly on the choice of synaptic model. PMID:24634645

Comparison of the dynamics of neural interactions between current-based and conductance-based integrate-and-fire recurrent networks.

PubMed

Cavallari, Stefano; Panzeri, Stefano; Mazzoni, Alberto

2014-01-01

Models of networks of Leaky Integrate-and-Fire (LIF) neurons are a widely used tool for theoretical investigations of brain function. These models have been used both with current- and conductance-based synapses. However, the differences in the dynamics expressed by these two approaches have been so far mainly studied at the single neuron level. To investigate how these synaptic models affect network activity, we compared the single neuron and neural population dynamics of conductance-based networks (COBNs) and current-based networks (CUBNs) of LIF neurons. These networks were endowed with sparse excitatory and inhibitory recurrent connections, and were tested in conditions including both low- and high-conductance states. We developed a novel procedure to obtain comparable networks by properly tuning the synaptic parameters not shared by the models. The so defined comparable networks displayed an excellent and robust match of first order statistics (average single neuron firing rates and average frequency spectrum of network activity). However, these comparable networks showed profound differences in the second order statistics of neural population interactions and in the modulation of these properties by external inputs. The correlation between inhibitory and excitatory synaptic currents and the cross-neuron correlation between synaptic inputs, membrane potentials and spike trains were stronger and more stimulus-modulated in the COBN. Because of these properties, the spike train correlation carried more information about the strength of the input in the COBN, although the firing rates were equally informative in both network models. Moreover, the network activity of COBN showed stronger synchronization in the gamma band, and spectral information about the input higher and spread over a broader range of frequencies. These results suggest that the second order statistics of network dynamics depend strongly on the choice of synaptic model.

ATM and ATR play complementary roles in the behavior of excitatory and inhibitory vesicle populations.

PubMed

Cheng, Aifang; Zhao, Teng; Tse, Kai-Hei; Chow, Hei-Man; Cui, Yong; Jiang, Liwen; Du, Shengwang; Loy, Michael M T; Herrup, Karl

2018-01-09

ATM (ataxia-telangiectasia mutated) and ATR (ATM and Rad3-related) are large PI3 kinases whose human mutations result in complex syndromes that include a compromised DNA damage response (DDR) and prominent nervous system phenotypes. Both proteins are nuclear-localized in keeping with their DDR functions, yet both are also found in cytoplasm, including on neuronal synaptic vesicles. In ATM- or ATR-deficient neurons, spontaneous vesicle release is reduced, but a drop in ATM or ATR level also slows FM4-64 dye uptake. In keeping with this, both proteins bind to AP-2 complex components as well as to clathrin, suggesting roles in endocytosis and vesicle recycling. The two proteins play complementary roles in the DDR; ATM is engaged in the repair of double-strand breaks, while ATR deals mainly with single-strand damage. Unexpectedly, this complementarity extends to these proteins' synaptic function as well. Superresolution microscopy and coimmunoprecipitation reveal that ATM associates exclusively with excitatory (VGLUT1 + ) vesicles, while ATR associates only with inhibitory (VGAT + ) vesicles. The levels of ATM and ATR respond to each other; when ATM is deficient, ATR levels rise, and vice versa. Finally, blocking NMDA, but not GABA, receptors causes ATM levels to rise while ATR levels respond to GABA, but not NMDA, receptor blockade. Taken together, our data suggest that ATM and ATR are part of the cellular "infrastructure" that maintains the excitatory/inhibitory balance of the nervous system. This idea has important implications for the human diseases resulting from their genetic deficiency.

Functional contributions of glutamate transporters at the parallel fibre to Purkinje neuron synapse-relevance for the progression of cerebellar ataxia.

PubMed

Power, Emmet M; Empson, Ruth M

2014-01-01

Rapid uptake of glutamate by neuronal and glial glutamate transporters (EAATs, a family of excitatory amino acid transporters) is critical for shaping synaptic responses and for preventing excitotoxicity. Two of these transporters, EAAT4 in Purkinje neurons (PN) and EAAT1 in Bergmann glia are both enriched within the cerebellum and altered in a variety of human ataxias. PN excitatory synaptic responses and firing behaviour following high frequency parallel fibre (PF) activity commonly encountered during sensory stimulation in vivo were adversely influenced by acute inhibition of glutamate transporters. In the presence of a non-transportable blocker of glutamate transporters we observed very large amplitude and duration excitatory postsynaptic currents accompanied by excessive firing of the PNs. A combination of AMPA and mGluR1, but not NMDA, type glutamate receptor activation powered the hyper-excitable PN state. The enhanced PN excitability also recruited a presynaptic mGluR4 dependent mechanism that modified short term plasticity at the PF synapse. Our findings indicate that reduced glutamate transporter activity, as occurs in the early stages of some forms of human cerebellar ataxias, excessively excites PNs and disrupts the timing of their output. Our findings raise the possibility that sustaining cerebellar glutamate uptake may provide a therapeutic approach to prevent this disruption and the glutamate excitotoxicity-induced PN death that signals the end point of the disease.

Retinal input to efferent target amacrine cells in the avian retina

PubMed Central

Lindstrom, Sarah H.; Azizi, Nason; Weller, Cynthia; Wilson, Martin

2012-01-01

The bird visual system includes a substantial projection, of unknown function, from a midbrain nucleus to the contralateral retina. Every centrifugal, or efferent, neuron originating in the midbrain nucleus makes synaptic contact with the soma of a single, unique amacrine cell, the target cell (TC). By labeling efferent neurons in the midbrain we have been able to identify their terminals in retinal slices and make patch clamp recordings from TCs. TCs generate Na+ based action potentials triggered by spontaneous EPSPs originating from multiple classes of presynaptic neurons. Exogenously applied glutamate elicited inward currents having the mixed pharmacology of NMDA, kainate and inward rectifying AMPA receptors. Exogenously applied GABA elicited currents entirely suppressed by GABAzine, and therefore mediated by GABAA receptors. Immunohistochemistry showed the vesicular glutamate transporter, vGluT2, to be present in the characteristic synaptic boutons of efferent terminals, whereas the GABA synthetic enzyme, GAD, was present in much smaller processes of intrinsic retinal neurons. Extracellular recording showed that exogenously applied GABA was directly excitatory to TCs and, consistent with this, NKCC, the Cl− transporter often associated with excitatory GABAergic synapses, was identified in TCs by antibody staining. The presence of excitatory retinal input to TCs implies that TCs are not merely slaves to their midbrain input; instead, their output reflects local retinal activity and descending input from the midbrain. PMID:20650017

Distinct Roles of NMDAR and mGluR5 in Light Exposure Reversal of Feedforward Synaptic Strength in V1 of Juvenile Mice after Binocular Vision Deprivation.

PubMed

Tie, Xiaoxiu; Li, Shuo; Feng, Yilin; Lai, Biqin; Liu, Sheng; Jiang, Bin

2018-06-01

In the visual cortex, sensory deprivation causes global augmentation of the amplitude of AMPA receptor-mediated miniature EPSCs in layer 2/3 pyramidal cells and enhancement of NMDA receptor-dependent long-term potentiation (LTP) in cells activated in layer 4, effects that are both rapidly reversed by light exposure. Layer 2/3 pyramidal cells receive both feedforward input from layer 4 and intra-cortical lateral input from the same layer, LTP is mainly induced by the former input. Whether feedforward excitatory synaptic strength is affected by visual deprivation and light exposure, how this synaptic strength correlates with the magnitude of LTP in this pathway, and the underlying mechanism have not been explored. Here, we showed that in juvenile mice, both dark rearing and dark exposure reduced the feedforward excitatory synaptic strength, and the effects can be reversed completely by 10-12 h and 6-8 h light exposure, respectively. However, inhibition of NMDA receptors by CPP or mGluR5 by MPEP, prevented the effect of light exposure on the mice reared in the dark from birth, while only inhibition of NMDAR prevented the effect of light exposure on dark-exposed mice. These results suggested that the activation of both NMDAR and mGluR5 are essential in the light exposure reversal of feedforward excitatory synaptic strength in the dark reared mice from birth; while in the dark exposed mice, only activation of NMDAR is required. Copyright © 2018. Published by Elsevier Ltd.

Running reorganizes the circuitry of one-week-old adult-born hippocampal neurons.

PubMed

Sah, Nirnath; Peterson, Benjamin D; Lubejko, Susan T; Vivar, Carmen; van Praag, Henriette

2017-09-07

Adult hippocampal neurogenesis is an important form of structural and functional plasticity in the mature mammalian brain. The existing consensus is that GABA regulates the initial integration of adult-born neurons, similar to neuronal development during embryogenesis. Surprisingly, virus-based anatomical tracing revealed that very young, one-week-old, new granule cells in male C57Bl/6 mice receive input not only from GABAergic interneurons, but also from multiple glutamatergic cell types, including mature dentate granule cells, area CA1-3 pyramidal cells and mossy cells. Consistently, patch-clamp recordings from retrovirally labeled new granule cells at 7-8 days post retroviral injection (dpi) show that these cells respond to NMDA application with tonic currents, and that both electrical and optogenetic stimulation can evoke NMDA-mediated synaptic responses. Furthermore, new dentate granule cell number, morphology and excitatory synaptic inputs at 7 dpi are modified by voluntary wheel running. Overall, glutamatergic and GABAergic innervation of newly born neurons in the adult hippocampus develops concurrently, and excitatory input is reorganized by exercise.

Selective Localization of Shanks to VGLUT1-Positive Excitatory Synapses in the Mouse Hippocampus

PubMed Central

Heise, Christopher; Schroeder, Jan C.; Schoen, Michael; Halbedl, Sonja; Reim, Dominik; Woelfle, Sarah; Kreutz, Michael R.; Schmeisser, Michael J.; Boeckers, Tobias M.

2016-01-01

Members of the Shank family of multidomain proteins (Shank1, Shank2, and Shank3) are core components of the postsynaptic density (PSD) of excitatory synapses. At synaptic sites Shanks serve as scaffolding molecules that cluster neurotransmitter receptors as well as cell adhesion molecules attaching them to the actin cytoskeleton. In this study we investigated the synapse specific localization of Shank1-3 and focused on well-defined synaptic contacts within the hippocampal formation. We found that all three family members are present only at VGLUT1-positive synapses, which is particularly visible at mossy fiber contacts. No costaining was found at VGLUT2-positive contacts indicating that the molecular organization of VGLUT2-associated PSDs diverges from classical VGLUT1-positive excitatory contacts in the hippocampus. In light of SHANK mutations in neuropsychiatric disorders, this study indicates which glutamatergic networks within the hippocampus will be primarily affected by shankopathies. PMID:27199660

Selective Localization of Shanks to VGLUT1-Positive Excitatory Synapses in the Mouse Hippocampus.

PubMed

Heise, Christopher; Schroeder, Jan C; Schoen, Michael; Halbedl, Sonja; Reim, Dominik; Woelfle, Sarah; Kreutz, Michael R; Schmeisser, Michael J; Boeckers, Tobias M

2016-01-01

Members of the Shank family of multidomain proteins (Shank1, Shank2, and Shank3) are core components of the postsynaptic density (PSD) of excitatory synapses. At synaptic sites Shanks serve as scaffolding molecules that cluster neurotransmitter receptors as well as cell adhesion molecules attaching them to the actin cytoskeleton. In this study we investigated the synapse specific localization of Shank1-3 and focused on well-defined synaptic contacts within the hippocampal formation. We found that all three family members are present only at VGLUT1-positive synapses, which is particularly visible at mossy fiber contacts. No costaining was found at VGLUT2-positive contacts indicating that the molecular organization of VGLUT2-associated PSDs diverges from classical VGLUT1-positive excitatory contacts in the hippocampus. In light of SHANK mutations in neuropsychiatric disorders, this study indicates which glutamatergic networks within the hippocampus will be primarily affected by shankopathies.

Transition to Chaos in Random Neuronal Networks

NASA Astrophysics Data System (ADS)

Kadmon, Jonathan; Sompolinsky, Haim

2015-10-01

Firing patterns in the central nervous system often exhibit strong temporal irregularity and considerable heterogeneity in time-averaged response properties. Previous studies suggested that these properties are the outcome of the intrinsic chaotic dynamics of the neural circuits. Indeed, simplified rate-based neuronal networks with synaptic connections drawn from Gaussian distribution and sigmoidal nonlinearity are known to exhibit chaotic dynamics when the synaptic gain (i.e., connection variance) is sufficiently large. In the limit of an infinitely large network, there is a sharp transition from a fixed point to chaos, as the synaptic gain reaches a critical value. Near the onset, chaotic fluctuations are slow, analogous to the ubiquitous, slow irregular fluctuations observed in the firing rates of many cortical circuits. However, the existence of a transition from a fixed point to chaos in neuronal circuit models with more realistic architectures and firing dynamics has not been established. In this work, we investigate rate-based dynamics of neuronal circuits composed of several subpopulations with randomly diluted connections. Nonzero connections are either positive for excitatory neurons or negative for inhibitory ones, while single neuron output is strictly positive with output rates rising as a power law above threshold, in line with known constraints in many biological systems. Using dynamic mean field theory, we find the phase diagram depicting the regimes of stable fixed-point, unstable-dynamic, and chaotic-rate fluctuations. We focus on the latter and characterize the properties of systems near this transition. We show that dilute excitatory-inhibitory architectures exhibit the same onset to chaos as the single population with Gaussian connectivity. In these architectures, the large mean excitatory and inhibitory inputs dynamically balance each other, amplifying the effect of the residual fluctuations. Importantly, the existence of a transition to chaos and its critical properties depend on the shape of the single-neuron nonlinear input-output transfer function, near firing threshold. In particular, for nonlinear transfer functions with a sharp rise near threshold, the transition to chaos disappears in the limit of a large network; instead, the system exhibits chaotic fluctuations even for small synaptic gain. Finally, we investigate transition to chaos in network models with spiking dynamics. We show that when synaptic time constants are slow relative to the mean inverse firing rates, the network undergoes a transition from fast spiking fluctuations with constant rates to a state where the firing rates exhibit chaotic fluctuations, similar to the transition predicted by rate-based dynamics. Systems with finite synaptic time constants and firing rates exhibit a smooth transition from a regime dominated by stationary firing rates to a regime of slow rate fluctuations. This smooth crossover obeys scaling properties, similar to crossover phenomena in statistical mechanics. The theoretical results are supported by computer simulations of several neuronal architectures and dynamics. Consequences for cortical circuit dynamics are discussed. These results advance our understanding of the properties of intrinsic dynamics in realistic neuronal networks and their functional consequences.

Regulation of glutamate receptor internalization by the spine cytoskeleton is mediated by its PKA-dependent association with CPG2

PubMed Central

Loebrich, Sven; Djukic, Biljana; Tong, Zachary J.; Cottrell, Jeffrey R.; Turrigiano, Gina G.; Nedivi, Elly

2013-01-01

A key neuronal mechanism for adjusting excitatory synaptic strength is clathrin-mediated endocytosis of postsynaptic glutamate receptors (GluRs). The actin cytoskeleton is critical for clathrin-mediated endocytosis, yet we lack a mechanistic understanding of its interaction with the endocytic process and how it may be regulated. Here we show that F-actin in dendritic spines physically binds the synaptic nuclear envelope 1 gene product candidate plasticity gene 2 (CPG2) in a PKA-dependent manner, and that this association is required for synaptic GluR internalization. Mutating two PKA sites on CPG2 disrupts its cytoskeletal association, attenuating GluR endocytosis and affecting the efficacy of synaptic transmission in vivo. These results identify CPG2 as an F-actin binding partner that functionally mediates interaction of the spine cytoskeleton with postsynaptic endocytosis. Further, the regulation of CPG2/F-actin association by PKA provides a gateway for cellular control of synaptic receptor internalization through second messenger signaling pathways. Recent identification of human synaptic nuclear envelope 1 as a risk locus for bipolar disorder suggests that CPG2 could play a role in synaptic dysfunction underlying neuropsychiatric disease. PMID:24191017

Maturation- and sex-sensitive depression of hippocampal excitatory transmission in a rat schizophrenia model.

PubMed

Patrich, Eti; Piontkewitz, Yael; Peretz, Asher; Weiner, Ina; Attali, Bernard

2016-01-01

Schizophrenia is associated with behavioral and brain structural abnormalities, of which the hippocampus appears to be one of the most consistent region affected. Previous studies performed on the poly I:C model of schizophrenia suggest that alterations in hippocampal synaptic transmission and plasticity take place in the offspring. However, these investigations yielded conflicting results and the neurophysiological alterations responsible for these deficits are still unclear. Here we performed for the first time a longitudinal study examining the impact of prenatal poly I:C treatment and of gender on hippocampal excitatory neurotransmission. In addition, we examined the potential preventive/curative effects of risperidone (RIS) treatment during the peri-adolescence period. Excitatory synaptic transmission was determined by stimulating Schaffer collaterals and monitoring fiber volley amplitude and slope of field-EPSP (fEPSP) in CA1 pyramidal neurons in male and female offspring hippocampal slices from postnatal days (PNDs) 18-20, 34, 70 and 90. Depression of hippocampal excitatory transmission appeared at juvenile age in male offspring of the poly I:C group, while it expressed with a delay in female, manifesting at adulthood. In addition, a reduced hippocampal size was found in both adult male and female offspring of poly I:C treated dams. Treatment with RIS at the peri-adolescence period fully restored in males but partly repaired in females these deficiencies. A maturation- and sex-dependent decrease in hippocampal excitatory transmission occurs in the offspring of poly I:C treated pregnant mothers. Pharmacological intervention with RIS during peri-adolescence can cure in a gender-sensitive fashion early occurring hippocampal synaptic deficits. Copyright © 2015 Elsevier Inc. All rights reserved.

Norepinephrine versus dopamine and their interaction in modulating synaptic function in the prefrontal cortex.

PubMed

Xing, Bo; Li, Yan-Chun; Gao, Wen-Jun

2016-06-15

Among the neuromodulators that regulate prefrontal cortical circuit function, the catecholamine transmitters norepinephrine (NE) and dopamine (DA) stand out as powerful players in working memory and attention. Perturbation of either NE or DA signaling is implicated in the pathogenesis of several neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), schizophrenia, and drug addiction. Although the precise mechanisms employed by NE and DA to cooperatively control prefrontal functions are not fully understood, emerging research indicates that both transmitters regulate electrical and biochemical aspects of neuronal function by modulating convergent ionic and synaptic signaling in the prefrontal cortex (PFC). This review summarizes previous studies that investigated the effects of both NE and DA on excitatory and inhibitory transmissions in the prefrontal cortical circuitry. Specifically, we focus on the functional interaction between NE and DA in prefrontal cortical local circuitry, synaptic integration, signaling pathways, and receptor properties. Although it is clear that both NE and DA innervate the PFC extensively and modulate synaptic function by activating distinctly different receptor subtypes and signaling pathways, it remains unclear how these two systems coordinate their actions to optimize PFC function for appropriate behavior. Throughout this review, we provide perspectives and highlight several critical topics for future studies. This article is part of a Special Issue entitled SI: Noradrenergic System. Copyright © 2016 Elsevier B.V. All rights reserved.

Aberrant excitatory rewiring of layer V pyramidal neurons early after neocortical trauma

PubMed Central

Takahashi, D. Koji; Isabel, Feng Gu; Parada, Shri Vyas; Prince, David A.

2016-01-01

Lesioned neuronal circuits form new functional connections after a traumatic brain injury (TBI). In humans and animal models, aberrant excitatory connections that form after TBI may contribute to the pathogenesis of post-traumatic epilepsy. Partial neocortical isolation (“undercut” or “UC”) leads to altered neuronal circuitry and network hyperexcitability recorded in vivo and in brain slices from chronically lesioned neocortex. Recent data suggest a critical period for maladaptive excitatory circuit formation within the first 3 days post UC injury (Graber and Prince, 1999, 2004; Li et al., 2011, 2012b). The present study focuses on alterations in excitatory connectivity within this critical period. Immunoreactivity (IR) for growth-associated protein (GAP)-43 was increased in the UC cortex 3 days after injury. Some GAP-43-expressing excitatory terminals targeted the somata of layer V pyramidal (Pyr) neurons, a domain usually innervated predominantly by inhibitory terminals. Immunocytochemical analysis of pre- and postsynaptic markers showed that putative excitatory synapses were present on somata of these neurons in UC neocortex. Excitatory postsynaptic currents from UC layer V Pyr cells displayed properties consistent with perisomatic inputs and also reflected an increase in the number of synaptic contacts. Laser scanning photostimulation (LSPS) experiments demonstrated reorganized excitatory connectivity after injury within the UC. Concurrent with these changes, spontaneous epileptiform bursts developed in UC slices. Results suggest that aberrant reorganization of excitatory connectivity contributes to early neocortical hyperexcitability in this model. The findings are relevant for understanding the pathophysiology of neocortical post-traumatic epileptogenesis and are important in terms of the timing of potential prophylactic treatments. PMID:26956396

Aberrant excitatory rewiring of layer V pyramidal neurons early after neocortical trauma.

PubMed

Takahashi, D Koji; Gu, Feng; Parada, Isabel; Vyas, Shri; Prince, David A

2016-07-01

Lesioned neuronal circuits form new functional connections after a traumatic brain injury (TBI). In humans and animal models, aberrant excitatory connections that form after TBI may contribute to the pathogenesis of post-traumatic epilepsy. Partial neocortical isolation ("undercut" or "UC") leads to altered neuronal circuitry and network hyperexcitability recorded in vivo and in brain slices from chronically lesioned neocortex. Recent data suggest a critical period for maladaptive excitatory circuit formation within the first 3days post UC injury (Graber and Prince 1999, 2004; Li et al. 2011, 2012b). The present study focuses on alterations in excitatory connectivity within this critical period. Immunoreactivity (IR) for growth-associated protein (GAP)-43 was increased in the UC cortex 3days after injury. Some GAP-43-expressing excitatory terminals targeted the somata of layer V pyramidal (Pyr) neurons, a domain usually innervated predominantly by inhibitory terminals. Immunocytochemical analysis of pre- and postsynaptic markers showed that putative excitatory synapses were present on somata of these neurons in UC neocortex. Excitatory postsynaptic currents from UC layer V Pyr cells displayed properties consistent with perisomatic inputs and also reflected an increase in the number of synaptic contacts. Laser scanning photostimulation (LSPS) experiments demonstrated reorganized excitatory connectivity after injury within the UC. Concurrent with these changes, spontaneous epileptiform bursts developed in UC slices. Results suggest that aberrant reorganization of excitatory connectivity contributes to early neocortical hyperexcitability in this model. The findings are relevant for understanding the pathophysiology of neocortical post-traumatic epileptogenesis and are important in terms of the timing of potential prophylactic treatments. Copyright © 2016 Elsevier Inc. All rights reserved.

Enhanced Excitatory Connectivity and Disturbed Sound Processing in the Auditory Brainstem of Fragile X Mice.

PubMed

Garcia-Pino, Elisabet; Gessele, Nikodemus; Koch, Ursula

2017-08-02

Hypersensitivity to sounds is one of the prevalent symptoms in individuals with Fragile X syndrome (FXS). It manifests behaviorally early during development and is often used as a landmark for treatment efficacy. However, the physiological mechanisms and circuit-level alterations underlying this aberrant behavior remain poorly understood. Using the mouse model of FXS ( Fmr1 KO ), we demonstrate that functional maturation of auditory brainstem synapses is impaired in FXS. Fmr1 KO mice showed a greatly enhanced excitatory synaptic input strength in neurons of the lateral superior olive (LSO), a prominent auditory brainstem nucleus, which integrates ipsilateral excitation and contralateral inhibition to compute interaural level differences. Conversely, the glycinergic, inhibitory input properties remained unaffected. The enhanced excitation was the result of an increased number of cochlear nucleus fibers converging onto one LSO neuron, without changing individual synapse properties. Concomitantly, immunolabeling of excitatory ending markers revealed an increase in the immunolabeled area, supporting abnormally elevated excitatory input numbers. Intrinsic firing properties were only slightly enhanced. In line with the disturbed development of LSO circuitry, auditory processing was also affected in adult Fmr1 KO mice as shown with single-unit recordings of LSO neurons. These processing deficits manifested as an increase in firing rate, a broadening of the frequency response area, and a shift in the interaural level difference function of LSO neurons. Our results suggest that this aberrant synaptic development of auditory brainstem circuits might be a major underlying cause of the auditory processing deficits in FXS. SIGNIFICANCE STATEMENT Fragile X Syndrome (FXS) is the most common inheritable form of intellectual impairment, including autism. A core symptom of FXS is extreme sensitivity to loud sounds. This is one reason why individuals with FXS tend to avoid social interactions, contributing to their isolation. Here, a mouse model of FXS was used to investigate the auditory brainstem where basic sound information is first processed. Loss of the Fragile X mental retardation protein leads to excessive excitatory compared with inhibitory inputs in neurons extracting information about sound levels. Functionally, this elevated excitation results in increased firing rates, and abnormal coding of frequency and binaural sound localization cues. Imbalanced early-stage sound level processing could partially explain the auditory processing deficits in FXS. Copyright © 2017 the authors 0270-6474/17/377403-17$15.00/0.

HCN1 channels in cerebellar Purkinje cells promote late stages of learning and constrain synaptic inhibition

PubMed Central

Rinaldi, Arianna; Defterali, Cagla; Mialot, Antoine; Garden, Derek L F; Beraneck, Mathieu; Nolan, Matthew F

2013-01-01

Neural computations rely on ion channels that modify neuronal responses to synaptic inputs. While single cell recordings suggest diverse and neurone type-specific computational functions for HCN1 channels, their behavioural roles in any single neurone type are not clear. Using a battery of behavioural assays, including analysis of motor learning in vestibulo-ocular reflex and rotarod tests, we find that deletion of HCN1 channels from cerebellar Purkinje cells selectively impairs late stages of motor learning. Because deletion of HCN1 modifies only a subset of behaviours involving Purkinje cells, we asked whether the channel also has functional specificity at a cellular level. We find that HCN1 channels in cerebellar Purkinje cells reduce the duration of inhibitory synaptic responses but, in the absence of membrane hyperpolarization, do not affect responses to excitatory inputs. Our results indicate that manipulation of subthreshold computation in a single neurone type causes specific modifications to behaviour. PMID:24000178

Dnmt1 and Dnmt3a are required for the maintenance of DNA methylation and synaptic function in adult forebrain neurons

PubMed Central

Feng, Jian; Zhou, Yu; Campbell, Susan L.; Le, Thuc; Li, En; Sweatt, J. David; Silva, Alcino J.; Fan, Guoping

2011-01-01

Dnmt1 and Dnmt3a, two major DNA methyltransferases, are expressed in postmitotic neurons, but their function in the central nervous system (CNS) is unclear. We generated conditional mutant mice that lack either Dnmt1, or Dnmt3a, or both exclusively in forebrain excitatory neurons and found only double knockout (DKO) mice exhibited abnormal hippocampal CA1 long-term plasticity and deficits of learning and memory. While no neuronal loss was found, the size of hippocampal neurons in DKO was smaller; furthermore, DKO neurons showed a deregulation of gene expression including class I MHC and Stat1 that are known to play a role in synaptic plasticity. In addition, we observed a significant decrease in DNA methylation in DKO neurons. We conclude that Dnmt1 and Dnmt3a are required for synaptic plasticity, learning and memory through their overlapping roles in maintaining DNA methylation and modulating neuronal gene expression in adult CNS neurons. PMID:20228804

Artificial neuron synapse transistor based on silicon nanomembrane on plastic substrate

NASA Astrophysics Data System (ADS)

Liu, Minjie; Huang, Gaoshan; Feng, Ping; Guo, Qinglei; Shao, Feng; Tian, Ziao; Li, Gongjin; Wan, Qing; Mei, Yongfeng

2017-06-01

Silicon nanomembrane (SiNM) transistors gated by chitosan membrane were fabricated on plastic substrate to mimic synapse behaviors. The device has both a bottom proton gate (BG) and multiple side gates (SG). Electrical transfer properties of BG show hysteresis curves different from those of typical SiO2 gate dielectric. Synaptic behaviors and functions by linear accumulation and release of protons have been mimicked on this device: excitatory post-synaptic current (EPSC) and paired pulse facilitation behavior of biological synapses were mimicked and the paired-pulse facilitation index could be effectively tuned by the spike interval applied on the BG. Synaptic behaviors and functions, including short-term memory and long-term memory, were also experimentally demonstrated in BG mode. Meanwhile, spiking logic operation and logic modulation were realized in SG mode. Project supported by the National Natural Science Foundation of China (No. 51322201), the Specialized Research Fund for the Doctoral Program of Higher Education (No. 20120071110025), and Science and Technology Commission of Shanghai Municipality (No. 14JC1400200).

Delayed excitatory and inhibitory feedback shape neural information transmission

NASA Astrophysics Data System (ADS)

Chacron, Maurice J.; Longtin, André; Maler, Leonard

2005-11-01

Feedback circuitry with conduction and synaptic delays is ubiquitous in the nervous system. Yet the effects of delayed feedback on sensory processing of natural signals are poorly understood. This study explores the consequences of delayed excitatory and inhibitory feedback inputs on the processing of sensory information. We show, through numerical simulations and theory, that excitatory and inhibitory feedback can alter the firing frequency response of stochastic neurons in opposite ways by creating dynamical resonances, which in turn lead to information resonances (i.e., increased information transfer for specific ranges of input frequencies). The resonances are created at the expense of decreased information transfer in other frequency ranges. Using linear response theory for stochastically firing neurons, we explain how feedback signals shape the neural transfer function for a single neuron as a function of network size. We also find that balanced excitatory and inhibitory feedback can further enhance information tuning while maintaining a constant mean firing rate. Finally, we apply this theory to in vivo experimental data from weakly electric fish in which the feedback loop can be opened. We show that it qualitatively predicts the observed effects of inhibitory feedback. Our study of feedback excitation and inhibition reveals a possible mechanism by which optimal processing may be achieved over selected frequency ranges.

Electrophysical properties, synaptic transmission and neuromodulation in serotonergic caudal raphe neurons.

PubMed

Li, Y W; Bayliss, D A

1998-06-01

1. We studied electrophysiological properties, synaptic transmission and modulation by 5-hydroxytryptamine (5-HT) of caudal raphe neurons using whole-cell recording in a neonatal rat brain slice preparation; recorded neurons were identified as serotonergic by post-hoc immunohistochemical detection of tryptophan hydroxylase, the 5-HT-synthesizing enzyme. 2. Serotonergic neurons fired spontaneously (approximately 1 Hz), with maximal steady state firing rates of < 4 Hz. 5-Hydroxytryptamine caused hyperpolarization and cessation of spike activity in these neurons by activating inwardly rectifying K+ conductance via somatodendritic 5-HT1A receptors. 3. Unitary glutamatergic excitatory post-synaptic potentials (EPSP) and currents (EPSC) were evoked in serotonergic neurons by local electrical stimulation. Evoked EPSC were potently inhibited by 5-HT, an effect mediated by presynaptic 5-HT1B receptors. 4. In conclusion, serotonergic caudal raphe neurons are spontaneously active in vitro; they receive prominent glutamatergic synaptic inputs. 5-Hydroxytryptamine regulates serotonergic neuronal activity of the caudal raphe by decreasing spontaneous activity via somatodendritic 5-HT1A receptors and by inhibiting excitatory synaptic transmission onto these neurons via presynaptic 5-HT1B receptors. These local modulatory mechanisms provide multiple levels of feedback autoregulation of serotonergic raphe neurons by 5-HT.

Diffusion-Based Model for Synaptic Molecular Communication Channel.

PubMed

Khan, Tooba; Bilgin, Bilgesu A; Akan, Ozgur B

2017-06-01

Computational methods have been extensively used to understand the underlying dynamics of molecular communication methods employed by nature. One very effective and popular approach is to utilize a Monte Carlo simulation. Although it is very reliable, this method can have a very high computational cost, which in some cases renders the simulation impractical. Therefore, in this paper, for the special case of an excitatory synaptic molecular communication channel, we present a novel mathematical model for the diffusion and binding of neurotransmitters that takes into account the effects of synaptic geometry in 3-D space and re-absorption of neurotransmitters by the transmitting neuron. Based on this model we develop a fast deterministic algorithm, which calculates expected value of the output of this channel, namely, the amplitude of excitatory postsynaptic potential (EPSP), for given synaptic parameters. We validate our algorithm by a Monte Carlo simulation, which shows total agreement between the results of the two methods. Finally, we utilize our model to quantify the effects of variation in synaptic parameters, such as position of release site, receptor density, size of postsynaptic density, diffusion coefficient, uptake probability, and number of neurotransmitters in a vesicle, on maximum number of bound receptors that directly affect the peak amplitude of EPSP.

Modulation of NMDA and AMPA-Mediated Synaptic Transmission by CB1 Receptors in Frontal Cortical Pyramidal Cells

PubMed Central

Li, Qiang; Yan, Haidun; Wilson, Wilkie A.; Swartzwelder, H. Scott

2010-01-01

Although the endogenous cannabinoid system modulates a variety of physiological and pharmacological processes, the specific role of cannabinoid CB1 receptors in the modulation of glutamatergic neurotransmission and neural plasticity is not well understood. Using whole-cell patch clamp recording techniques, evoked or spontaneous excitatory postsynaptic currents (eEPSCs or sEPSCs) were recorded from visualized, layer II/III pyramidal cells in frontal cortical slices from rat brain. Bath application of the CB1 receptor agonist, WIN 55212-2 (WIN), reduced the amplitude of NMDA receptor-mediated EPSCs in a concentration-dependent manner. When co-applied with the specific CB1 antagonists, AM251 or AM281, WIN did not suppress NMDA receptor mediated EPSCs. WIN also reduced the amplitude of evoked AMPA receptor-mediated EPSCs, an effect that was also reversed by AM251. Both the frequency and amplitude of spontaneous AMPA receptor-mediated EPSCs were significantly reduced by WIN. In contrast, WIN reduced the frequency, but not the amplitude of miniature EPSCs, suggesting that the suppression of glutmatergic activity by CB1 receptors in the frontal neocortex is mediated by a pre-synaptic mechanism. Taken together, these data indicate a critical role for endocannabinoid signaling in the regulation of excitatory synaptic transmission in frontal neocortex, and suggest a possible neuronal mechanism whereby THC regulates cortical function. PMID:20420813

Autism-Associated Insertion Mutation (InsG) of Shank3 Exon 21 Causes Impaired Synaptic Transmission and Behavioral Deficits.

PubMed

Speed, Haley E; Kouser, Mehreen; Xuan, Zhong; Reimers, Jeremy M; Ochoa, Christine F; Gupta, Natasha; Liu, Shunan; Powell, Craig M

2015-07-01

SHANK3 (also known as PROSAP2) is a postsynaptic scaffolding protein at excitatory synapses in which mutations and deletions have been implicated in patients with idiopathic autism, Phelan-McDermid (aka 22q13 microdeletion) syndrome, and other neuropsychiatric disorders. In this study, we have created a novel mouse model of human autism caused by the insertion of a single guanine nucleotide into exon 21 (Shank3(G)). The resulting frameshift causes a premature STOP codon and loss of major higher molecular weight Shank3 isoforms at the synapse. Shank3(G/G) mice exhibit deficits in hippocampus-dependent spatial learning, impaired motor coordination, altered response to novelty, and sensory processing deficits. At the cellular level, Shank3(G/G) mice also exhibit impaired hippocampal excitatory transmission and plasticity as well as changes in baseline NMDA receptor-mediated synaptic responses. This work identifies clear alterations in synaptic function and behavior in a novel, genetically accurate mouse model of autism mimicking an autism-associated insertion mutation. Furthermore, these findings lay the foundation for future studies aimed to validate and study region-selective and temporally selective genetic reversal studies in the Shank3(G/G) mouse that was engineered with such future experiments in mind. Copyright © 2015 the authors 0270-6474/15/359648-18$15.00/0.

Melatonin inhibits voltage-sensitive Ca(2+) channel-mediated neurotransmitter release.

PubMed

Choi, Tae-Yong; Kwon, Ji Eun; Durrance, Eunice Sung; Jo, Su-Hyun; Choi, Se-Young; Kim, Kyong-Tai

2014-04-04

Melatonin is involved in various neuronal functions such as circadian rhythmicity and thermoregulation. Melatonin has a wide range of pharmacologically effective concentration levels from the nanomolar to millimolar levels. Recently, the antiepileptic effect of high dose melatonin has been the focus of clinical studies; however, its detailed mechanism especially in relation to neurotransmitter release and synaptic transmission remains unclear. We studied the effect of melatonin at high concentrations on the neurotransmitter release by monitoring norepinephrine release in PC12 cells, and excitatory postsynaptic potential in rat hippocampal slices. Melatonin inhibits the 70mM K(+)-induced Ca(2+) increase at millimolar levels without effect on bradykinin-triggered Ca(2+) increase in PC12 cells. Melatonin (1mM) did not affect A2A adenosine receptor-evoked cAMP production, and classical melatonin receptor antagonists did not reverse the melatonin-induced inhibitory effect, suggesting G-protein coupled receptor independency. Melatonin inhibits the 70mM K(+)-induced norepinephrine release at a similar effective concentration range in PC12 cells. We confirmed that melatonin (100µM) inhibits excitatory synaptic transmission of the hippocampal Schaffer collateral pathway with the decrease in basal synaptic transmission and the increase in paired pulse ratio. These results show that melatonin inhibits neurotransmitter release through the blocking of voltage-sensitive Ca(2+) channels and suggest a possible mechanism for the antiepileptic effect of melatonin. Copyright © 2014 Elsevier B.V. All rights reserved.

Domestication of the dog from the wolf was promoted by enhanced excitatory synaptic plasticity: a hypothesis.

PubMed

Li, Yan; Wang, Guo-Dong; Wang, Ming-Shan; Irwin, David M; Wu, Dong-Dong; Zhang, Ya-Ping

2014-11-05

Dogs shared a much closer relationship with humans than any other domesticated animals, probably due to their unique social cognitive capabilities, which were hypothesized to be a by-product of selection for tameness toward humans. Here, we demonstrate that genes involved in glutamate metabolism, which account partially for fear response, indeed show the greatest population differentiation by whole-genome comparison of dogs and wolves. However, the changing direction of their expression supports a role in increasing excitatory synaptic plasticity in dogs rather than reducing fear response. Because synaptic plasticity are widely believed to be cellular correlates of learning and memory, this change may alter the learning and memory abilities of ancient scavenging wolves, weaken the fear reaction toward humans, and prompt the initial interspecific contact. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Directional hearing by linear summation of binaural inputs at the medial superior olive

PubMed Central

van der Heijden, Marcel; Lorteije, Jeannette A. M.; Plauška, Andrius; Roberts, Michael T.; Golding, Nace L.; Borst, J. Gerard G.

2013-01-01

SUMMARY Neurons in the medial superior olive (MSO) enable sound localization by their remarkable sensitivity to submillisecond interaural time differences (ITDs). Each MSO neuron has its own “best ITD” to which it responds optimally. A difference in physical path length of the excitatory inputs from both ears cannot fully account for the ITD tuning of MSO neurons. As a result, it is still debated how these inputs interact and whether the segregation of inputs to opposite dendrites, well-timed synaptic inhibition, or asymmetries in synaptic potentials or cellular morphology further optimize coincidence detection or ITD tuning. Using in vivo whole-cell and juxtacellular recordings, we show here that ITD tuning of MSO neurons is determined by the timing of their excitatory inputs. The inputs from both ears sum linearly, whereas spike probability depends nonlinearly on the size of synaptic inputs. This simple coincidence detection scheme thus makes accurate sound localization possible. PMID:23764292

Development of excitatory synaptic transmission to the superior paraolivary and lateral superior olivary nuclei optimizes differential decoding strategies.

PubMed

Felix, Richard A; Magnusson, Anna K

2016-10-15

The superior paraolivary nucleus (SPON) is a prominent structure in the mammalian auditory brainstem with a proposed role in encoding transient broadband sounds such as vocalized utterances. Currently, the source of excitatory pathways that project to the SPON and how these inputs contribute to SPON function are poorly understood. To shed light on the nature of these inputs, we measured evoked excitatory postsynaptic currents (EPSCs) in the SPON originating from the intermediate acoustic stria and compared them with the properties of EPSCs in the lateral superior olive (LSO) originating from the ventral acoustic stria during auditory development from postnatal day 5 to 22 in mice. Before hearing onset, EPSCs in the SPON and LSO are very similar in size and kinetics. After the onset of hearing, SPON excitation is refined to extremely few (2:1) fibers, with each strengthened by an increase in release probability, yielding fast and strong EPSCs. LSO excitation is recruited from more fibers (5:1), resulting in strong EPSCs with a comparatively broader stimulus-response range after hearing onset. Evoked SPON excitation is comparatively weaker than evoked LSO excitation, likely due to a larger fraction of postsynaptic GluR2-containing Ca 2+ -impermeable AMPA receptors after hearing onset. Taken together, SPON excitation develops synaptic properties that are suited for transmitting single events with high temporal reliability and the strong, dynamic LSO excitation is compatible with high rate-level sensitivity. Thus, the excitatory input pathways to the SPON and LSO mature to support different decoding strategies of respective coarse temporal and sound intensity information at the brainstem level. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Dopamine depresses excitatory synaptic transmission onto rat subicular neurons via presynaptic D1-like dopamine receptors.

PubMed

Behr, J; Gloveli, T; Schmitz, D; Heinemann, U

2000-07-01

Schizophrenia is considered to be associated with an abnormal functioning of the hippocampal output. The high clinical potency of antipsychotics that act as antagonists at dopamine (DA) receptors indicate a hyperfunction of the dopaminergic system. The subiculum obtains information from area CA1 and the entorhinal cortex and represents the major output region of the hippocampal complex. To clarify whether an enhanced dopaminergic activity alters the hippocampal output, the effect of DA on alveus- and perforant path-evoked excitatory postsynaptic currents (EPSCs) in subicular neurons was examined using conventional intracellular and whole cell voltage-clamp recordings. Dopamine (100 microM) depressed alveus-elicited (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated EPSCs to 56 +/- 8% of control while perforant path-evoked EPSCs were attenuated to only 76 +/- 7% of control. Dopamine had no effect on the EPSC kinetics. Dopamine reduced the frequency of spontaneous miniature EPSCs without affecting their amplitudes. The sensitivity of subicular neurons to the glutamate receptor agonist (S)-alpha-amino-3-hydoxy-5-methyl-4-isoxazolepropionic acid was unchanged by DA pretreatment, excluding a postsynaptic mechanism for the observed reduction of excitatory synaptic transmission. The effect of DA on evoked EPSCs was mimicked by the D1 receptor agonist SFK 38393 and partially antagonized by the D1 receptor antagonist SCH 23390. While the D2 receptor agonist quinelorane failed to reduce the EPSCs, the D2 receptor antagonist sulpiride did not block the action of DA. The results indicate that DA strongly depresses the hippocampal and the entorhinal excitatory input onto subicular neurons by decreasing the glutamate release following activation of presynaptic D1-like DA receptors.

Differential Roles of Postsynaptic Density-93 Isoforms in Regulating Synaptic Transmission

PubMed Central

Krüger, Juliane M.; Favaro, Plinio D.; Liu, Mingna; Kitlińska, Agata; Huang, Xiaojie; Raabe, Monika; Akad, Derya S.; Liu, Yanling; Urlaub, Henning; Dong, Yan; Xu, Weifeng

2013-01-01

In the postsynaptic density of glutamatergic synapses, the discs large (DLG)-membrane-associated guanylate kinase (MAGUK) family of scaffolding proteins coordinates a multiplicity of signaling pathways to maintain and regulate synaptic transmission. Postsynaptic density-93 (PSD-93) is the most variable paralog in this family; it exists in six different N-terminal isoforms. Probably because of the structural and functional variability of these isoforms, the synaptic role of PSD-93 remains controversial. To accurately characterize the synaptic role of PSD-93, we quantified the expression of all six isoforms in the mouse hippocampus and examined them individually in hippocampal synapses. Using molecular manipulations, including overexpression, gene knockdown, PSD-93 knock-out mice combined with biochemical assays, and slice electrophysiology both in rat and mice, we demonstrate that PSD-93 is required at different developmental synaptic states to maintain the strength of excitatory synaptic transmission. This strength is differentially regulated by the six isoforms of PSD-93, including regulations of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-active and inactive synapses, and activity-dependent modulations. Collectively, these results demonstrate that alternative combinations of N-terminal PSD-93 isoforms and DLG-MAGUK paralogs can fine-tune signaling scaffolds to adjust synaptic needs to regulate synaptic transmission. PMID:24068818

Autism-like behaviours and enhanced memory formation and synaptic plasticity in Lrfn2/SALM1-deficient mice

PubMed Central

Morimura, Naoko; Yasuda, Hiroki; Yamaguchi, Kazuhiko; Katayama, Kei-ichi; Hatayama, Minoru; Tomioka, Naoko H.; Odagawa, Maya; Kamiya, Akiko; Iwayama, Yoshimi; Maekawa, Motoko; Nakamura, Kazuhiko; Matsuzaki, Hideo; Tsujii, Masatsugu; Yamada, Kazuyuki; Yoshikawa, Takeo; Aruga, Jun

2017-01-01

Lrfn2/SALM1 is a PSD-95-interacting synapse adhesion molecule, and human LRFN2 is associated with learning disabilities. However its role in higher brain function and underlying mechanisms remain unknown. Here, we show that Lrfn2 knockout mice exhibit autism-like behavioural abnormalities, including social withdrawal, decreased vocal communications, increased stereotyped activities and prepulse inhibition deficits, together with enhanced learning and memory. In the hippocampus, the levels of synaptic PSD-95 and GluA1 are decreased. The synapses are structurally and functionally immature with spindle shaped spines, smaller postsynaptic densities, reduced AMPA/NMDA ratio, and enhanced LTP. In vitro experiments reveal that synaptic surface expression of AMPAR depends on the direct interaction between Lrfn2 and PSD-95. Furthermore, we detect functionally defective LRFN2 missense mutations in autism and schizophrenia patients. Together, these findings indicate that Lrfn2/LRFN2 serve as core components of excitatory synapse maturation and maintenance, and their dysfunction causes immature/silent synapses with pathophysiological state. PMID:28604739

Activation of NMDA receptors reduces metabotropic glutamate receptor-induced long-term depression in the nucleus accumbens via a CaMKII-dependent mechanism.

PubMed

Huang, Chiung-Chun; Hsu, Kuei-Sen

2012-12-01

Glutamate is the major excitatory neurotransmitter in the brain and exerts its actions through two distinct types of receptors, ionotropic and metabotropic glutamate receptors (mGluR). Although functional interplay between ionotropic N-methyl-d-aspartate receptors (NMDAR) and mGluR has been convincingly demonstrated in native and recombinant systems, the mechanism by which NMDAR activation leads to modulation of mGluR function has yet to be elucidated. Using whole-cell patch-clamp recordings in mouse nucleus accumbens (NAc) slices, we found that tetanic stimulation (TS) of excitatory afferents with a naturally occurring frequency (10 min at 13 Hz) reliably induces a mGluR1/5-dependent long-term depression (mGluR1/5-LTD) of excitatory synaptic transmission. Blockade of NMDAR during but not after TS showed enhanced mGluR1/5-LTD induction, which is associated with its antagonism of TS-induced calcium/calmodulin-dependent protein kinase II (CaMKII) activation. The ability of NMDAR antagonists to promote mGluR1/5-LTD induction was mimicked by a selective CaMKII inhibitor KN-62. However, the induction of mGluR1/5-LTD by bath-applied agonist (S)-3,5-dihydrophenylglycine was not affected by NMDAR blockade. We also observed that NMDAR or CaMKII blockade during TS significantly blunted TS-induced increased serine/threonine phosphorylation of the scaffold protein Homer1b/c and resulted in an increased interaction of mGluR5 with the Homer1b/c. These results indicate that synaptically released glutamate during TS of excitatory afferents can activate both NMDAR and mGluR1/5 in NAc neurons concomitantly and that activation of NMDAR may stimulate CaMKII-mediated phosphorylation of Homer1b/c and impair the interaction between mGluR5 and Homer1b/c, thereby attenuating mGluR1/5-LTD induction. This study provides a novel molecular mechanism by which NMDAR could regulate mGluR5 function. Copyright © 2012 Elsevier Ltd. All rights reserved.

Study of the Size and Shape of Synapses in the Juvenile Rat Somatosensory Cortex with 3D Electron Microscopy

PubMed Central

Rodríguez, José-Rodrigo; DeFelipe, Javier

2018-01-01

Abstract Changes in the size of the synaptic junction are thought to have significant functional consequences. We used focused ion beam milling and scanning electron microscopy (FIB/SEM) to obtain stacks of serial sections from the six layers of the rat somatosensory cortex. We have segmented in 3D a large number of synapses (n = 6891) to analyze the size and shape of excitatory (asymmetric) and inhibitory (symmetric) synapses, using dedicated software. This study provided three main findings. Firstly, the mean synaptic sizes were smaller for asymmetric than for symmetric synapses in all cortical layers. In all cases, synaptic junction sizes followed a log-normal distribution. Secondly, most cortical synapses had disc-shaped postsynaptic densities (PSDs; 93%). A few were perforated (4.5%), while a smaller proportion (2.5%) showed a tortuous horseshoe-shaped perimeter. Thirdly, the curvature was larger for symmetric than for asymmetric synapses in all layers. However, there was no correlation between synaptic area and curvature. PMID:29387782

Study of the Size and Shape of Synapses in the Juvenile Rat Somatosensory Cortex with 3D Electron Microscopy.

PubMed

Santuy, Andrea; Rodríguez, José-Rodrigo; DeFelipe, Javier; Merchán-Pérez, Angel

2018-01-01

Changes in the size of the synaptic junction are thought to have significant functional consequences. We used focused ion beam milling and scanning electron microscopy (FIB/SEM) to obtain stacks of serial sections from the six layers of the rat somatosensory cortex. We have segmented in 3D a large number of synapses ( n = 6891) to analyze the size and shape of excitatory (asymmetric) and inhibitory (symmetric) synapses, using dedicated software. This study provided three main findings. Firstly, the mean synaptic sizes were smaller for asymmetric than for symmetric synapses in all cortical layers. In all cases, synaptic junction sizes followed a log-normal distribution. Secondly, most cortical synapses had disc-shaped postsynaptic densities (PSDs; 93%). A few were perforated (4.5%), while a smaller proportion (2.5%) showed a tortuous horseshoe-shaped perimeter. Thirdly, the curvature was larger for symmetric than for asymmetric synapses in all layers. However, there was no correlation between synaptic area and curvature.

SCRAPPER-Dependent Ubiquitination of Active Zone Protein RIM1 Regulates Synaptic Vesicle Release

PubMed Central

Yao, Ikuko; Takagi, Hiroshi; Ageta, Hiroshi; Kahyo, Tomoaki; Sato, Showbu; Hatanaka, Ken; Fukuda, Yoshiyuki; Chiba, Tomoki; Morone, Nobuhiro; Yuasa, Shigeki; Inokuchi, Kaoru; Ohtsuka, Toshihisa; MacGregor, Grant R.; Tanaka, Keiji; Setou, Mitsutoshi

2011-01-01

SUMMARY Little is known about how synaptic activity is modulated in the central nervous system. We have identified SCRAPPER, a synapse-localized E3 ubiquitin ligase, which regulates neural transmission. SCRAPPER directly binds and ubiquitinates RIM1, a modulator of presynaptic plasticity. In neurons from Scrapper-knockout (SCR-KO) mice, RIM1 had a longer half-life with significant reduction in ubiquitination, indicating that SCRAPPER is the predominant ubiquitin ligase that mediates RIM1 degradation. As anticipated in a RIM1 degradation defect mutant, SCR-KO mice displayed altered electrophysiological synaptic activity, i.e., increased frequency of miniature excitatory postsynaptic currents. This phenotype of SCR-KO mice was phenocopied by RIM1 overexpression and could be rescued by re-expression of SCRAPPER or knockdown of RIM1. The acute effects of proteasome inhibitors, such as upregulation of RIM1 and the release probability, were blocked by the impairment of SCRAPPER. Thus, SCRAPPER has an essential function in regulating proteasome-mediated degradation of RIM1 required for synaptic tuning. PMID:17803915

Synaptic Basis for Differential Orientation Selectivity between Complex and Simple Cells in Mouse Visual Cortex

PubMed Central

Li, Ya-tang; Liu, Bao-hua; Chou, Xiao-lin; Zhang, Li I.

2015-01-01

In the primary visual cortex (V1), orientation-selective neurons can be categorized into simple and complex cells primarily based on their receptive field (RF) structures. In mouse V1, although previous studies have examined the excitatory/inhibitory interplay underlying orientation selectivity (OS) of simple cells, the synaptic bases for that of complex cells have remained obscure. Here, by combining in vivo loose-patch and whole-cell recordings, we found that complex cells, identified by their overlapping on/off subfields, had significantly weaker OS than simple cells at both spiking and subthreshold membrane potential response levels. Voltage-clamp recordings further revealed that although excitatory inputs to complex and simple cells exhibited a similar degree of OS, inhibition in complex cells was more narrowly tuned than excitation, whereas in simple cells inhibition was more broadly tuned than excitation. The differential inhibitory tuning can primarily account for the difference in OS between complex and simple cells. Interestingly, the differential synaptic tuning correlated well with the spatial organization of synaptic input: the inhibitory visual RF in complex cells was more elongated in shape than its excitatory counterpart and also was more elongated than that in simple cells. Together, our results demonstrate that OS of complex and simple cells is differentially shaped by cortical inhibition based on its orientation tuning profile relative to excitation, which is contributed at least partially by the spatial organization of RFs of presynaptic inhibitory neurons. SIGNIFICANCE STATEMENT Simple and complex cells, two classes of principal neurons in the primary visual cortex (V1), are generally thought to be equally selective for orientation. In mouse V1, we report that complex cells, identified by their overlapping on/off subfields, has significantly weaker orientation selectivity (OS) than simple cells. This can be primarily attributed to the differential tuning selectivity of inhibitory synaptic input: inhibition in complex cells is more narrowly tuned than excitation, whereas in simple cells inhibition is more broadly tuned than excitation. In addition, there is a good correlation between inhibitory tuning selectivity and the spatial organization of inhibitory inputs. These complex and simple cells with differential degree of OS may provide functionally distinct signals to different downstream targets. PMID:26245969

Synaptic Basis for Differential Orientation Selectivity between Complex and Simple Cells in Mouse Visual Cortex.

PubMed

Li, Ya-tang; Liu, Bao-hua; Chou, Xiao-lin; Zhang, Li I; Tao, Huizhong W

2015-08-05

In the primary visual cortex (V1), orientation-selective neurons can be categorized into simple and complex cells primarily based on their receptive field (RF) structures. In mouse V1, although previous studies have examined the excitatory/inhibitory interplay underlying orientation selectivity (OS) of simple cells, the synaptic bases for that of complex cells have remained obscure. Here, by combining in vivo loose-patch and whole-cell recordings, we found that complex cells, identified by their overlapping on/off subfields, had significantly weaker OS than simple cells at both spiking and subthreshold membrane potential response levels. Voltage-clamp recordings further revealed that although excitatory inputs to complex and simple cells exhibited a similar degree of OS, inhibition in complex cells was more narrowly tuned than excitation, whereas in simple cells inhibition was more broadly tuned than excitation. The differential inhibitory tuning can primarily account for the difference in OS between complex and simple cells. Interestingly, the differential synaptic tuning correlated well with the spatial organization of synaptic input: the inhibitory visual RF in complex cells was more elongated in shape than its excitatory counterpart and also was more elongated than that in simple cells. Together, our results demonstrate that OS of complex and simple cells is differentially shaped by cortical inhibition based on its orientation tuning profile relative to excitation, which is contributed at least partially by the spatial organization of RFs of presynaptic inhibitory neurons. Simple and complex cells, two classes of principal neurons in the primary visual cortex (V1), are generally thought to be equally selective for orientation. In mouse V1, we report that complex cells, identified by their overlapping on/off subfields, has significantly weaker orientation selectivity (OS) than simple cells. This can be primarily attributed to the differential tuning selectivity of inhibitory synaptic input: inhibition in complex cells is more narrowly tuned than excitation, whereas in simple cells inhibition is more broadly tuned than excitation. In addition, there is a good correlation between inhibitory tuning selectivity and the spatial organization of inhibitory inputs. These complex and simple cells with differential degree of OS may provide functionally distinct signals to different downstream targets. Copyright © 2015 the authors 0270-6474/15/3511081-13$15.00/0.

Short-term Synaptic Depression in the Feedforward Inhibitory Circuit in the Dorsal Lateral Geniculate Nucleus.

PubMed

Augustinaite, Sigita; Heggelund, Paul

2018-05-24

Synaptic short-term plasticity (STP) regulates synaptic transmission in an activity-dependent manner and thereby has important roles in the signal processing in the brain. In some synapses, a presynaptic train of action potentials elicits post-synaptic potentials that gradually increase during the train (facilitation), but in other synapses, these potentials gradually decrease (depression). We studied STP in neurons in the visual thalamic relay, the dorsal lateral geniculate nucleus (dLGN). The dLGN contains two types of neurons: excitatory thalamocortical (TC) neurons, which transfer signals from retinal afferents to visual cortex, and local inhibitory interneurons, which form an inhibitory feedforward loop that regulates the thalamocortical signal transmission. The overall STP in the retino-thalamic relay is short-term depression, but the distinct kind and characteristics of the plasticity at the different types of synapses are unknown. We studied STP in the excitatory responses of interneurons to stimulation of retinal afferents, in the inhibitory responses of TC neurons to stimulation of afferents from interneurons, and in the disynaptic inhibitory responses of TC neurons to stimulation of retinal afferents. Moreover, we studied STP at the direct excitatory input to TC neurons from retinal afferents. The STP at all types of the synapses showed short-term depression. This depression can accentuate rapid changes in the stream of signals and thereby promote detectability of significant features in the sensory input. In vision, detection of edges and contours is essential for object perception, and the synaptic short-term depression in the early visual pathway provides important contributions to this detection process. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

Loss of mTOR repressors Tsc1 or Pten has divergent effects on excitatory and inhibitory synaptic transmission in single hippocampal neuron cultures.

PubMed

Weston, Matthew C; Chen, Hongmei; Swann, John W

2014-01-01

The Pten and Tsc1 genes both encode proteins that repress mechanistic target of rapamycin (mTOR) signaling. Disruption of either gene in the brain results in epilepsy and autism-like symptoms in humans and mouse models, therefore it is important to understand the molecular and physiological events that lead from gene disruption to disease phenotypes. Given the similar roles these two molecules play in the regulation of cellular growth and the overlap in the phenotypes that result from their loss, we predicted that the deletion of either the Pten or Tsc1 gene from autaptic hippocampal neurons would have similar effects on neuronal morphology and synaptic transmission. Accordingly, we found that loss of either Pten or Tsc1 caused comparable increases in soma size, dendrite length and action potential properties. However, the effects of Pten and Tsc1 loss on synaptic transmission were different. Loss of Pten lead to an increase in both excitatory and inhibitory neurotransmission, while loss of Tsc1 did not affect excitatory neurotransmission and reduced inhibitory transmission by decreasing mIPSC amplitude. Although the loss of Pten or Tsc1 both increased downstream mTORC1 signaling, phosphorylation of Akt was increased in Pten-ko and decreased in Tsc1-ko neurons, potentially accounting for the different effects on synaptic transmission. Despite the different effects at the synaptic level, our data suggest that loss of Pten or Tsc1 may both lead to an increase in the ratio of excitation to inhibition at the network level, an effect that has been proposed to underlie both epilepsy and autism.

Obesity-driven synaptic remodeling affects endocannabinoid control of orexinergic neurons

PubMed Central

Cristino, Luigia; Busetto, Giuseppe; Imperatore, Roberta; Ferrandino, Ida; Palomba, Letizia; Silvestri, Cristoforo; Petrosino, Stefania; Orlando, Pierangelo; Bentivoglio, Marina; Mackie, Kenneth; Di Marzo, Vincenzo

2013-01-01

Acute or chronic alterations in energy status alter the balance between excitatory and inhibitory synaptic transmission and associated synaptic plasticity to allow for the adaptation of energy metabolism to new homeostatic requirements. The impact of such changes on endocannabinoid and cannabinoid receptor type 1 (CB1)-mediated modulation of synaptic transmission and strength is not known, despite the fact that this signaling system is an important target for the development of new drugs against obesity. We investigated whether CB1-expressing excitatory vs. inhibitory inputs to orexin-A–containing neurons in the lateral hypothalamus are altered in obesity and how this modifies endocannabinoid control of these neurons. In lean mice, these inputs are mostly excitatory. By confocal and ultrastructural microscopic analyses, we observed that in leptin-knockout (ob/ob) obese mice, and in mice with diet-induced obesity, orexinergic neurons receive predominantly inhibitory CB1-expressing inputs and overexpress the biosynthetic enzyme for the endocannabinoid 2-arachidonoylglycerol, which retrogradely inhibits synaptic transmission at CB1-expressing axon terminals. Patch-clamp recordings also showed increased CB1-sensitive inhibitory innervation of orexinergic neurons in ob/ob mice. These alterations are reversed by leptin administration, partly through activation of the mammalian target of rapamycin pathway in neuropeptide-Y-ergic neurons of the arcuate nucleus, and are accompanied by CB1-mediated enhancement of orexinergic innervation of target brain areas. We propose that enhanced inhibitory control of orexin-A neurons, and their CB1-mediated disinhibition, are a consequence of leptin signaling impairment in the arcuate nucleus. We also provide initial evidence of the participation of this phenomenon in hyperphagia and hormonal dysregulation in obesity. PMID:23630288

Genetic analysis of neuronal ionotropic glutamate receptor subunits

PubMed Central

Granger, Adam J; Gray, John A; Lu, Wei; Nicoll, Roger A

2011-01-01

Abstract In the brain, fast, excitatory synaptic transmission occurs primarily through AMPA- and NMDA-type ionotropic glutamate receptors. These receptors are composed of subunit proteins that determine their biophysical properties and trafficking behaviour. Therefore, determining the function of these subunits and receptor subunit composition is essential for understanding the physiological properties of synaptic transmission. Here, we discuss and evaluate various genetic approaches that have been used to study AMPA and NMDA receptor subunits. These approaches have demonstrated that the GluA1 AMPA receptor subunit is required for activity-dependent trafficking and contributes to basal synaptic transmission, while the GluA2 subunit regulates Ca2+ permeability, homeostasis and trafficking to the synapse under basal conditions. In contrast, the GluN2A and GluN2B NMDA receptor subunits regulate synaptic AMPA receptor content, both during synaptic development and plasticity. Ongoing research in this field is focusing on the molecular interactions and mechanisms that control these functions. To accomplish this, molecular replacement techniques are being used, where native subunits are replaced with receptors containing targeted mutations. In this review, we discuss a single-cell molecular replacement approach which should arguably advance our physiological understanding of ionotropic glutamate receptor subunits, but is generally applicable to study of any neuronal protein. PMID:21768264

Genetic analysis of neuronal ionotropic glutamate receptor subunits.

PubMed

Granger, Adam J; Gray, John A; Lu, Wei; Nicoll, Roger A

2011-09-01

In the brain, fast, excitatory synaptic transmission occurs primarily through AMPA- and NMDA-type ionotropic glutamate receptors. These receptors are composed of subunit proteins that determine their biophysical properties and trafficking behaviour. Therefore, determining the function of these subunits and receptor subunit composition is essential for understanding the physiological properties of synaptic transmission. Here, we discuss and evaluate various genetic approaches that have been used to study AMPA and NMDA receptor subunits. These approaches have demonstrated that the GluA1 AMPA receptor subunit is required for activity-dependent trafficking and contributes to basal synaptic transmission, while the GluA2 subunit regulates Ca(2+) permeability, homeostasis and trafficking to the synapse under basal conditions. In contrast, the GluN2A and GluN2B NMDA receptor subunits regulate synaptic AMPA receptor content, both during synaptic development and plasticity. Ongoing research in this field is focusing on the molecular interactions and mechanisms that control these functions. To accomplish this, molecular replacement techniques are being used, where native subunits are replaced with receptors containing targeted mutations. In this review, we discuss a single-cell molecular replacement approach which should arguably advance our physiological understanding of ionotropic glutamate receptor subunits, but is generally applicable to study of any neuronal protein.

Rapid Long-Range Disynaptic Inhibition Explains the Formation of Cortical Orientation Maps

PubMed Central

Antolík, Ján

2017-01-01

Competitive interactions are believed to underlie many types of cortical processing, ranging from memory formation, attention and development of cortical functional organization (e.g., development of orientation maps in primary visual cortex). In the latter case, the competitive interactions happen along the cortical surface, with local populations of neurons reinforcing each other, while competing with those displaced more distally. This specific configuration of lateral interactions is however in stark contrast with the known properties of the anatomical substrate, i.e., excitatory connections (mediating reinforcement) having longer reach than inhibitory ones (mediating competition). No satisfactory biologically plausible resolution of this conflict between anatomical measures, and assumed cortical function has been proposed. Recently a specific pattern of delays between different types of neurons in cat cortex has been discovered, where direct mono-synaptic excitation has approximately the same delay, as the combined delays of the disynaptic inhibitory interactions between excitatory neurons (i.e., the sum of delays from excitatory to inhibitory and from inhibitory to excitatory neurons). Here we show that this specific pattern of delays represents a biologically plausible explanation for how short-range inhibition can support competitive interactions that underlie the development of orientation maps in primary visual cortex. We demonstrate this statement analytically under simplifying conditions, and subsequently show using network simulations that development of orientation maps is preserved when long-range excitation, direct inhibitory to inhibitory interactions, and moderate inequality in the delays between excitatory and inhibitory pathways is added. PMID:28408869

Anterograde Activin signaling regulates postsynaptic membrane potential and GluRIIA/B abundance at the Drosophila neuromuscular junction.

PubMed

Kim, Myung-Jun; O'Connor, Michael B

2014-01-01

Members of the TGF-β superfamily play numerous roles in nervous system development and function. In Drosophila, retrograde BMP signaling at the neuromuscular junction (NMJ) is required presynaptically for proper synapse growth and neurotransmitter release. In this study, we analyzed whether the Activin branch of the TGF-β superfamily also contributes to NMJ development and function. We find that elimination of the Activin/TGF-β type I receptor babo, or its downstream signal transducer smox, does not affect presynaptic NMJ growth or evoked excitatory junctional potentials (EJPs), but instead results in a number of postsynaptic defects including depolarized membrane potential, small size and frequency of miniature excitatory junction potentials (mEJPs), and decreased synaptic densities of the glutamate receptors GluRIIA and B. The majority of the defective smox synaptic phenotypes were rescued by muscle-specific expression of a smox transgene. Furthermore, a mutation in actβ, an Activin-like ligand that is strongly expressed in motor neurons, phenocopies babo and smox loss-of-function alleles. Our results demonstrate that anterograde Activin/TGF-β signaling at the Drosophila NMJ is crucial for achieving normal abundance and localization of several important postsynaptic signaling molecules and for regulating postsynaptic membrane physiology. Together with the well-established presynaptic role of the retrograde BMP signaling, our findings indicate that the two branches of the TGF-β superfamily are differentially deployed on each side of the Drosophila NMJ synapse to regulate distinct aspects of its development and function.

Anterograde Activin Signaling Regulates Postsynaptic Membrane Potential and GluRIIA/B Abundance at the Drosophila Neuromuscular Junction

PubMed Central

Kim, Myung-Jun; O’Connor, Michael B.

2014-01-01

Members of the TGF-β superfamily play numerous roles in nervous system development and function. In Drosophila, retrograde BMP signaling at the neuromuscular junction (NMJ) is required presynaptically for proper synapse growth and neurotransmitter release. In this study, we analyzed whether the Activin branch of the TGF-β superfamily also contributes to NMJ development and function. We find that elimination of the Activin/TGF-β type I receptor babo, or its downstream signal transducer smox, does not affect presynaptic NMJ growth or evoked excitatory junctional potentials (EJPs), but instead results in a number of postsynaptic defects including depolarized membrane potential, small size and frequency of miniature excitatory junction potentials (mEJPs), and decreased synaptic densities of the glutamate receptors GluRIIA and B. The majority of the defective smox synaptic phenotypes were rescued by muscle-specific expression of a smox transgene. Furthermore, a mutation in actβ, an Activin-like ligand that is strongly expressed in motor neurons, phenocopies babo and smox loss-of-function alleles. Our results demonstrate that anterograde Activin/TGF-β signaling at the Drosophila NMJ is crucial for achieving normal abundance and localization of several important postsynaptic signaling molecules and for regulating postsynaptic membrane physiology. Together with the well-established presynaptic role of the retrograde BMP signaling, our findings indicate that the two branches of the TGF-β superfamily are differentially deployed on each side of the Drosophila NMJ synapse to regulate distinct aspects of its development and function. PMID:25255438

Oscillations and Synchrony in Large-scale Cortical Network Models

DTIC Science & Technology

2008-06-17

synaptic current is computed as In = −gn(xpostn − xrp ), (7) where gsyn is the strength of the synaptic coupling and the indices pre and post stand... xrp defines the reversal potential and, therefore, the type of synapse: excitatory ( xrp = 0) or inhibitory ( xrp = −1.1). To include the effects of short

A Postsynaptic AMPK→p21-Activated Kinase Pathway Drives Fasting-Induced Synaptic Plasticity in AgRP Neurons.

PubMed

Kong, Dong; Dagon, Yossi; Campbell, John N; Guo, Yikun; Yang, Zongfang; Yi, Xinchi; Aryal, Pratik; Wellenstein, Kerry; Kahn, Barbara B; Sabatini, Bernardo L; Lowell, Bradford B

2016-07-06

AMP-activated protein kinase (AMPK) plays an important role in regulating food intake. The downstream AMPK substrates and neurobiological mechanisms responsible for this, however, are ill defined. Agouti-related peptide (AgRP)-expressing neurons in the arcuate nucleus regulate hunger. Their firing increases with fasting, and once engaged they cause feeding. AgRP neuron activity is regulated by state-dependent synaptic plasticity: fasting increases dendritic spines and excitatory synaptic activity; feeding does the opposite. The signaling mechanisms underlying this, however, are also unknown. Using neuron-specific approaches to measure and manipulate kinase activity specifically within AgRP neurons, we establish that fasting increases AMPK activity in AgRP neurons, that increased AMPK activity in AgRP neurons is both necessary and sufficient for fasting-induced spinogenesis and excitatory synaptic activity, and that the AMPK phosphorylation target mediating this plasticity is p21-activated kinase. This provides a signaling and neurobiological basis for both AMPK regulation of energy balance and AgRP neuron state-dependent plasticity. Copyright © 2016 Elsevier Inc. All rights reserved.

Frequency-selective augmenting responses by short-term synaptic depression in cat neocortex

PubMed Central

Houweling, Arthur R; Bazhenov, Maxim; Timofeev, Igor; Grenier, François; Steriade, Mircea; Sejnowski, Terrence J

2002-01-01

Thalamic stimulation at frequencies between 5 and 15 Hz elicits incremental or ‘augmenting’ cortical responses. Augmenting responses can also be evoked in cortical slices and isolated cortical slabs in vivo. Here we show that a realistic network model of cortical pyramidal cells and interneurones including short-term plasticity of inhibitory and excitatory synapses replicates the main features of augmenting responses as obtained in isolated slabs in vivo. Repetitive stimulation of synaptic inputs at frequencies around 10 Hz produced postsynaptic potentials that grew in size and carried an increasing number of action potentials resulting from the depression of inhibitory synaptic currents. Frequency selectivity was obtained through the relatively weak depression of inhibitory synapses at low frequencies, and strong depression of excitatory synapses together with activation of a calcium-activated potassium current at high frequencies. This network resonance is a consequence of short-term synaptic plasticity in a network of neurones without intrinsic resonances. These results suggest that short-term plasticity of cortical synapses could shape the dynamics of synchronized oscillations in the brain. PMID:12122156

Synchronous firing patterns of induced pluripotent stem cell-derived cortical neurons depend on the network structure consisting of excitatory and inhibitory neurons.

PubMed

Iida, Shoko; Shimba, Kenta; Sakai, Koji; Kotani, Kiyoshi; Jimbo, Yasuhiko

2018-06-18

The balance between glutamate-mediated excitation and GABA-mediated inhibition is critical to cortical functioning. However, the contribution of network structure consisting of the both neurons to cortical functioning has not been elucidated. We aimed to evaluate the relationship between the network structure and functional activity patterns in vitro. We used mouse induced pluripotent stem cells (iPSCs) to construct three types of neuronal populations; excitatory-rich (Exc), inhibitory-rich (Inh), and control (Cont). Then, we analyzed the activity patterns of these neuronal populations using microelectrode arrays (MEAs). Inhibitory synaptic densities differed between the three types of iPSC-derived neuronal populations, and the neurons showed spontaneously synchronized bursting activity with functional maturation for one month. Moreover, different firing patterns were observed between the three populations; Exc demonstrated the highest firing rates, including frequent, long, and dominant bursts. In contrast, Inh demonstrated the lowest firing rates and the least dominant bursts. Synchronized bursts were enhanced by disinhibition via GABA A receptor blockade. The present study, using iPSC-derived neurons and MEAs, for the first time show that synchronized bursting of cortical networks in vitro depends on the network structure consisting of excitatory and inhibitory neurons. Copyright © 2018 Elsevier Inc. All rights reserved.

A 2D Material based Gate Tunable Memristive Device for Emulating Modulatory Input-dependent Hetero-synaptic Plasticity.

NASA Astrophysics Data System (ADS)

Yan, Xiaodong; Tian, He; Xie, Yujun; Kostelec, Andrew; Zhao, Huan; Cha, Judy J.; Tice, Jesse; Wang, Han

Modulatory input-dependent plasticity is a well-known type of hetero-synaptic response where the release of neuromodulators can alter the efficacy of neurotransmission in a nearby chemical synapse. Solid-state devices that can mimic such phenomenon are desirable for enhancing the functionality and reconfigurability of neuromorphic electronics. In this work, we demonstrated a tunable artificial synaptic device concept based on the properties of graphene and tin oxide that can mimic the modulatory input-dependent plasticity. By using graphene as the contact electrode, a third electrode terminal can be used to modulate the conductive filament formation in the vertical tin oxide based resistive memory device. The resulting synaptic characteristics of this device, in terms of the profile of synaptic weight change and the spike-timing-dependent-plasticity, is tunable with the bias at the modulating terminal. Furthermore, the synaptic response can be reconfigured between excitatory and inhibitory modes by this modulating bias. The operation mechanism of the device is studied with combined experimental and theoretical analysis. The device is attractive for application in neuromorphic electronics. This work is supported by ARO and NG-ION2 at USC.

SAD-B kinase regulates pre-synaptic vesicular dynamics at hippocampal Schaffer collateral synapses and affects contextual fear memory.

PubMed

Watabe, Ayako M; Nagase, Masashi; Hagiwara, Akari; Hida, Yamato; Tsuji, Megumi; Ochiai, Toshitaka; Kato, Fusao; Ohtsuka, Toshihisa

2016-01-01

Synapses of amphids defective (SAD)-A/B kinases control various steps in neuronal development and differentiation, such as axon specifications and maturation in central and peripheral nervous systems. At mature pre-synaptic terminals, SAD-B is associated with synaptic vesicles and the active zone cytomatrix; however, how SAD-B regulates neurotransmission and synaptic plasticity in vivo remains unclear. Thus, we used SAD-B knockout (KO) mice to study the function of this pre-synaptic kinase in the brain. We found that the paired-pulse ratio was significantly enhanced at Shaffer collateral synapses in the hippocampal CA1 region in SAD-B KO mice compared with wild-type littermates. We also found that the frequency of the miniature excitatory post-synaptic current was decreased in SAD-B KO mice. Moreover, synaptic depression following prolonged low-frequency synaptic stimulation was significantly enhanced in SAD-B KO mice. These results suggest that SAD-B kinase regulates vesicular release probability at pre-synaptic terminals and is involved in vesicular trafficking and/or regulation of the readily releasable pool size. Finally, we found that hippocampus-dependent contextual fear learning was significantly impaired in SAD-B KO mice. These observations suggest that SAD-B kinase plays pivotal roles in controlling vesicular release properties and regulating hippocampal function in the mature brain. Synapses of amphids defective (SAD)-A/B kinases control various steps in neuronal development and differentiation, but their roles in mature brains were only partially known. Here, we demonstrated, at mature pre-synaptic terminals, that SAD-B regulates vesicular release probability and synaptic plasticity. Moreover, hippocampus-dependent contextual fear learning was significantly impaired in SAD-B KO mice, suggesting that SAD-B kinase plays pivotal roles in controlling vesicular release properties and regulating hippocampal function in the mature brain. © 2015 International Society for Neurochemistry.

Somatodendritic and excitatory postsynaptic distribution of neuron-type dystrophin isoform, Dp40, in hippocampal neurons

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fujimoto, Takahiro; Itoh, Kyoko, E-mail: kxi14@koto.kpu-m.ac.jp; Yaoi, Takeshi

2014-09-12

Highlights: • Identification of dystrophin (Dp) shortest isoform, Dp40, is a neuron-type Dp. • Dp40 expression is temporally and differentially regulated in comparison to Dp71. • Somatodendritic and nuclear localization of Dp40. • Dp40 is localized to excitatory postsynapses. • Dp40 might play roles in dendritic and synaptic functions. - Abstract: The Duchenne muscular dystrophy (DMD) gene produces multiple dystrophin (Dp) products due to the presence of several promoters. We previously reported the existence of a novel short isoform of Dp, Dp40, in adult mouse brain. However, the exact biochemical expression profile and cytological distribution of the Dp40 protein remainmore » unknown. In this study, we generated a polyclonal antibody against the NH{sub 2}-terminal region of the Dp40 and identified the expression profile of Dp40 in the mouse brain. Through an analysis using embryonic and postnatal mouse cerebrums, we found that Dp40 emerged from the early neonatal stages until adulthood, whereas Dp71, an another Dp short isoform, was highly detected in both prenatal and postnatal cerebrums. Intriguingly, relative expressions of Dp40 and Dp71 were prominent in cultured dissociated neurons and non-neuronal cells derived from mouse hippocampus, respectively. Furthermore, the immunocytological distribution of Dp40 was analyzed in dissociated cultured neurons, revealing that Dp40 is detected in the soma and its dendrites, but not in the axon. It is worthy to note that Dp40 is localized along the subplasmalemmal region of the dendritic shafts, as well as at excitatory postsynaptic sites. Thus, Dp40 was identified as a neuron-type Dp possibly involving dendritic and synaptic functions.« less

Cell-type specific circuit connectivity of hippocampal CA1 revealed through Cre-dependent rabies tracing

PubMed Central

Sun, Yanjun; Nguyen, Amanda; Nguyen, Joseph; Le, Luc; Saur, Dieter; Choi, Jiwon; Callaway, Edward M.; Xu, Xiangmin

2014-01-01

Summary We applied a new Cre-dependent, genetically modified rabies-based tracing system to map direct synaptic connections to CA1 excitatory and inhibitory neuron types in mouse hippocampus. We found common inputs to excitatory and inhibitory CA1 neurons from CA3, CA2, entorhinal cortex and the medial septum (MS), and unexpectedly also from the subiculum. Excitatory CA1 neurons receive inputs from both cholinergic and GABAergic MS neurons while inhibitory CA1 neurons receive a great majority of input from GABAergic MS neurons; both cell types also receive weaker input from glutamatergic MS neurons. Comparisons of inputs to CA1 PV+ interneurons versus SOM+ interneurons showed similar strengths of input from the subiculum, but PV+ interneurons receive much stronger input than SOM+ neurons from CA3, entorhinal cortex and MS. Differential input from CA3 to specific CA1 cell types was also demonstrated functionally using laser scanning photostimulation and whole cell recordings. PMID:24656815

Depolarizing GABA/glycine synaptic events switch from excitation to inhibition during frequency increases

NASA Astrophysics Data System (ADS)

Branchereau, Pascal; Cattaert, Daniel; Delpy, Alain; Allain, Anne-Emilie; Martin, Elodie; Meyrand, Pierre

2016-02-01

By acting on their ionotropic chloride channel receptors, GABA and glycine represent the major inhibitory transmitters of the central nervous system. Nevertheless, in various brain structures, depolarizing GABAergic/glycinergic postsynaptic potentials (dGPSPs) lead to dual inhibitory (shunting) and excitatory components, the functional consequences of which remain poorly acknowledged. Indeed, the extent to which each component prevails during dGPSP is unclear. Understanding the mechanisms predicting the dGPSP outcome on neural network activity is therefore a major issue in neurobiology. By combining electrophysiological recordings of spinal embryonic mouse motoneurons and modelling study, we demonstrate that increasing the chloride conductance (gCl) favors inhibition either during a single dGPSP or during trains in which gCl summates. Finally, based on this summation mechanism, the excitatory effect of EPSPs is overcome by dGPSPs in a frequency-dependent manner. These results reveal an important mechanism by which dGPSPs protect against the overexcitation of neural excitatory circuits.

Human embryonic stem cell-derived neurons adopt and regulate the activity of an established neural network

PubMed Central

Weick, Jason P.; Liu, Yan; Zhang, Su-Chun

2011-01-01

Whether hESC-derived neurons can fully integrate with and functionally regulate an existing neural network remains unknown. Here, we demonstrate that hESC-derived neurons receive unitary postsynaptic currents both in vitro and in vivo and adopt the rhythmic firing behavior of mouse cortical networks via synaptic integration. Optical stimulation of hESC-derived neurons expressing Channelrhodopsin-2 elicited both inhibitory and excitatory postsynaptic currents and triggered network bursting in mouse neurons. Furthermore, light stimulation of hESC-derived neurons transplanted to the hippocampus of adult mice triggered postsynaptic currents in host pyramidal neurons in acute slice preparations. Thus, hESC-derived neurons can participate in and modulate neural network activity through functional synaptic integration, suggesting they are capable of contributing to neural network information processing both in vitro and in vivo. PMID:22106298

Substance P and cocaine employ convergent mechanisms to depress excitatory synaptic transmission in the rat nucleus accumbens in vitro.

PubMed

Kombian, Samuel B; Ananthalakshmi, Kethireddy V V; Zidichouski, Jeffrey A; Saleh, Tarek M

2009-04-01

Substance P (SP) has been reported to produce effects on excitatory synaptic transmission in the nucleus accumbens (NAc) that are similar to those induced by cocaine. To address the question of whether SP serves as an endogenous mediator producing cocaine-like effects that are known to be D1-receptor-mediated, we tested the hypothesis that the effects of SP and cocaine on excitatory postsynaptic currents (EPSCs) in the NAc occlude one another. We report here that SP and SP(5-11) actions occlude the effect of cocaine and vice versa. SP, SP(5-11) and cocaine all depressed evoked, non-N-methyl-D-aspartate (NMDA) receptor-mediated synaptic currents in a concentration-dependent manner, with EC50 values of 0.12, 0.17 and 8.3 microm, respectively. Although cocaine was the least potent, it was most efficacious. SP, SP(5-11) and cocaine all suppressed isolated NMDA receptor-mediated evoked EPSCs. SP(5-11) (1 microm)-induced EPSC depression was blocked by the neurokinin-1 antagonist L732138 and by the D1-like receptor antagonist SCH23390. Pretreatment of slices with cocaine (30 microm) depressed the EPSC by 39.1% +/- 4.8%. Application of SP or SP(5-11) (1 microm) at the peak of the cocaine depressive effect on the EPSC did not produce any additional diminution of the response (5.7% +/- 2.8%). In the reverse experiments, in which either SP or SP(5-11) was applied first, subsequent application of cocaine at the peak of the peptide's effect (30.3% +/- 2.3%) produced a further but smaller depression (15.5% +/- 3.6%) of the remaining EPSC. These data indicate that cocaine and SP produce similar effects on excitatory synaptic transmission in the NAc, and that their actions occlude one another. This suggests that SP may act like cocaine in its absence, and may be an endogenous trigger for the reward and behaviors associated with cocaine.

Laminar- and Target-Specific Amygdalar Inputs in Rat Primary Gustatory Cortex.

PubMed

Haley, Melissa S; Fontanini, Alfredo; Maffei, Arianna

2016-03-02

The primary gustatory cortex (GC) receives projections from the basolateral nucleus of the amygdala (BLA). Behavioral and electrophysiological studies demonstrated that this projection is involved in encoding the hedonic value of taste and is a source of anticipatory activity in GC. Anatomically, this projection is largest in the agranular portion of GC; however, its synaptic targets and synaptic properties are currently unknown. In vivo electrophysiological recordings report conflicting evidence about BLA afferents either selectively activating excitatory neurons or driving a compound response consistent with the activation of inhibitory circuits. Here we demonstrate that BLA afferents directly activate excitatory neurons and two distinct populations of inhibitory neurons in both superficial and deep layers of rat GC. BLA afferents recruit different proportions of excitatory and inhibitory neurons and show distinct patterns of circuit activation in the superficial and deep layers of GC. These results provide the first circuit-level analysis of BLA inputs to a sensory area. Laminar- and target-specific differences of BLA inputs likely explain the complexity of amygdalocortical interactions during sensory processing. Projections from the basolateral nucleus of the amygdala (BLA) to the cortex convey information about the emotional value and the expectation of a sensory stimulus. Although much work has been done to establish the behavioral role of BLA inputs to sensory cortices, very little is known about the circuit organization of BLA projections. Here we provide the first in-depth analysis of connectivity and synaptic properties of the BLA input to the gustatory cortex. We show that BLA afferents activate excitatory and inhibitory circuits in a layer-specific and pattern-specific manner. Our results provide important new information about how neural circuits establishing the hedonic value of sensory stimuli and driving anticipatory behaviors are organized at the synaptic level. Copyright © 2016 the authors 0270-6474/16/362623-15$15.00/0.

Targeted intracellular voltage recordings from dendritic spines using quantum-dot-coated nanopipettes

NASA Astrophysics Data System (ADS)

Jayant, Krishna; Hirtz, Jan J.; Plante, Ilan Jen-La; Tsai, David M.; de Boer, Wieteke D. A. M.; Semonche, Alexa; Peterka, Darcy S.; Owen, Jonathan S.; Sahin, Ozgur; Shepard, Kenneth L.; Yuste, Rafael

2017-05-01

Dendritic spines are the primary site of excitatory synaptic input onto neurons, and are biochemically isolated from the parent dendritic shaft by their thin neck. However, due to the lack of direct electrical recordings from spines, the influence that the neck resistance has on synaptic transmission, and the extent to which spines compartmentalize voltage, specifically excitatory postsynaptic potentials, albeit critical, remains controversial. Here, we use quantum-dot-coated nanopipette electrodes (tip diameters ∼15-30 nm) to establish the first intracellular recordings from targeted spine heads under two-photon visualization. Using simultaneous somato-spine electrical recordings, we find that back propagating action potentials fully invade spines, that excitatory postsynaptic potentials are large in the spine head (mean 26 mV) but are strongly attenuated at the soma (0.5-1 mV) and that the estimated neck resistance (mean 420 MΩ) is large enough to generate significant voltage compartmentalization. Nanopipettes can thus be used to electrically probe biological nanostructures.

Targeted intracellular voltage recordings from dendritic spines using quantum-dot-coated nanopipettes

PubMed Central

Jayant, Krishna; Hirtz, Jan J.; Plante, Ilan Jen-La; Tsai, David M.; De Boer, Wieteke D. A. M.; Semonche, Alexa; Peterka, Darcy S.; Owen, Jonathan S.; Sahin, Ozgur; Shepard, Kenneth L.; Yuste, Rafael

2017-01-01

Dendritic spines are the primary site of excitatory synaptic input onto neurons, and are biochemically isolated from the parent dendritic shaft by their thin neck. However, due to the lack of direct electrical recordings from spines, the influence that the neck resistance has on synaptic transmission, and the extent to which spines compartmentalize voltage, specifically excitatory postsynaptic potentials, albeit critical, remains controversial. Here, we use quantum-dot-coated nanopipette electrodes (tip diameters ~15–30 nm) to establish the first intracellular recordings from targeted spine heads under two-photon visualization. Using simultaneous somato-spine electrical recordings, we find that back propagating action potentials fully invade spines, that excitatory postsynaptic potentials are large in the spine head (mean 26 mV) but are strongly attenuated at the soma (0.5–1 mV) and that the estimated neck resistance (mean 420 MΩ) is large enough to generate significant voltage compartmentalization. Nanopipettes can thus be used to electrically probe biological nanostructures. PMID:27941898

Targeted intracellular voltage recordings from dendritic spines using quantum-dot-coated nanopipettes.

PubMed

Jayant, Krishna; Hirtz, Jan J; Plante, Ilan Jen-La; Tsai, David M; De Boer, Wieteke D A M; Semonche, Alexa; Peterka, Darcy S; Owen, Jonathan S; Sahin, Ozgur; Shepard, Kenneth L; Yuste, Rafael

2017-05-01

Dendritic spines are the primary site of excitatory synaptic input onto neurons, and are biochemically isolated from the parent dendritic shaft by their thin neck. However, due to the lack of direct electrical recordings from spines, the influence that the neck resistance has on synaptic transmission, and the extent to which spines compartmentalize voltage, specifically excitatory postsynaptic potentials, albeit critical, remains controversial. Here, we use quantum-dot-coated nanopipette electrodes (tip diameters ∼15-30 nm) to establish the first intracellular recordings from targeted spine heads under two-photon visualization. Using simultaneous somato-spine electrical recordings, we find that back propagating action potentials fully invade spines, that excitatory postsynaptic potentials are large in the spine head (mean 26 mV) but are strongly attenuated at the soma (0.5-1 mV) and that the estimated neck resistance (mean 420 MΩ) is large enough to generate significant voltage compartmentalization. Nanopipettes can thus be used to electrically probe biological nanostructures.

Learning place cells, grid cells and invariances with excitatory and inhibitory plasticity

PubMed Central

2018-01-01

Neurons in the hippocampus and adjacent brain areas show a large diversity in their tuning to location and head direction, and the underlying circuit mechanisms are not yet resolved. In particular, it is unclear why certain cell types are selective to one spatial variable, but invariant to another. For example, place cells are typically invariant to head direction. We propose that all observed spatial tuning patterns – in both their selectivity and their invariance – arise from the same mechanism: Excitatory and inhibitory synaptic plasticity driven by the spatial tuning statistics of synaptic inputs. Using simulations and a mathematical analysis, we show that combined excitatory and inhibitory plasticity can lead to localized, grid-like or invariant activity. Combinations of different input statistics along different spatial dimensions reproduce all major spatial tuning patterns observed in rodents. Our proposed model is robust to changes in parameters, develops patterns on behavioral timescales and makes distinctive experimental predictions. PMID:29465399

Prevention of posttraumatic axon sprouting by blocking CRMP2-mediated neurite outgrowth and tubulin polymerization

PubMed Central

Wilson, Sarah M.; Xiong, Wenhui; Wang, Yuying; Ping, Xingjie; Head, Jessica D.; Brittain, Joel M.; Gagare, Pravin D.; Ramachandran, P. Veeraraghavan; Jin, Xiaoming; Khanna, Rajesh

2012-01-01

Epileptogenesis following traumatic brain injury (TBI) is likely due to a combination of increased excitability, disinhibition, and increased excitatory connectivity via aberrant axon sprouting. Targeting these pathways could be beneficial in the prevention and treatment of posttraumatic epilepsy. Here, we tested this possibility using the novel anticonvulsant (R)-N-benzyl 2-acetamido-3-methoxypropionamide ((R)-lacosamide (LCM) which acts on both voltage-gated sodium channels and collapsin response mediator protein 2 (CRMP2), an axonal growth/guidance protein. LCM inhibited CRMP2-mediated neurite outgrowth, an effect phenocopied by CRMP2 knockdown. Mutation of LCM binding sites in CRMP2 reduced the neurite inhibitory effect of LCM by ~8-fold. LCM also reduced CRMP2-mediated tubulin polymerization. Thus, LCM selectively impairs CRMP2-mediated microtubule polymerization which underlies its neurite outgrowth and branching. To determine whether LCM inhibits axon sprouting in vivo, LCM was injected into rats subjected to partial cortical isolation, an animal model of posttraumatic epileptogenesis that exhibits axon sprouting in cortical pyramidal neurons. Two weeks following injury, excitatory synaptic connectivity of cortical layer V pyramidal neurons was mapped using patch clamp recordings and laser scanning photostimulation of caged glutamate. In comparison to injured control animals, there was a significant decrease in the map size of excitatory synaptic connectivity in LCM-treated rats, suggesting that LCM treatment prevented enhanced excitatory synaptic connectivity due to posttraumatic axon sprouting. These findings suggest, for the first time, that LCM’s mode of action involves interactions with CRMP2 to inhibit posttraumatic axon sprouting. PMID:22433297

Xenon inhibits excitatory but not inhibitory transmission in rat spinal cord dorsal horn neurons

PubMed Central

2010-01-01

Background The molecular targets for the promising gaseous anaesthetic xenon are still under investigation. Most studies identify N-methyl-D-aspartate (NMDA) receptors as the primary molecular target for xenon, but the role of α-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionic acid (AMPA) receptors is less clear. In this study we evaluated the effect of xenon on excitatory and inhibitory synaptic transmission in the superficial dorsal horn of the spinal cord using in vitro patch-clamp recordings from rat spinal cord slices. We further evaluated the effects of xenon on innocuous and noxious stimuli using in vivo patch-clamp method. Results In vitro, xenon decreased the amplitude and area under the curve of currents induced by exogenous NMDA and AMPA and inhibited dorsal root stimulation-evoked excitatory postsynaptic currents. Xenon decreased the amplitude, but not the frequency, of miniature excitatory postsynaptic currents. There was no discernible effect on miniature or evoked inhibitory postsynaptic currents or on the current induced by inhibitory neurotransmitters. In vivo, xenon inhibited responses to tactile and painful stimuli even in the presence of NMDA receptor antagonist. Conclusions Xenon inhibits glutamatergic excitatory transmission in the superficial dorsal horn via a postsynaptic mechanism. There is no substantial effect on inhibitory synaptic transmission at the concentration we used. The blunting of excitation in the dorsal horn lamina II neurons could underlie the analgesic effect of xenon. PMID:20444263

Functional dependence of neuroligin on a new non-PDZ intracellular domain

PubMed Central

Shipman, Seth L; Schnell, Eric; Hirai, Takaaki; Chen, Bo-Shiun; Roche, Katherine W; Nicoll, Roger A

2011-01-01

Neuroligins, a family of postsynaptic adhesion molecules, are important in synaptogenesis through a well-characterized trans-synaptic interaction with neurexin. In addition, neuroligins are thought to drive postsynaptic assembly through binding of their intracellular domain to PSD-95. However, there is little direct evidence to support the functional necessity of the neuroligin intracellular domain in postsynaptic development. We found that presence of endogenous neuroligin obscured the study of exogenous mutated neuroligin. We therefore used chained microRNAs in rat organotypic hippocampal slices to generate a reduced background of endogenous neuroligin. On this reduced background, we found that neuroligin function was critically dependent on the cytoplasmic tail. However, this function required neither the PDZ ligand nor any other previously described cytoplasmic binding domain, but rather required a previously unknown conserved region. Mutation of a single critical residue in this region inhibited neuroligin-mediated excitatory synaptic potentiation. Finally, we found a functional distinction between neuroligins 1 and 3. PMID:21532576

Reduced synaptic density and deficient locomotor response in neuronal activity-regulated pentraxin 2a mutant zebrafish.

PubMed

Elbaz, Idan; Lerer-Goldshtein, Tali; Okamoto, Hitoshi; Appelbaum, Lior

2015-04-01

Neuronal-activity-regulated pentraxin (NARP/NPTX2/NP2) is a secreted synaptic protein that regulates the trafficking of glutamate receptors and mediates learning, memory, and drug addiction. The role of NPTX2 in regulating structural synaptic plasticity and behavior in a developing vertebrate is indefinite. We characterized the expression of nptx2a in larvae and adult zebrafish and established a transcription activator-like effector nuclease (TALEN)-mediated nptx2a mutant (nptx2a(-/-)) to study the role of Nptx2a in regulating structural synaptic plasticity and behavior. Similar to mammals, the zebrafish nptx2a was expressed in excitatory neurons in the brain and spinal cord. Its expression was induced in response to a mechanosensory stimulus but did not change during day and night. Behavioral assays showed that loss of Nptx2a results in reduced locomotor response to light-to-dark transition states and to a sound stimulus. Live imaging of synapses using the transgenic nptx2a:GAL4VP16 zebrafish and a fluorescent presynaptic synaptophysin (SYP) marker revealed reduced synaptic density in the axons of the spinal motor neurons and the anterodorsal lateral-line ganglion (gAD), which regulate locomotor activity and locomotor response to mechanosensory stimuli, respectively. These results suggest that Nptx2a affects locomotor response to external stimuli by mediating structural synaptic plasticity in excitatory neuronal circuits. © FASEB.

Modelling Feedback Excitation, Pacemaker Properties and Sensory Switching of Electrically Coupled Brainstem Neurons Controlling Rhythmic Activity

PubMed Central

Hull, Michael J.; Soffe, Stephen R.; Willshaw, David J.; Roberts, Alan

2016-01-01

What cellular and network properties allow reliable neuronal rhythm generation or firing that can be started and stopped by brief synaptic inputs? We investigate rhythmic activity in an electrically-coupled population of brainstem neurons driving swimming locomotion in young frog tadpoles, and how activity is switched on and off by brief sensory stimulation. We build a computational model of 30 electrically-coupled conditional pacemaker neurons on one side of the tadpole hindbrain and spinal cord. Based on experimental estimates for neuron properties, population sizes, synapse strengths and connections, we show that: long-lasting, mutual, glutamatergic excitation between the neurons allows the network to sustain rhythmic pacemaker firing at swimming frequencies following brief synaptic excitation; activity persists but rhythm breaks down without electrical coupling; NMDA voltage-dependency doubles the range of synaptic feedback strengths generating sustained rhythm. The network can be switched on and off at short latency by brief synaptic excitation and inhibition. We demonstrate that a population of generic Hodgkin-Huxley type neurons coupled by glutamatergic excitatory feedback can generate sustained asynchronous firing switched on and off synaptically. We conclude that networks of neurons with NMDAR mediated feedback excitation can generate self-sustained activity following brief synaptic excitation. The frequency of activity is limited by the kinetics of the neuron membrane channels and can be stopped by brief inhibitory input. Network activity can be rhythmic at lower frequencies if the neurons are electrically coupled. Our key finding is that excitatory synaptic feedback within a population of neurons can produce switchable, stable, sustained firing without synaptic inhibition. PMID:26824331

Experience-Dependent Regulation of Presynaptic NMDARs Enhances Neurotransmitter Release at Neocortical Synapses

ERIC Educational Resources Information Center

Urban-Ciecko, Joanna; Wen, Jing A.; Parekh, Puja K.; Barth, Alison L.

2015-01-01

Sensory experience can selectively alter excitatory synaptic strength at neocortical synapses. The rapid increase in synaptic strength induced by selective whisker stimulation (single-row experience/SRE, where all but one row of whiskers has been removed from the mouse face) is due, at least in part, to the trafficking of AMPA receptors (AMPARs)…

High-frequency stimulation-induced peptide release synchronizes arcuate kisspeptin neurons and excites GnRH neurons

PubMed Central

Qiu, Jian; Nestor, Casey C; Zhang, Chunguang; Padilla, Stephanie L; Palmiter, Richard D

2016-01-01

Kisspeptin (Kiss1) and neurokinin B (NKB) neurocircuits are essential for pubertal development and fertility. Kisspeptin neurons in the hypothalamic arcuate nucleus (Kiss1ARH) co-express Kiss1, NKB, dynorphin and glutamate and are postulated to provide an episodic, excitatory drive to gonadotropin-releasing hormone 1 (GnRH) neurons, the synaptic mechanisms of which are unknown. We characterized the cellular basis for synchronized Kiss1ARH neuronal activity using optogenetics, whole-cell electrophysiology, molecular pharmacology and single cell RT-PCR in mice. High-frequency photostimulation of Kiss1ARH neurons evoked local release of excitatory (NKB) and inhibitory (dynorphin) neuropeptides, which were found to synchronize the Kiss1ARH neuronal firing. The light-evoked synchronous activity caused robust excitation of GnRH neurons by a synaptic mechanism that also involved glutamatergic input to preoptic Kiss1 neurons from Kiss1ARH neurons. We propose that Kiss1ARH neurons play a dual role of driving episodic secretion of GnRH through the differential release of peptide and amino acid neurotransmitters to coordinate reproductive function. DOI: http://dx.doi.org/10.7554/eLife.16246.001 PMID:27549338

Calcium sensor regulation of the CaV2.1 Ca2+ channel contributes to short-term synaptic plasticity in hippocampal neurons.

PubMed

Nanou, Evanthia; Sullivan, Jane M; Scheuer, Todd; Catterall, William A

2016-01-26

Short-term synaptic plasticity is induced by calcium (Ca(2+)) accumulating in presynaptic nerve terminals during repetitive action potentials. Regulation of voltage-gated CaV2.1 Ca(2+) channels by Ca(2+) sensor proteins induces facilitation of Ca(2+) currents and synaptic facilitation in cultured neurons expressing exogenous CaV2.1 channels. However, it is unknown whether this mechanism contributes to facilitation in native synapses. We introduced the IM-AA mutation into the IQ-like motif (IM) of the Ca(2+) sensor binding site. This mutation does not alter voltage dependence or kinetics of CaV2.1 currents, or frequency or amplitude of spontaneous miniature excitatory postsynaptic currents (mEPSCs); however, synaptic facilitation is completely blocked in excitatory glutamatergic synapses in hippocampal autaptic cultures. In acutely prepared hippocampal slices, frequency and amplitude of mEPSCs and amplitudes of evoked EPSCs are unaltered. In contrast, short-term synaptic facilitation in response to paired stimuli is reduced by ∼ 50%. In the presence of EGTA-AM to prevent global increases in free Ca(2+), the IM-AA mutation completely blocks short-term synaptic facilitation, indicating that synaptic facilitation by brief, local increases in Ca(2+) is dependent upon regulation of CaV2.1 channels by Ca(2+) sensor proteins. In response to trains of action potentials, synaptic facilitation is reduced in IM-AA synapses in initial stimuli, consistent with results of paired-pulse experiments; however, synaptic depression is also delayed, resulting in sustained increases in amplitudes of later EPSCs during trains of 10 stimuli at 10-20 Hz. Evidently, regulation of CaV2.1 channels by CaS proteins is required for normal short-term plasticity and normal encoding of information in native hippocampal synapses.

Pyruvate incubation enhances glycogen stores and sustains neuronal function during subsequent glucose deprivation.

PubMed

Shetty, Pavan K; Sadgrove, Matthew P; Galeffi, Francesca; Turner, Dennis A

2012-01-01

The use of energy substrates, such as lactate and pyruvate, has been shown to improve synaptic function when administered during glucose deprivation. In the present study, we investigated whether prolonged incubation with monocarboxylate (pyruvate or lactate) prior rather than during glucose deprivation can also sustain synaptic and metabolic function. Pyruvate pre-incubation(3-4h) significantly prolonged (>25 min) the tolerance of rat hippocampal slices to delayed glucose deprivation compared to control and lactate pre-incubated slices, as revealed by field excitatory post synaptic potentials (fEPSPs); pre-incubation with pyruvate also reduced the marked decrease in NAD(P)H fluorescence resulting from glucose deprivation. Moreover, pyruvate exposure led to the enhancement of glycogen stores with time, compared to glucose alone (12 μmol/g tissue at 4h vs. 3.5 μmol/g tissue). Prolonged resistance to glucose deprivation following exogenous pyruvate incubation was prevented by glycogenolysis inhibitors, suggesting that enhanced glycogen mediates the delay in synaptic activity failure. The application of an adenosine A1 receptor antagonist enhanced glycogen utilization and prolonged the time to synaptic failure, further confirming this hypothesis of the importance of glycogen. Moreover, tissue levels of ATP were also significantly maintained during glucose deprivation in pyruvate pretreated slices compared to control and lactate. In summary, these experiments indicate that pyruvate exposure prior to glucose deprivation significantly increased the energy buffering capacity of hippocampal slices, particularly by enhancing internal glycogen stores, delaying synaptic failure during glucose deprivation by maintaining ATP levels, and minimizing the decrease in the levels of NAD(P)H. Copyright © 2011 Elsevier Inc. All rights reserved.

Effects of chronic stress in adolescence on learned fear, anxiety, and synaptic transmission in the rat prelimbic cortex.

PubMed

Negrón-Oyarzo, Ignacio; Pérez, Miguel Ángel; Terreros, Gonzalo; Muñoz, Pablo; Dagnino-Subiabre, Alexies

2014-02-01

The prelimbic cortex and amygdala regulate the extinction of conditioned fear and anxiety, respectively. In adult rats, chronic stress affects the dendritic morphology of these brain areas, slowing extinction of learned fear and enhancing anxiety. The aim of this study was to determine whether rats subjected to chronic stress in adolescence show changes in learned fear, anxiety, and synaptic transmission in the prelimbic cortex during adulthood. Male Sprague Dawley rats were subjected to seven days of restraint stress on postnatal day forty-two (PND 42, adolescence). Afterward, the fear-conditioning paradigm was used to study conditioned fear extinction. Anxiety-like behavior was measured one day (PND 50) and twenty-one days (PND 70, adulthood) after stress using the elevated-plus maze and dark-light box tests, respectively. With another set of rats, excitatory synaptic transmission was analyzed with slices of the prelimbic cortex. Rats that had been stressed during adolescence and adulthood had higher anxiety-like behavior levels than did controls, while stress-induced slowing of learned fear extinction in adolescence was reversed during adulthood. As well, the field excitatory postsynaptic potentials of stressed adolescent rats had significantly lower amplitudes than those of controls, although the amplitudes were higher in adulthood. Our results demonstrate that short-term stress in adolescence induces strong effects on excitatory synaptic transmission in the prelimbic cortex and extinction of learned fear, where the effect of stress on anxiety is more persistent than on the extinction of learned fear. These data contribute to the understanding of stress neurobiology. Copyright © 2013 Elsevier B.V. All rights reserved.

Dynamics of excitatory synaptic components in sustained firing at low rates.

PubMed

Wyart, Claire; Cocco, Simona; Bourdieu, Laurent; Léger, Jean-Francois; Herr, Catherine; Chatenay, Didier

2005-06-01

Sustained firing is necessary for the persistent activity associated with working memory. The relative contributions of the reverberation of excitation and of the temporal dynamics of the excitatory postsynaptic potential (EPSP) to the maintenance of activity are difficult to evaluate in classical preparations. We used simplified models of synchronous excitatory networks, hippocampal autapses and pairs, to study the synaptic mechanisms underlying firing at low rates. Calcium imaging and cell attached recordings showed that these neurons spontaneously fired bursts of action potentials that lasted for seconds over a wide range of frequencies. In 2-wk-old cells, the median firing frequency was low (11 +/- 8.8 Hz), whereas in 3- to 4-wk-old cells, it decreased to a very low value (2 +/- 1.3 Hz). In both cases, we have shown that the slowest synaptic component supported firing. In 2-wk-old autapses, antagonists of N-methyl-d-aspartate receptors (NMDARs) induced rare isolated spikes showing that the NMDA component of the EPSP was essential for bursts at low frequency. In 3- to 4-wk-old neurons, the very low frequency firing was maintained without the NMDAR activation. However EGTA-AM or alpha-methyl-4-carboxyphenylglycine (MCPG) removed the very slow depolarizing component of the EPSP and prevented the sustained firing at very low rate. A metabotropic glutamate receptor (mGluR)-activated calcium sensitive conductance is therefore responsible for a very slow synaptic component associated with firing at very low rate. In addition, our observations suggested that the asynchronous release of glutamate might participate also in the recurring bursting.

Nanogranular SiO2 proton gated silicon layer transistor mimicking biological synapses

NASA Astrophysics Data System (ADS)

Liu, M. J.; Huang, G. S.; Feng, P.; Guo, Q. L.; Shao, F.; Tian, Z. A.; Li, G. J.; Wan, Q.; Mei, Y. F.

2016-06-01

Silicon on insulator (SOI)-based transistors gated by nanogranular SiO2 proton conducting electrolytes were fabricated to mimic synapse behaviors. This SOI-based device has both top proton gate and bottom buried oxide gate. Electrical transfer properties of top proton gate show hysteresis curves different from those of bottom gate, and therefore, excitatory post-synaptic current and paired pulse facilitation (PPF) behavior of biological synapses are mimicked. Moreover, we noticed that PPF index can be effectively tuned by the spike interval applied on the top proton gate. Synaptic behaviors and functions, like short-term memory, and its properties are also experimentally demonstrated in our device. Such SOI-based electronic synapses are promising for building neuromorphic systems.

Brain region-dependent differential expression of alpha-synuclein.

PubMed

Taguchi, Katsutoshi; Watanabe, Yoshihisa; Tsujimura, Atsushi; Tanaka, Masaki

2016-04-15

α-Synuclein, the major constituent of Lewy bodies (LBs), is normally expressed in presynapses and is involved in synaptic function. Abnormal intracellular aggregation of α-synuclein is observed as LBs and Lewy neurites in neurodegenerative disorders, such as Parkinson's disease (PD) or dementia with Lewy bodies. Accumulated evidence suggests that abundant intracellular expression of α-synuclein is one of the risk factors for pathological aggregation. Recently, we reported differential expression patterns of α-synuclein between excitatory and inhibitory hippocampal neurons. Here we further investigated the precise expression profile in the adult mouse brain with special reference to vulnerable regions along the progression of idiopathic PD. The results show that α-synuclein was highly expressed in the neuronal cell bodies of some early PD-affected brain regions, such as the olfactory bulb, dorsal motor nucleus of the vagus, and substantia nigra pars compacta. Synaptic expression of α-synuclein was mostly accompanied by expression of vesicular glutamate transporter-1, an excitatory presynaptic marker. In contrast, expression of α-synuclein in the GABAergic inhibitory synapses was different among brain regions. α-Synuclein was clearly expressed in inhibitory synapses in the external plexiform layer of the olfactory bulb, globus pallidus, and substantia nigra pars reticulata, but not in the cerebral cortex, subthalamic nucleus, or thalamus. These results suggest that some neurons in early PD-affected human brain regions express high levels of perikaryal α-synuclein, as happens in the mouse brain. Additionally, synaptic profiles expressing α-synuclein are different in various brain regions. © 2015 Wiley Periodicals, Inc.

Changes in hippocampal synaptic functions and protein expression in monosodium glutamate-treated obese mice during development of glucose intolerance.

PubMed

Sasaki-Hamada, Sachie; Hojo, Yuki; Koyama, Hajime; Otsuka, Hayuma; Oka, Jun-Ichiro

2015-05-01

Glucose is the sole neural fuel for the brain and is essential for cognitive function. Abnormalities in glucose tolerance may be associated with impairments in cognitive function. Experimental obese model mice can be generated by an intraperitoneal injection of monosodium glutamate (MSG; 2 mg/g) once a day for 5 days from 1 day after birth. MSG-treated mice have been shown to develop glucose intolerance and exhibit chronic neuroendocrine dysfunction associated with marked cognitive malfunctions at 28-29  weeks old. Although hippocampal synaptic plasticity is impaired in MSG-treated mice, changes in synaptic transmission remain unknown. Here, we investigated whether glucose intolerance influenced cognitive function, synaptic properties and protein expression in the hippocampus. We demonstrated that MSG-treated mice developed glucose intolerance due to an impairment in the effectiveness of insulin actions, and showed cognitive impairments in the Y-maze test. Moreover, long-term potentiation (LTP) at Schaffer collateral-CA1 pyramidal synapses in hippocampal slices was impaired, and the relationship between the slope of extracellular field excitatory postsynaptic potential and stimulus intensity of synaptic transmission was weaker in MSG-treated mice. The protein levels of vesicular glutamate transporter 1 and GluA1 glutamate receptor subunits decreased in the CA1 region of MSG-treated mice. These results suggest that deficits in glutamatergic presynapses as well as postsynapses lead to impaired synaptic plasticity in MSG-treated mice during the development of glucose intolerance, though it remains unknown whether impaired LTP is due to altered inhibitory transmission. It may be important to examine changes in glucose tolerance in order to prevent cognitive malfunctions associated with diabetes. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Chronic stress induces a selective decrease in AMPA receptor-mediated synaptic excitation at hippocampal temporoammonic-CA1 synapses.

PubMed

Kallarackal, Angy J; Kvarta, Mark D; Cammarata, Erin; Jaberi, Leelah; Cai, Xiang; Bailey, Aileen M; Thompson, Scott M

2013-10-02

Chronic stress promotes depression, but how it disrupts cognition and mood remains unknown. Chronic stress causes atrophy of pyramidal cell dendrites in the hippocampus and cortex in human and animal models, and a depressive-like behavioral state. We now test the hypothesis that excitatory temporoammonic (TA) synapses in the distal dendrites of CA1 pyramidal cells in rats are altered by chronic unpredictable stress (CUS) and restored by chronic antidepressant treatment, in conjunction with the behavioral consequences of CUS. We observed a decrease in AMPAR-mediated excitation at TA-CA1 synapses, but not Schaffer collateral-CA1 synapses, after CUS, with a corresponding layer-specific decrease in GluA1 expression. Both changes were reversed by chronic fluoxetine. CUS also disrupted long-term memory consolidation in the Morris water maze, a function of TA-CA1 synapses. The decreases in TA-CA1 AMPAR-mediated excitation and performance in the consolidation test were correlated positively with decreases in sucrose preference, a measure of anhedonia. We conclude that chronic stress selectively decreases AMPAR number and function at specific synapses and suggest that this underlies various depressive endophenotypes. Our findings provide evidence that glutamatergic dysfunction is an underlying cause of depression and that current first-line antidepressant drugs act by restoring excitatory synaptic strength. Our findings suggest novel therapeutic targets for this debilitating disease.

Behavioral and Electrophysiological Characterization of Dyt1 Heterozygous Knockout Mice

PubMed Central

Yokoi, Fumiaki; Chen, Huan-Xin; Dang, Mai Tu; Cheetham, Chad C.; Campbell, Susan L.; Roper, Steven N.; Sweatt, J. David; Li, Yuqing

2015-01-01

DYT1 dystonia is an inherited movement disorder caused by mutations in DYT1 (TOR1A), which codes for torsinA. Most of the patients have a trinucleotide deletion (ΔGAG) corresponding to a glutamic acid in the C-terminal region (torsinAΔE). Dyt1 ΔGAG heterozygous knock-in (KI) mice, which mimic ΔGAG mutation in the endogenous gene, exhibit motor deficits and deceased frequency of spontaneous excitatory post-synaptic currents (sEPSCs) and normal theta-burst-induced long-term potentiation (LTP) in the hippocampal CA1 region. Although Dyt1 KI mice show decreased hippocampal torsinA levels, it is not clear whether the decreased torsinA level itself affects the synaptic plasticity or torsinAΔE does it. To analyze the effect of partial torsinA loss on motor behaviors and synaptic transmission, Dyt1 heterozygous knock-out (KO) mice were examined as a model of a frame-shift DYT1 mutation in patients. Consistent with Dyt1 KI mice, Dyt1 heterozygous KO mice showed motor deficits in the beam-walking test. Dyt1 heterozygous KO mice showed decreased hippocampal torsinA levels lower than those in Dyt1 KI mice. Reduced sEPSCs and normal miniature excitatory post-synaptic currents (mEPSCs) were also observed in the acute hippocampal brain slices from Dyt1 heterozygous KO mice, suggesting that the partial loss of torsinA function in Dyt1 KI mice causes action potential-dependent neurotransmitter release deficits. On the other hand, Dyt1 heterozygous KO mice showed enhanced hippocampal LTP, normal input-output relations and paired pulse ratios in the extracellular field recordings. The results suggest that maintaining an appropriate torsinA level is important to sustain normal motor performance, synaptic transmission and plasticity. Developing therapeutics to restore a normal torsinA level may help to prevent and treat the symptoms in DYT1 dystonia. PMID:25799505

Behavioral and electrophysiological characterization of Dyt1 heterozygous knockout mice.

PubMed

Yokoi, Fumiaki; Chen, Huan-Xin; Dang, Mai Tu; Cheetham, Chad C; Campbell, Susan L; Roper, Steven N; Sweatt, J David; Li, Yuqing

2015-01-01

DYT1 dystonia is an inherited movement disorder caused by mutations in DYT1 (TOR1A), which codes for torsinA. Most of the patients have a trinucleotide deletion (ΔGAG) corresponding to a glutamic acid in the C-terminal region (torsinA(ΔE)). Dyt1 ΔGAG heterozygous knock-in (KI) mice, which mimic ΔGAG mutation in the endogenous gene, exhibit motor deficits and deceased frequency of spontaneous excitatory post-synaptic currents (sEPSCs) and normal theta-burst-induced long-term potentiation (LTP) in the hippocampal CA1 region. Although Dyt1 KI mice show decreased hippocampal torsinA levels, it is not clear whether the decreased torsinA level itself affects the synaptic plasticity or torsinA(ΔE) does it. To analyze the effect of partial torsinA loss on motor behaviors and synaptic transmission, Dyt1 heterozygous knock-out (KO) mice were examined as a model of a frame-shift DYT1 mutation in patients. Consistent with Dyt1 KI mice, Dyt1 heterozygous KO mice showed motor deficits in the beam-walking test. Dyt1 heterozygous KO mice showed decreased hippocampal torsinA levels lower than those in Dyt1 KI mice. Reduced sEPSCs and normal miniature excitatory post-synaptic currents (mEPSCs) were also observed in the acute hippocampal brain slices from Dyt1 heterozygous KO mice, suggesting that the partial loss of torsinA function in Dyt1 KI mice causes action potential-dependent neurotransmitter release deficits. On the other hand, Dyt1 heterozygous KO mice showed enhanced hippocampal LTP, normal input-output relations and paired pulse ratios in the extracellular field recordings. The results suggest that maintaining an appropriate torsinA level is important to sustain normal motor performance, synaptic transmission and plasticity. Developing therapeutics to restore a normal torsinA level may help to prevent and treat the symptoms in DYT1 dystonia.

Ablation of SNX6 leads to defects in synaptic function of CA1 pyramidal neurons and spatial memory

PubMed Central

Niu, Yang; Dai, Zhonghua; Liu, Wenxue; Zhang, Cheng; Yang, Yanrui; Guo, Zhenzhen; Li, Xiaoyu; Xu, Chenchang; Huang, Xiahe; Wang, Yingchun; Shi, Yun S; Liu, Jia-Jia

2017-01-01

SNX6 is a ubiquitously expressed PX-BAR protein that plays important roles in retromer-mediated retrograde vesicular transport from endosomes. Here we report that CNS-specific Snx6 knockout mice exhibit deficits in spatial learning and memory, accompanied with loss of spines from distal dendrites of hippocampal CA1 pyramidal cells. SNX6 interacts with Homer1b/c, a postsynaptic scaffold protein crucial for the synaptic distribution of other postsynaptic density (PSD) proteins and structural integrity of dendritic spines. We show that SNX6 functions independently of retromer to regulate distribution of Homer1b/c in the dendritic shaft. We also find that Homer1b/c translocates from shaft to spines by protein diffusion, which does not require SNX6. Ablation of SNX6 causes reduced distribution of Homer1b/c in distal dendrites, decrease in surface levels of AMPAR and impaired AMPAR-mediated synaptic transmission. These findings reveal a physiological role of SNX6 in CNS excitatory neurons. DOI: http://dx.doi.org/10.7554/eLife.20991.001 PMID:28134614

Molecular and Epigenetic Mechanisms for the Complex Effects of Stress on Synaptic Physiology and Cognitive Functions

PubMed Central

Yuen, Eunice Y.; Wei, Jing

2017-01-01

Abstract Evidence over the past decades has found that stress, particularly through the corticosterone stress hormones, produces complex changes in glutamatergic signaling in prefrontal cortex, which leads to the alteration of cognitive processes medicated by this brain region. Interestingly, the effects of stress on glutamatergic transmission appear to be “U-shaped,” depending upon the duration and severity of the stressor. These biphasic effects of acute vs chronic stress represent the adaptive vs maladaptive responses to stressful stimuli. Animal studies suggest that the stress-induced modulation of excitatory synaptic transmission involves changes in presynaptic glutamate release, postsynaptic glutamate receptor membrane trafficking and degradation, spine structure and cytoskeleton network, and epigenetic control of gene expression. This review will discuss current findings on the key molecules involved in the stress-induced regulation of prefrontal cortex synaptic physiology and prefrontal cortex-mediated functions. Understanding the molecular and epigenetic mechanisms that underlie the complex effects of stress will help to develop novel strategies to cope with stress-related mental disorders. PMID:29016816

Molecular and Epigenetic Mechanisms for the Complex Effects of Stress on Synaptic Physiology and Cognitive Functions.

PubMed

Yuen, Eunice Y; Wei, Jing; Yan, Zhen

2017-11-01

Evidence over the past decades has found that stress, particularly through the corticosterone stress hormones, produces complex changes in glutamatergic signaling in prefrontal cortex, which leads to the alteration of cognitive processes medicated by this brain region. Interestingly, the effects of stress on glutamatergic transmission appear to be "U-shaped," depending upon the duration and severity of the stressor. These biphasic effects of acute vs chronic stress represent the adaptive vs maladaptive responses to stressful stimuli. Animal studies suggest that the stress-induced modulation of excitatory synaptic transmission involves changes in presynaptic glutamate release, postsynaptic glutamate receptor membrane trafficking and degradation, spine structure and cytoskeleton network, and epigenetic control of gene expression. This review will discuss current findings on the key molecules involved in the stress-induced regulation of prefrontal cortex synaptic physiology and prefrontal cortex-mediated functions. Understanding the molecular and epigenetic mechanisms that underlie the complex effects of stress will help to develop novel strategies to cope with stress-related mental disorders. © The Author 2017. Published by Oxford University Press on behalf of CINP.

The Plasminogen Activation System Promotes Dendritic Spine Recovery and Improvement in Neurological Function After an Ischemic Stroke

PubMed Central

Jeanneret, Valerie; Yepes, Manuel

2016-01-01

Advances in neurocritical care and interventional neuroradiology have led to a significant decrease in acute ischemic stroke (AIS) mortality. In contrast, due to the lack of an effective therapeutic strategy to promote neuronal recovery among AIS survivors, cerebral ischemia is still a leading cause of disability in the world. Ischemic stroke has a harmful impact on synaptic structure and function, and plasticity-mediated synaptic recovery is associated with neurological improvement following an AIS. Dendritic spines (DSs) are specialized dendritic protrusions that receive most of the excitatory input in the brain. The deleterious effect of cerebral ischemia on DSs morphology and function has been associated with impaired synaptic transmission and neurological deterioration. However, these changes are reversible if cerebral blood flow is restored on time, and this recovery has been associated with neurological improvement following an AIS. Tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) are two serine proteases that besides catalyzing the conversion of plasminogen into plasmin in the intravascular and pericellular environment, respectively, are also are efficient inductors of synaptic plasticity. Accordingly, recent evidence indicates that both, tPA and uPA, protect DSs from the metabolic stress associated with the ischemic injury, and promote their morphological and functional recovery during the recovery phase from an AIS. Here we will review data indicating that plasticity-induced changes in DSs and the associated post-synaptic density play a pivotal role in the recovery process from AIS, making special emphasis on the role of tPA and uPA in this process. PMID:26846991

Synaptic Modifications in the Medial Prefrontal Cortex in Susceptibility and Resilience to Stress

PubMed Central

Wang, Minghui; Perova, Zinaida; Arenkiel, Benjamin R.

2014-01-01

When facing stress, most individuals are resilient whereas others are prone to developing mood disorders. The brain mechanisms underlying such divergent behavioral responses remain unclear. Here we used the learned helplessness procedure in mice to examine the role of the medial prefrontal cortex (mPFC), a brain region highly implicated in both clinical and animal models of depression, in adaptive and maladaptive behavioral responses to stress. We found that uncontrollable and inescapable stress induced behavioral state-dependent changes in the excitatory synapses onto a subset of mPFC neurons: those that were activated during behavioral responses as indicated by their expression of the activity reporter c-Fos. Whereas synaptic potentiation was linked to learned helplessness, a depression-like behavior, synaptic weakening, was associated with resilience to stress. Notably, enhancing the activity of mPFC neurons using a chemical–genetic method was sufficient to convert the resilient behavior into helplessness. Our results provide direct evidence that mPFC dysfunction is linked to maladaptive behavioral responses to stress, and suggest that enhanced excitatory synaptic drive onto mPFC neurons may underlie the previously reported hyperactivity of this brain region in depression. PMID:24872553

Acute and Chronic Effects of Ethanol on Learning-Related Synaptic Plasticity

PubMed Central

Zorumski, Charles F.; Mennerick, Steven; Izumi, Yukitoshi

2014-01-01

Alcoholism is associated with acute and long-term cognitive dysfunction including memory impairment, resulting in substantial disability and cost to society. Thus, understanding how ethanol impairs cognition is essential for developing treatment strategies to dampen its adverse impact. Memory processing is thought to involve persistent, use-dependent changes in synaptic transmission, and ethanol alters the activity of multiple signaling molecules involved in synaptic processing, including modulation of the glutamate and gamma-aminobutyric acid (GABA) transmitter systems that mediate most fast excitatory and inhibitory transmission in the brain. Effects on glutamate and GABA receptors contribute to ethanol-induced changes in long-term potentiation (LTP) and long-term depression (LTD), forms of synaptic plasticity thought to underlie memory acquisition. In this paper, we review the effects of ethanol on learning-related forms of synaptic plasticity with emphasis on changes observed in the hippocampus, a brain region that is critical for encoding contextual and episodic memories. We also include studies in other brain regions as they pertain to altered cognitive and mental function. Comparison of effects in the hippocampus to other brain regions is instructive for understanding the complexities of ethanol’s acute and long-term pharmacological consequences. PMID:24447472

Acetyl-L-carnitine improves aged brain function.

PubMed

Kobayashi, Satoru; Iwamoto, Machiko; Kon, Kazuo; Waki, Hatsue; Ando, Susumu; Tanaka, Yasukazu

2010-07-01

The effects of acetyl-L-carnitine (ALCAR), an acetyl derivative of L-carnitine, on memory and learning capacity and on brain synaptic functions of aged rats were examined. Male Fischer 344 rats were given ALCAR (100 mg/kg bodyweight) per os for 3 months and were subjected to the Hebb-Williams tasks and AKON-1 task to assess their learning capacity. Cholinergic activities were determined with synaptosomes isolated from brain cortices of the rats. Choline parameters, the high-affinity choline uptake, acetylcholine (ACh) synthesis and depolarization-evoked ACh release were all enhanced in the ALCAR group. An increment of depolarization-induced calcium ion influx into synaptosomes was also evident in rats given ALCAR. Electrophysiological studies using hippocampus slices indicated that the excitatory postsynaptic potential slope and population spike size were both increased in ALCAR-treated rats. These results indicate that ALCAR increases synaptic neurotransmission in the brain and consequently improves learning capacity in aging rats.

Ba2+- and bupivacaine-sensitive background K+ conductances mediate rapid EPSP attenuation in oligodendrocyte precursor cells

PubMed Central

Chan, Chu-Fang; Kuo, Tzu-Wei; Weng, Ju-Yun; Lin, Yen-Chu; Chen, Ting-Yu; Cheng, Jen-Kun; Lien, Cheng-Chang

2013-01-01

Glutamatergic transmission onto oligodendrocyte precursor cells (OPCs) may regulate OPC proliferation, migration and differentiation. Dendritic integration of excitatory postsynaptic potentials (EPSPs) is critical for neuronal functions, and mechanisms regulating dendritic propagation and summation of EPSPs are well understood. However, little is known about EPSP attenuation and integration in OPCs. We developed realistic OPC models for synaptic integration, based on passive membrane responses of OPCs obtained by simultaneous dual whole-cell patch-pipette recordings. Compared with neurons, OPCs have a very low value of membrane resistivity, which is largely mediated by Ba2+- and bupivacaine-sensitive background K+ conductances. The very low membrane resistivity not only leads to rapid EPSP attenuation along OPC processes but also sharpens EPSPs and narrows the temporal window for EPSP summation. Thus, background K+ conductances regulate synaptic responses and integration in OPCs, thereby affecting activity-dependent neuronal control of OPC development and function. PMID:23940377

Neurolastin, a dynamin family GTPase, regulates excitatory synapses and spine density

PubMed Central

Madan Lomash, Richa; Gu, Xinglong; Youle, Richard J.; Lu, Wei; Roche, Katherine W.

2015-01-01

SUMMARY Membrane trafficking and spinogenesis contribute significantly to changes in synaptic strength during development and in various paradigms of synaptic plasticity. GTPases of the dynamin family are key players regulating membrane trafficking. Here, we identify a brain-specific dynamin family GTPase, neurolastin (RNF112/Znf179), with closest homology to atlastin. We demonstrate that neurolastin has functional GTPase and RING domains, making it a unique protein identified with this multi-enzymatic domain organization. We also show that neurolastin is a peripheral membrane protein, which localizes to endosomes and affects endosomal membrane dynamics via its RING domain. In addition, neurolastin knockout mice have fewer dendritic spines, and rescue of the wildtype phenotype requires both the GTPase and RING domains. Furthermore, we find fewer functional synapses and reduced paired pulse facilitation in neurolastin knockout mice. Thus, we identify neurolastin as a dynamin family GTPase that affects endosome size and spine density. PMID:26212327

Electromyographic reflexes evoked in human flexor carpi radialis by tendon vibration.

PubMed

Cody, F W; Goodwin, C N; Richardson, H C

1990-10-01

The rectified, electromyographic (EMG) reflexes evoked in the voluntarily contracting flexor carpi radialis (FCR) muscle by vibration of its tendon were studied in healthy human subjects. Responses comprised a prominent, transient, short-latency (SL, 20-25 ms) increase in EMG, attributed to Ia mono- and/or oligo-synaptic action, followed by a series of less pronounced troughs and peaks of activity. Evidence of continuing Ia mono- or oligo-synaptic action was indicated by (i) the presence of small subpeaks, at vibration frequency, superimposed upon the excitatory components and (ii) the occurrence of a separate reduction in EMG, of consistent latency (ca. 30 ms), after cessation of stimulation. Progressively shortening the train of vibration from 29 cycles (at 145 Hz) to a single cycle significantly reduced net, excitatory reflex activity. Gradually increasing the level (10-50% maximum) of pre-existing voluntary contraction on top of which reflexes were elicited, by moderately prolonged (29 cycles) trains of vibration, resulted in small increases, in absolute terms, in SL peaks and in later, excitatory EMG activity. Excitatory reflexes, when normalised for pre-stimulus EMG, however, declined in an approximately hyperbolic manner with increasing background activity over this range. Thus, effective "automatic gain compensation" does not operate for vibration reflexes in FCR.

Repeated Neck Restraint Stress Bidirectionally Modulates Excitatory Transmission in the Dentate Gyrus and Performance in a Hippocampus-dependent Memory Task.

PubMed

Spyrka, Jadwiga; Hess, Grzegorz

2018-05-21

The consequences of stress depend on characteristics of the stressor, including the duration of exposure, severity, and predictability. Exposure of mice to repeated neck restraint has been shown to bidirectionally modulate the potential for long-term potentiation (LTP) in the dentate gyrus (DG) in a manner dependent on the number of restraint repetitions, but the influence of repeated brief neck restraint on electrophysiology of single DG neurons has not yet been investigated. Here, we aimed at finding the effects of 1, 3, 7, 14, or 21 daily neck restraint sessions lasting 10 min on electrophysiological characteristics of DG granule cells as well as excitatory and inhibitory synaptic inputs to these neurons. While the excitability of DG granule cells and inhibitory synaptic transmission were unchanged, neck restraint decreased the frequency of spontaneous excitatory currents after three repetitions but enhanced it after 14 and 21 repetitions. The consequences of repeated neck restraint on hippocampus-dependent memory were investigated using the object location test (OLT). Neck restraint stress impaired cognitive performance in the OLT after three repetitions but improved it after 14 and 21 repetitions. Mice subjected to three neck restraint sessions displayed an increase in the measures of depressive and anxiety-like behaviors, however, prolongation of the exposure to neck restraint resulted in a gradual decline in the intensity of these measures. These data indicate that stress imposed by an increasing number of repeated neck restraint episodes bidirectionally modulates both excitatory synaptic transmission in the DG and cognitive performance in the object location memory task. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

Multi-level characterization of balanced inhibitory-excitatory cortical neuron network derived from human pluripotent stem cells.

PubMed

Nadadhur, Aishwarya G; Emperador Melero, Javier; Meijer, Marieke; Schut, Desiree; Jacobs, Gerbren; Li, Ka Wan; Hjorth, J J Johannes; Meredith, Rhiannon M; Toonen, Ruud F; Van Kesteren, Ronald E; Smit, August B; Verhage, Matthijs; Heine, Vivi M

2017-01-01

Generation of neuronal cultures from induced pluripotent stem cells (hiPSCs) serve the studies of human brain disorders. However we lack neuronal networks with balanced excitatory-inhibitory activities, which are suitable for single cell analysis. We generated low-density networks of hPSC-derived GABAergic and glutamatergic cortical neurons. We used two different co-culture models with astrocytes. We show that these cultures have balanced excitatory-inhibitory synaptic identities using confocal microscopy, electrophysiological recordings, calcium imaging and mRNA analysis. These simple and robust protocols offer the opportunity for single-cell to multi-level analysis of patient hiPSC-derived cortical excitatory-inhibitory networks; thereby creating advanced tools to study disease mechanisms underlying neurodevelopmental disorders.

Astrocyte transforming growth factor beta 1 promotes inhibitory synapse formation via CaM kinase II signaling.

PubMed

Diniz, Luan Pereira; Tortelli, Vanessa; Garcia, Matheus Nunes; Araújo, Ana Paula Bérgamo; Melo, Helen M; Silva, Gisele S Seixas da; Felice, Fernanda G De; Alves-Leon, Soniza Vieira; Souza, Jorge Marcondes de; Romão, Luciana Ferreira; Castro, Newton Gonçalves; Gomes, Flávia Carvalho Alcantara

2014-12-01

The balance between excitatory and inhibitory synaptic inputs is critical for the control of brain function. Astrocytes play important role in the development and maintenance of neuronal circuitry. Whereas astrocytes-derived molecules involved in excitatory synapses are recognized, molecules and molecular mechanisms underlying astrocyte-induced inhibitory synapses remain unknown. Here, we identified transforming growth factor beta 1 (TGF-β1), derived from human and murine astrocytes, as regulator of inhibitory synapse in vitro and in vivo. Conditioned media derived from human and murine astrocytes induce inhibitory synapse formation in cerebral cortex neurons, an event inhibited by pharmacologic and genetic manipulation of the TGF-β pathway. TGF-β1-induction of inhibitory synapse depends on glutamatergic activity and activation of CaM kinase II, which thus induces localization and cluster formation of the synaptic adhesion protein, Neuroligin 2, in inhibitory postsynaptic terminals. Additionally, intraventricular injection of TGF-β1 enhanced inhibitory synapse number in the cerebral cortex. Our results identify TGF-β1/CaMKII pathway as a novel molecular mechanism underlying astrocyte control of inhibitory synapse formation. We propose here that the balance between excitatory and inhibitory inputs might be provided by astrocyte signals, at least partly achieved via TGF-β1 downstream pathways. Our work contributes to the understanding of the GABAergic synapse formation and may be of relevance to further the current knowledge on the mechanisms underlying the development of various neurological disorders, which commonly involve impairment of inhibitory synapse transmission. © 2014 Wiley Periodicals, Inc.

Electron tomographic analysis of gap junctions in lateral giant fibers of crayfish.

PubMed

Ohta, Yasumi; Nishikawa, Kouki; Hiroaki, Yoko; Fujiyoshi, Yoshinori

2011-07-01

Innexin-gap junctions in crayfish lateral giant fibers (LGFs) have an important role in escape behavior as a key component of rapid signal transduction. Knowledge of the structure and function of characteristic vesicles on the both sides of the gap junction, however, is limited. We used electron tomography to analyze the three-dimensional structure of crayfish gap junctions and gap junctional vesicles (GJVs). Tomographic analyses showed that some vesicles were anchored to innexons and almost all vesicles were connected by thin filaments. High densities inside the GJVs and projecting densities on the GJV membranes were observed in fixed and stained samples. Because the densities inside synaptic vesicles were dependent on the fixative conditions, different fixative conditions were used to elucidate the molecules included in the GJVs. The projecting densities on the GJVs were studied by immunoelectron microscopy with anti-vesicular monoamine transporter (anti-VMAT) and anti-vesicular nucleotide transporter (anti-VNUT) antibodies. Some of the projecting densities were labeled by anti-VNUT, but not anti-VMAT. Three-dimensional analyses of GJVs and excitatory chemical synaptic vesicles (CSVs) revealed clear differences in their sizes and central densities. Furthermore, the imaging data obtained under different fixative conditions and the immunolabeling results, in which GJVs were positively labeled for anti-VNUT but excitatory CSVs were not, support our model that GJVs contain nucleotides and excitatory CSVs do not. We propose a model in which characteristic GJVs containing nucleotides play an important role in the signal processing in gap junctions of crayfish LGFs. Copyright © 2011 Elsevier Inc. All rights reserved.

Functional Convergence of Neurons Generated in the Developing and Adult Hippocampus

PubMed Central

Piatti, Verónica C; Morgenstern, Nicolás A; Zhao, Chunmei; van Praag, Henriette; Gage, Fred H; Schinder, Alejandro F

2006-01-01

The dentate gyrus of the hippocampus contains neural progenitor cells (NPCs) that generate neurons throughout life. Developing neurons of the adult hippocampus have been described in depth. However, little is known about their functional properties as they become fully mature dentate granule cells (DGCs). To compare mature DGCs generated during development and adulthood, NPCs were labeled at both time points using retroviruses expressing different fluorescent proteins. Sequential electrophysiological recordings from neighboring neurons of different ages were carried out to quantitatively study their major synaptic inputs: excitatory projections from the entorhinal cortex and inhibitory afferents from local interneurons. Our results show that DGCs generated in the developing and adult hippocampus display a remarkably similar afferent connectivity with regard to both glutamate and GABA, the major neurotransmitters. We also demonstrate that adult-born neurons can fire action potentials in response to an excitatory drive, exhibiting a firing behavior comparable to that of neurons generated during development. We propose that neurons born in the developing and adult hippocampus constitute a functionally homogeneous neuronal population. These observations are critical to understanding the role of adult neurogenesis in hippocampal function. PMID:17121455

Altered Striatal Synaptic Function and Abnormal Behaviour in Shank3 Exon4-9 Deletion Mouse Model of Autism.

PubMed

Jaramillo, Thomas C; Speed, Haley E; Xuan, Zhong; Reimers, Jeremy M; Liu, Shunan; Powell, Craig M

2016-03-01

Shank3 is a multi-domain, synaptic scaffolding protein that organizes proteins in the postsynaptic density of excitatory synapses. Clinical studies suggest that ∼ 0.5% of autism spectrum disorder (ASD) cases may involve SHANK3 mutation/deletion. Patients with SHANK3 mutations exhibit deficits in cognition along with delayed/impaired speech/language and repetitive and obsessive/compulsive-like (OCD-like) behaviors. To examine how mutation/deletion of SHANK3 might alter brain function leading to ASD, we have independently created mice with deletion of Shank3 exons 4-9, a region implicated in ASD patients. We find that homozygous deletion of exons 4-9 (Shank3(e4-9) KO) results in loss of the two highest molecular weight isoforms of Shank3 and a significant reduction in other isoforms. Behaviorally, both Shank3(e4-9) heterozygous (HET) and Shank3(e4-9) KO mice display increased repetitive grooming, deficits in novel and spatial object recognition learning and memory, and abnormal ultrasonic vocalizations. Shank3(e4-9) KO mice also display abnormal social interaction when paired with one another. Analysis of synaptosome fractions from striata of Shank3(e4-9) KO mice reveals decreased Homer1b/c, GluA2, and GluA3 expression. Both Shank3(e4-9) HET and KO demonstrated a significant reduction in NMDA/AMPA ratio at excitatory synapses onto striatal medium spiny neurons. Furthermore, Shank3(e4-9) KO mice displayed reduced hippocampal LTP despite normal baseline synaptic transmission. Collectively these behavioral, biochemical and physiological changes suggest Shank3 isoforms have region-specific roles in regulation of AMPAR subunit localization and NMDAR function in the Shank3(e4-9) mutant mouse model of autism. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

Chaos and Correlated Avalanches in Excitatory Neural Networks with Synaptic Plasticity

NASA Astrophysics Data System (ADS)

Pittorino, Fabrizio; Ibáñez-Berganza, Miguel; di Volo, Matteo; Vezzani, Alessandro; Burioni, Raffaella

2017-03-01

A collective chaotic phase with power law scaling of activity events is observed in a disordered mean field network of purely excitatory leaky integrate-and-fire neurons with short-term synaptic plasticity. The dynamical phase diagram exhibits two transitions from quasisynchronous and asynchronous regimes to the nontrivial, collective, bursty regime with avalanches. In the homogeneous case without disorder, the system synchronizes and the bursty behavior is reflected into a period doubling transition to chaos for a two dimensional discrete map. Numerical simulations show that the bursty chaotic phase with avalanches exhibits a spontaneous emergence of persistent time correlations and enhanced Kolmogorov complexity. Our analysis reveals a mechanism for the generation of irregular avalanches that emerges from the combination of disorder and deterministic underlying chaotic dynamics.

Glutamatergic postsynaptic block by Pamphobeteus spider venoms in crayfish.

PubMed

Araque, A; Ferreira, W; Lucas, S; Buño, W

1992-01-31

The effects of toxins from venom glands of two south american spiders (Pamphobeteus platyomma and P. soracabae) on glutamatergic excitatory synaptic transmission were studied in the neuromuscular junction of the opener muscle of crayfish. The toxins selectively and reversibly blocked both excitatory postsynaptic currents and potentials in a dose-dependent manner. They also reversibly abolished glutamate-induced postsynaptic membrane depolarization. They had no effect on resting postsynaptic membrane conductance nor on postsynaptic voltage-gated currents. The synaptic facilitation and the frequency of miniature postsynaptic potentials were unaffected by the toxins, indicating that presynaptic events were not modified. Picrotoxin, a selective antagonist of the gamma-aminobutyric acid (GABA)A receptor, did not modify toxin effects. We conclude that both toxins specifically block the postsynaptic glutamate receptor-channel complex.

Low-Frequency rTMS Ameliorates Autistic-Like Behaviors in Rats Induced by Neonatal Isolation Through Regulating the Synaptic GABA Transmission

PubMed Central

Tan, Tao; Wang, Wei; Xu, Haitao; Huang, Zhilin; Wang, Yu Tian; Dong, Zhifang

2018-01-01

Patients with autism spectrum disorder (ASD) display abnormalities in neuronal development, synaptic function and neural circuits. The imbalance of excitatory and inhibitory (E/I) synaptic transmission has been proposed to cause the main behavioral characteristics of ASD. Repetitive transcranial magnetic stimulation (rTMS) can directly or indirectly induce excitability and synaptic plasticity changes in the brain noninvasively. However, whether rTMS can ameliorate autistic-like behaviors in animal model via regulating the balance of E/I synaptic transmission is unknown. By using our recent reported animal model with autistic-like behaviors induced by neonatal isolation (postnatal days 1–9), we found that low-frequency rTMS (LF-rTMS, 1 Hz) treatment for 2 weeks effectively alleviated the acquired autistic-like symptoms, as reflected by an increase in social interaction and decrease in self-grooming, anxiety- and depressive-like behaviors in young adult rats compared to those in untreated animals. Furthermore, the amelioration in autistic-like behavior was accompanied by a restoration of the balance between E/I activity, especially at the level of synaptic transmission and receptors in synaptosomes. These findings indicated that LF-rTMS may alleviate the symptoms of ASD-like behaviors caused by neonatal isolation through regulating the synaptic GABA transmission, suggesting that LF-rTMS may be a potential therapeutic technique to treat ASD. PMID:29541022

Noise Trauma-Induced Behavioral Gap Detection Deficits Correlate with Reorganization of Excitatory and Inhibitory Local Circuits in the Inferior Colliculus and Are Prevented by Acoustic Enrichment

PubMed Central

Zhang-Hooks, Ying-Xin; Roos, Hannah

2017-01-01

Hearing loss leads to a host of cellular and synaptic changes in auditory brain areas that are thought to give rise to auditory perception deficits such as temporal processing impairments, hyperacusis, and tinnitus. However, little is known about possible changes in synaptic circuit connectivity that may underlie these hearing deficits. Here, we show that mild hearing loss as a result of brief noise exposure leads to a pronounced reorganization of local excitatory and inhibitory circuits in the mouse inferior colliculus. The exact nature of these reorganizations correlated with the presence or absence of the animals' impairments in detecting brief sound gaps, a commonly used behavioral sign for tinnitus in animal models. Mice with gap detection deficits (GDDs) showed a shift in the balance of synaptic excitation and inhibition that was present in both glutamatergic and GABAergic neurons, whereas mice without GDDs showed stable excitation–inhibition balances. Acoustic enrichment (AE) with moderate intensity, pulsed white noise immediately after noise trauma prevented both circuit reorganization and GDDs, raising the possibility of using AE immediately after cochlear damage to prevent or alleviate the emergence of central auditory processing deficits. SIGNIFICANCE STATEMENT Noise overexposure is a major cause of central auditory processing disorders, including tinnitus, yet the changes in synaptic connectivity underlying these disorders remain poorly understood. Here, we find that brief noise overexposure leads to distinct reorganizations of excitatory and inhibitory synaptic inputs onto glutamatergic and GABAergic neurons and that the nature of these reorganizations correlates with animals' impairments in detecting brief sound gaps, which is often considered a sign of tinnitus. Acoustic enrichment immediately after noise trauma prevents circuit reorganizations and gap detection deficits, highlighting the potential for using sound therapy soon after cochlear damage to prevent the development of central processing deficits. PMID:28583912

[Effect of trimebutine on cholinergic transmission in neurons of the inferior mesenteric ganglion of the rabbit].

PubMed

Julé, Y

1987-01-01

We analyzed the effects of trimebutine on the synaptic activity of neurons of the rabbit inferior mesenteric ganglion, using intracellular recording techniques. The synaptic activity was produced by subthreshold stimuli (0.5 Hz) applied individually, on lumbar splanchnic and lumbar colonic nerves. These stimuli triggered cholinergic responses corresponding to fast excitatory postsynaptic potentials. In 8 of 20 neurones tested trimebutine (10(-6) g/ml) produced an inhibition of excitatory postsynaptic potentials, without any change in the resting membrane potential. In 6 of 20 neurons tested, trimebutine produced, successively, an early facilitation followed by a late inhibition of excitatory postsynaptic potentials. Both effects occurred without change in the resting membrane potential. The inhibitory and facilitatory effects of trimebutine were accompanied, by an increase and a decrease in the number of failures of nerve stimulation respectively. These results indicate that inhibitory and facilitatory effects of trimebutine correspond respectively to a decrease and an increase in the amount of acetylcholine released from presynaptic nerve terminals originating from the spinal cord and the distal colon.

Disruption of Fgf13 causes synaptic excitatory-inhibitory imbalance and genetic epilepsy and febrile seizures plus.

PubMed

Puranam, Ram S; He, Xiao Ping; Yao, Lijun; Le, Tri; Jang, Wonjo; Rehder, Catherine W; Lewis, Darrell V; McNamara, James O

2015-06-10

We identified a family in which a translocation between chromosomes X and 14 was associated with cognitive impairment and a complex genetic disorder termed "Genetic Epilepsy and Febrile Seizures Plus" (GEFS(+)). We demonstrate that the breakpoint on the X chromosome disrupted a gene that encodes an auxiliary protein of voltage-gated Na(+) channels, fibroblast growth factor 13 (Fgf13). Female mice in which one Fgf13 allele was deleted exhibited hyperthermia-induced seizures and epilepsy. Anatomic studies revealed expression of Fgf13 mRNA in both excitatory and inhibitory neurons of hippocampus. Electrophysiological recordings revealed decreased inhibitory and increased excitatory synaptic inputs in hippocampal neurons of Fgf13 mutants. We speculate that reduced expression of Fgf13 impairs excitability of inhibitory interneurons, resulting in enhanced excitability within local circuits of hippocampus and the clinical phenotype of epilepsy. These findings reveal a novel cause of this syndrome and underscore the powerful role of FGF13 in control of neuronal excitability. Copyright © 2015 the authors 0270-6474/15/358866-16$15.00/0.

Cocaine sensitization does not alter SP effects on locomotion or excitatory synaptic transmission in the NAc of rats.

PubMed

Kombian, Samuel B; Ananthalakshmi, Kethireddy V V; Zidichouski, Jeffrey A; Saleh, Tarek M

2012-02-01

Substance P (SP) and cocaine employ similar mechanisms to modify excitatory synaptic transmission in the nucleus accumbens (NAc), a region implicated in substance abuse. Here we explored, using NAc slices, whether SP effects on these synaptic responses were altered in rats that have been sensitized to cocaine and whether SP could mimic cocaine in triggering increased locomotion in sensitized rats. Intraperitoneal (IP) injection of naïve rats with cocaine (15 mg/kg) caused increased locomotion by 408.5 ± 85.9% (n = 5) which further increased by 733.1 ± 157.8% (n = 5) following a week of cocaine sensitization. A similar challenge with 10 mg/kg of SP after cocaine sensitization did not produce significant changes in locomotion (170.6 ± 61.0%; n = 4). In contrast to cocaine, IP injection of rats with SP or SP(5-11) (10-100 mg/kg) with or without phosphoramidon did not elicit changes in locomotion. In electrophysiological studies, both cocaine and SP depressed evoked NMDA and non-NMDA receptor-mediated excitatory synaptic currents (EPSCs) in slices obtained from naïve rats. In slices derived from cocaine-sensitized rats, cocaine but not SP produced a more profound decrease in non-NMDA compared to NMDA responses. Similar to that in naïve rats, cocaine's effect on the EPSCs in these sensitized rats occluded those of SP. Thus, although SP and cocaine may employ similar mechanisms to depress EPSCs in the NAc, IP injection of SP does not mimic cocaine-induced hyperlocomotion indicating that not all of cocaine's effects are mimicked by SP. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'. Copyright © 2011 Elsevier Ltd. All rights reserved.

Postsynaptic N-type or P/Q-type calcium channels mediate long-term potentiation by group I metabotropic glutamate receptors in the trigeminal oralis.

PubMed

Weon, Haein; Kim, Tae Wan; Youn, Dong-Ho

2017-11-01

Both N-type and P/Q-type voltage-gated Ca 2+ channels (VGCCs) are involved in the induction of long-term potentiation (LTP), the long-lasting increase of synaptic strength, in the central nervous system. To provide further information on the roles of N-type and P/Q-type VGCCs in the induction of LTP at excitatory synapses of trigeminal primary afferents in the spinal trigeminal subnucleus oralis (Vo), we investigated whether they contribute to the induction of LTP by activation of group I metabotropic glutamate receptors (mGluRs). (S)-3,5-Dihydroxyphenylglycine (DHPG; 10μM for 5min), the group I mGluR agonist, was used to induce LTP of excitatory postsynaptic currents that were evoked in the Vo neurons by stimulating the trigeminal track. Weak blockade of the N-type or P/Q-type VGCCs by ω-conotoxin GVIA or ω-agatoxin IVA, respectively, which inhibited only 20-40% of Ca 2+ currents recorded in isolated trigeminal ganglion neurons but had no effect on the basal excitatory synaptic transmission, completely blocked the induction of LTP. In contrast, stronger blockade of the channels, which inhibited >50% of Ca 2+ currents and about 30% of basal synaptic transmission, resulted in the development of long-term depression (LTD), the long-lasting decrease of synaptic strength. Interestingly, the postsynaptic mechanism of DHPG-induced LTP, which was determined by paired-pulse ratio, disappeared when LTP was blocked, or LTD occurred, while a presynaptic mechanism still remained. Our data suggest that postsynaptic N-type and P/Q-type VGCCs mediate the DHPG-induced LTP at the trigeminal afferent synapses in the Vo. Copyright © 2017 Elsevier Inc. All rights reserved.

Intracellular Physiology of the Rat Suprachiasmatic Nucleus: Electrical Properties, Neurotransmission, and Effects of Neuromodulators.

DTIC Science & Technology

1992-08-24

Rat Suprachiasmatic Nucleus: Electrical Properties, Neurotransmission, and Effects of Neuromodulators 12. PERSONAL AUTHOR(S) F. Edward Dudek 13a...intrinsic electrical properties, synaptic and non-synaptic transmission, and neuromodulation . We have studied the role of excitatory and inhibitory amino... Neuromodulation : Smithson. K.G.. MacVicar. B.A. and Hatton. G.I. (1983) The Biochemical Control of Neuronal Excitability. Oxford Polyethylene glycol

Synaptic Mechanisms Generating Orientation Selectivity in the ON Pathway of the Rabbit Retina

PubMed Central

Venkataramani, Sowmya

2016-01-01

Neurons that signal the orientation of edges within the visual field have been widely studied in primary visual cortex. Much less is known about the mechanisms of orientation selectivity that arise earlier in the visual stream. Here we examine the synaptic and morphological properties of a subtype of orientation-selective ganglion cell in the rabbit retina. The receptive field has an excitatory ON center, flanked by excitatory OFF regions, a structure similar to simple cell receptive fields in primary visual cortex. Examination of the light-evoked postsynaptic currents in these ON-type orientation-selective ganglion cells (ON-OSGCs) reveals that synaptic input is mediated almost exclusively through the ON pathway. Orientation selectivity is generated by larger excitation for preferred relative to orthogonal stimuli, and conversely larger inhibition for orthogonal relative to preferred stimuli. Excitatory orientation selectivity arises in part from the morphology of the dendritic arbors. Blocking GABAA receptors reduces orientation selectivity of the inhibitory synaptic inputs and the spiking responses. Negative contrast stimuli in the flanking regions produce orientation-selective excitation in part by disinhibition of a tonic NMDA receptor-mediated input arising from ON bipolar cells. Comparison with earlier studies of OFF-type OSGCs indicates that diverse synaptic circuits have evolved in the retina to detect the orientation of edges in the visual input. SIGNIFICANCE STATEMENT A core goal for visual neuroscientists is to understand how neural circuits at each stage of the visual system extract and encode features from the visual scene. This study documents a novel type of orientation-selective ganglion cell in the retina and shows that the receptive field structure is remarkably similar to that of simple cells in primary visual cortex. However, the data indicate that, unlike in the cortex, orientation selectivity in the retina depends on the activity of inhibitory interneurons. The results further reveal the physiological basis for feature detection in the visual system, elucidate the synaptic mechanisms that generate orientation selectivity at an early stage of visual processing, and illustrate a novel role for NMDA receptors in retinal processing. PMID:26985041

Synaptic Mechanisms Generating Orientation Selectivity in the ON Pathway of the Rabbit Retina.

PubMed

Venkataramani, Sowmya; Taylor, W Rowland

2016-03-16

Neurons that signal the orientation of edges within the visual field have been widely studied in primary visual cortex. Much less is known about the mechanisms of orientation selectivity that arise earlier in the visual stream. Here we examine the synaptic and morphological properties of a subtype of orientation-selective ganglion cell in the rabbit retina. The receptive field has an excitatory ON center, flanked by excitatory OFF regions, a structure similar to simple cell receptive fields in primary visual cortex. Examination of the light-evoked postsynaptic currents in these ON-type orientation-selective ganglion cells (ON-OSGCs) reveals that synaptic input is mediated almost exclusively through the ON pathway. Orientation selectivity is generated by larger excitation for preferred relative to orthogonal stimuli, and conversely larger inhibition for orthogonal relative to preferred stimuli. Excitatory orientation selectivity arises in part from the morphology of the dendritic arbors. Blocking GABAA receptors reduces orientation selectivity of the inhibitory synaptic inputs and the spiking responses. Negative contrast stimuli in the flanking regions produce orientation-selective excitation in part by disinhibition of a tonic NMDA receptor-mediated input arising from ON bipolar cells. Comparison with earlier studies of OFF-type OSGCs indicates that diverse synaptic circuits have evolved in the retina to detect the orientation of edges in the visual input. A core goal for visual neuroscientists is to understand how neural circuits at each stage of the visual system extract and encode features from the visual scene. This study documents a novel type of orientation-selective ganglion cell in the retina and shows that the receptive field structure is remarkably similar to that of simple cells in primary visual cortex. However, the data indicate that, unlike in the cortex, orientation selectivity in the retina depends on the activity of inhibitory interneurons. The results further reveal the physiological basis for feature detection in the visual system, elucidate the synaptic mechanisms that generate orientation selectivity at an early stage of visual processing, and illustrate a novel role for NMDA receptors in retinal processing. Copyright © 2016 the authors 0270-6474/16/363336-14$15.00/0.

Mapping Inhibitory Neuronal Circuits by Laser Scanning Photostimulation

PubMed Central

Ikrar, Taruna; Olivas, Nicholas D.; Shi, Yulin; Xu, Xiangmin

2011-01-01

Inhibitory neurons are crucial to cortical function. They comprise about 20% of the entire cortical neuronal population and can be further subdivided into diverse subtypes based on their immunochemical, morphological, and physiological properties1-4. Although previous research has revealed much about intrinsic properties of individual types of inhibitory neurons, knowledge about their local circuit connections is still relatively limited3,5,6. Given that each individual neuron's function is shaped by its excitatory and inhibitory synaptic input within cortical circuits, we have been using laser scanning photostimulation (LSPS) to map local circuit connections to specific inhibitory cell types. Compared to conventional electrical stimulation or glutamate puff stimulation, LSPS has unique advantages allowing for extensive mapping and quantitative analysis of local functional inputs to individually recorded neurons3,7-9. Laser photostimulation via glutamate uncaging selectively activates neurons perisomatically, without activating axons of passage or distal dendrites, which ensures a sub-laminar mapping resolution. The sensitivity and efficiency of LSPS for mapping inputs from many stimulation sites over a large region are well suited for cortical circuit analysis. Here we introduce the technique of LSPS combined with whole-cell patch clamping for local inhibitory circuit mapping. Targeted recordings of specific inhibitory cell types are facilitated by use of transgenic mice expressing green fluorescent proteins (GFP) in limited inhibitory neuron populations in the cortex3,10, which enables consistent sampling of the targeted cell types and unambiguous identification of the cell types recorded. As for LSPS mapping, we outline the system instrumentation, describe the experimental procedure and data acquisition, and present examples of circuit mapping in mouse primary somatosensory cortex. As illustrated in our experiments, caged glutamate is activated in a spatially restricted region of the brain slice by UV laser photolysis; simultaneous voltage-clamp recordings allow detection of photostimulation-evoked synaptic responses. Maps of either excitatory or inhibitory synaptic input to the targeted neuron are generated by scanning the laser beam to stimulate hundreds of potential presynaptic sites. Thus, LSPS enables the construction of detailed maps of synaptic inputs impinging onto specific types of inhibitory neurons through repeated experiments. Taken together, the photostimulation-based technique offers neuroscientists a powerful tool for determining the functional organization of local cortical circuits. PMID:22006064

Hippocampal 5-HT Input Regulates Memory Formation and Schaffer Collateral Excitation.

PubMed

Teixeira, Catia M; Rosen, Zev B; Suri, Deepika; Sun, Qian; Hersh, Marc; Sargin, Derya; Dincheva, Iva; Morgan, Ashlea A; Spivack, Stephen; Krok, Anne C; Hirschfeld-Stoler, Tessa; Lambe, Evelyn K; Siegelbaum, Steven A; Ansorge, Mark S

2018-06-06

The efficacy and duration of memory storage is regulated by neuromodulatory transmitter actions. While the modulatory transmitter serotonin (5-HT) plays an important role in implicit forms of memory in the invertebrate Aplysia, its function in explicit memory mediated by the mammalian hippocampus is less clear. Specifically, the consequences elicited by the spatio-temporal gradient of endogenous 5-HT release are not known. Here we applied optogenetic techniques in mice to gain insight into this fundamental biological process. We find that activation of serotonergic terminals in the hippocampal CA1 region both potentiates excitatory transmission at CA3-to-CA1 synapses and enhances spatial memory. Conversely, optogenetic silencing of CA1 5-HT terminals inhibits spatial memory. We furthermore find that synaptic potentiation is mediated by 5-HT4 receptors and that systemic modulation of 5-HT4 receptor function can bidirectionally impact memory formation. Collectively, these data reveal powerful modulatory influence of serotonergic synaptic input on hippocampal function and memory formation. Copyright © 2018 Elsevier Inc. All rights reserved.

Decrease of SYNGAP1 in GABAergic cells impairs inhibitory synapse connectivity, synaptic inhibition and cognitive function

PubMed Central

Berryer, Martin H.; Chattopadhyaya, Bidisha; Xing, Paul; Riebe, Ilse; Bosoi, Ciprian; Sanon, Nathalie; Antoine-Bertrand, Judith; Lévesque, Maxime; Avoli, Massimo; Hamdan, Fadi F.; Carmant, Lionel; Lamarche-Vane, Nathalie; Lacaille, Jean-Claude; Michaud, Jacques L.; Di Cristo, Graziella

2016-01-01

Haploinsufficiency of the SYNGAP1 gene, which codes for a Ras GTPase-activating protein, impairs cognition both in humans and in mice. Decrease of Syngap1 in mice has been previously shown to cause cognitive deficits at least in part by inducing alterations in glutamatergic neurotransmission and premature maturation of excitatory connections. Whether Syngap1 plays a role in the development of cortical GABAergic connectivity and function remains unclear. Here, we show that Syngap1 haploinsufficiency significantly reduces the formation of perisomatic innervations by parvalbumin-positive basket cells, a major population of GABAergic neurons, in a cell-autonomous manner. We further show that Syngap1 haploinsufficiency in GABAergic cells derived from the medial ganglionic eminence impairs their connectivity, reduces inhibitory synaptic activity and cortical gamma oscillation power, and causes cognitive deficits. Our results indicate that Syngap1 plays a critical role in GABAergic circuit function and further suggest that Syngap1 haploinsufficiency in GABAergic circuits may contribute to cognitive deficits. PMID:27827368

Molecular Mechanisms at the Basis of Plasticity in the Developing Visual Cortex: Epigenetic Processes and Gene Programs

PubMed Central

Maya-Vetencourt, José Fernando; Pizzorusso, Tommaso

2013-01-01

Neuronal circuitries in the mammalian visual system change as a function of experience. Sensory experience modifies neuronal networks connectivity via the activation of different physiological processes such as excitatory/inhibitory synaptic transmission, neurotrophins, and signaling of extracellular matrix molecules. Long-lasting phenomena of plasticity occur when intracellular signal transduction pathways promote epigenetic alterations of chromatin structure that regulate the induction of transcription factors that in turn drive the expression of downstream targets, the products of which then work via the activation of structural and functional mechanisms that modify synaptic connectivity. Here, we review recent findings in the field of visual cortical plasticity while focusing on how physiological mechanisms associated with experience promote structural changes that determine functional modifications of neural circuitries in V1. We revise the role of microRNAs as molecular transducers of environmental stimuli and the role of immediate early genes that control gene expression programs underlying plasticity in the developing visual cortex. PMID:25157210

Unraveling Synaptic GCaMP Signals: Differential Excitability and Clearance Mechanisms Underlying Distinct Ca2+ Dynamics in Tonic and Phasic Excitatory, and Aminergic Modulatory Motor Terminals in Drosophila

PubMed Central

Xing, Xiaomin

2018-01-01

Abstract GCaMP is an optogenetic Ca2+ sensor widely used for monitoring neuronal activities but the precise physiological implications of GCaMP signals remain to be further delineated among functionally distinct synapses. The Drosophila neuromuscular junction (NMJ), a powerful genetic system for studying synaptic function and plasticity, consists of tonic and phasic glutamatergic and modulatory aminergic motor terminals of distinct properties. We report a first simultaneous imaging and electric recording study to directly contrast the frequency characteristics of GCaMP signals of the three synapses for physiological implications. Different GCaMP variants were applied in genetic and pharmacological perturbation experiments to examine the Ca2+ influx and clearance processes underlying the GCaMP signal. Distinct mutational and drug effects on GCaMP signals indicate differential roles of Na+ and K+ channels, encoded by genes including paralytic (para), Shaker (Sh), Shab, and ether-a-go-go (eag), in excitability control of different motor terminals. Moreover, the Ca2+ handling properties reflected by the characteristic frequency dependence of the synaptic GCaMP signals were determined to a large extent by differential capacity of mitochondria-powered Ca2+ clearance mechanisms. Simultaneous focal recordings of synaptic activities further revealed that GCaMPs were ineffective in tracking the rapid dynamics of Ca2+ influx that triggers transmitter release, especially during low-frequency activities, but more adequately reflected cytosolic residual Ca2+ accumulation, a major factor governing activity-dependent synaptic plasticity. These results highlight the vast range of GCaMP response patterns in functionally distinct synaptic types and provide relevant information for establishing basic guidelines for the physiological interpretations of presynaptic GCaMP signals from in situ imaging studies. PMID:29464198

Influence of ionotropic receptor location on their dynamics at glutamatergic synapses.

PubMed

Allam, Sushmita L; Bouteiller, Jean-Marie C; Hu, Eric; Greget, Renaud; Ambert, Nicolas; Bischoff, Serge; Baudry, Michel; Berger, Theodore W

2012-01-01

In this paper we study the effects of the location of ionotropic receptors, especially AMPA and NMDA receptors, on their function at excitatory glutamatergic synapses. As few computational models only allow to evaluate the influence of receptor location on state transition and receptor dynamics, we present an elaborate computational model of a glutamatergic synapse that takes into account detailed parametric models of ionotropic receptors along with glutamate diffusion within the synaptic cleft. Our simulation results underscore the importance of the wide spread distribution of AMPA receptors which is required to avoid massive desensitization of these receptors following a single glutamate release event while NMDA receptor location is potentially optimal relative to the glutamate release site thus, emphasizing the contribution of location dependent effects of the two major ionotropic receptors to synaptic efficacy.

A neural network model of memory and higher cognitive functions.

PubMed

Vogel, David D

2005-01-01

I first describe a neural network model of associative memory in a small region of the brain. The model depends, unconventionally, on disinhibition of inhibitory links between excitatory neurons rather than long-term potentiation (LTP) of excitatory projections. The model may be shown to have advantages over traditional neural network models both in terms of information storage capacity and biological plausibility. The learning and recall algorithms are independent of network architecture, and require no thresholds or finely graded synaptic strengths. Several copies of this local network are then connected by means of many, weak, reciprocal, excitatory projections that allow one region to control the recall of information in another to produce behaviors analogous to serial memory, classical and operant conditioning, secondary reinforcement, refabrication of memory, and fabrication of possible future events. The network distinguishes between perceived and recalled events, and can predicate its response on the absence as well as the presence of particular stimuli. Some of these behaviors are achieved in ways that seem to provide instances of self-awareness and imagination, suggesting that consciousness may emerge as an epiphenomenon in simple brains.

Irregular behavior in an excitatory-inhibitory neuronal network

NASA Astrophysics Data System (ADS)

Park, Choongseok; Terman, David

2010-06-01

Excitatory-inhibitory networks arise in many regions throughout the central nervous system and display complex spatiotemporal firing patterns. These neuronal activity patterns (of individual neurons and/or the whole network) are closely related to the functional status of the system and differ between normal and pathological states. For example, neurons within the basal ganglia, a group of subcortical nuclei that are responsible for the generation of movement, display a variety of dynamic behaviors such as correlated oscillatory activity and irregular, uncorrelated spiking. Neither the origins of these firing patterns nor the mechanisms that underlie the patterns are well understood. We consider a biophysical model of an excitatory-inhibitory network in the basal ganglia and explore how specific biophysical properties of the network contribute to the generation of irregular spiking. We use geometric dynamical systems and singular perturbation methods to systematically reduce the model to a simpler set of equations, which is suitable for analysis. The results specify the dependence on the strengths of synaptic connections and the intrinsic firing properties of the cells in the irregular regime when applied to the subthalamopallidal network of the basal ganglia.

Comparing development of synaptic proteins in rat visual, somatosensory, and frontal cortex.

PubMed

Pinto, Joshua G A; Jones, David G; Murphy, Kathryn M

2013-01-01

Two theories have influenced our understanding of cortical development: the integrated network theory, where synaptic development is coordinated across areas; and the cascade theory, where the cortex develops in a wave-like manner from sensory to non-sensory areas. These different views on cortical development raise challenges for current studies aimed at comparing detailed maturation of the connectome among cortical areas. We have taken a different approach to compare synaptic development in rat visual, somatosensory, and frontal cortex by measuring expression of pre-synaptic (synapsin and synaptophysin) proteins that regulate vesicle cycling, and post-synaptic density (PSD-95 and Gephyrin) proteins that anchor excitatory or inhibitory (E-I) receptors. We also compared development of the balances between the pairs of pre- or post-synaptic proteins, and the overall pre- to post-synaptic balance, to address functional maturation and emergence of the E-I balance. We found that development of the individual proteins and the post-synaptic index overlapped among the three cortical areas, but the pre-synaptic index matured later in frontal cortex. Finally, we applied a neuroinformatics approach using principal component analysis and found that three components captured development of the synaptic proteins. The first component accounted for 64% of the variance in protein expression and reflected total protein expression, which overlapped among the three cortical areas. The second component was gephyrin and the E-I balance, it emerged as sequential waves starting in somatosensory, then frontal, and finally visual cortex. The third component was the balance between pre- and post-synaptic proteins, and this followed a different developmental trajectory in somatosensory cortex. Together, these results give the most support to an integrated network of synaptic development, but also highlight more complex patterns of development that vary in timing and end point among the cortical areas.

Spike-timing dependent inhibitory plasticity to learn a selective gating of backpropagating action potentials.

PubMed

Wilmes, Katharina Anna; Schleimer, Jan-Hendrik; Schreiber, Susanne

2017-04-01

Inhibition is known to influence the forward-directed flow of information within neurons. However, also regulation of backward-directed signals, such as backpropagating action potentials (bAPs), can enrich the functional repertoire of local circuits. Inhibitory control of bAP spread, for example, can provide a switch for the plasticity of excitatory synapses. Although such a mechanism is possible, it requires a precise timing of inhibition to annihilate bAPs without impairment of forward-directed excitatory information flow. Here, we propose a specific learning rule for inhibitory synapses to automatically generate the correct timing to gate bAPs in pyramidal cells when embedded in a local circuit of feedforward inhibition. Based on computational modeling of multi-compartmental neurons with physiological properties, we demonstrate that a learning rule with anti-Hebbian shape can establish the required temporal precision. In contrast to classical spike-timing dependent plasticity of excitatory synapses, the proposed inhibitory learning mechanism does not necessarily require the definition of an upper bound of synaptic weights because of its tendency to self-terminate once annihilation of bAPs has been reached. Our study provides a functional context in which one of the many time-dependent learning rules that have been observed experimentally - specifically, a learning rule with anti-Hebbian shape - is assigned a relevant role for inhibitory synapses. Moreover, the described mechanism is compatible with an upregulation of excitatory plasticity by disinhibition. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Recombinant probes for visualizing endogenous synaptic proteins in living neurons

PubMed Central

Gross, Garrett G.; Junge, Jason A.; Mora, Rudy J.; Kwon, Hyung-Bae; Olson, C. Anders; Takahashi, Terry T.; Liman, Emily R.; Ellis-Davies, Graham C.R.; McGee, Aaron W.; Sabatini, Bernardo L.; Roberts, Richard W.; Arnold, Don B.

2013-01-01

Summary The ability to visualize endogenous proteins in living neurons provides a powerful means to interrogate neuronal structure and function. Here we generate recombinant antibody-like proteins, termed FingRs (Fibronectin intrabodies generated with mRNA display), that bind endogenous neuronal proteins PSD-95 and Gephyrin with high affinity and which, when fused to GFP, allow excitatory and inhibitory synapses to be visualized in living neurons. Design of the FingR incorporates a novel transcriptional regulation system that ties FingR expression to the level of the target and reduces background fluorescence. In dissociated neurons and brain slices FingRs generated against PSD-95 and Gephyrin did not affect the expression patterns of their endogenous target proteins or the number or strength of synapses. Together, our data indicate that PSD-95 and Gephyrin FingRs can report the localization and amount of endogenous synaptic proteins in living neurons and thus may be used to study changes in synaptic strength in vivo. PMID:23791193

Synaptic Transmission Optimization Predicts Expression Loci of Long-Term Plasticity.

PubMed

Costa, Rui Ponte; Padamsey, Zahid; D'Amour, James A; Emptage, Nigel J; Froemke, Robert C; Vogels, Tim P

2017-09-27

Long-term modifications of neuronal connections are critical for reliable memory storage in the brain. However, their locus of expression-pre- or postsynaptic-is highly variable. Here we introduce a theoretical framework in which long-term plasticity performs an optimization of the postsynaptic response statistics toward a given mean with minimal variance. Consequently, the state of the synapse at the time of plasticity induction determines the ratio of pre- and postsynaptic modifications. Our theory explains the experimentally observed expression loci of the hippocampal and neocortical synaptic potentiation studies we examined. Moreover, the theory predicts presynaptic expression of long-term depression, consistent with experimental observations. At inhibitory synapses, the theory suggests a statistically efficient excitatory-inhibitory balance in which changes in inhibitory postsynaptic response statistics specifically target the mean excitation. Our results provide a unifying theory for understanding the expression mechanisms and functions of long-term synaptic transmission plasticity. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

The impact of perinatal stress on the functional maturation of prefronto-cortical synaptic circuits: implications for the pathophysiology of ADHD?

PubMed

Bock, Jörg; Braun, Katharina

2011-01-01

Enriched as well as impoverished or adverse perinatal environment plays an essential role in the development and refinement of neuronal pathways, which are the neural substrate of intellectual capacity and socioemotional competence. Perinatal experience and learning events continuously interact with the adaptive shaping of excitatory, inhibitory, and neuromodulatory synaptic as well as the endocrine stress systems, including the neuronal corticotropin-releasing factor (CRF) pathways. Adverse environments, such as stress and emotional deprivation can not only delay experience-dependent maturation of these pathways, but also induce permanent changes in prefronto-cortical wiring patterns. We assume that such dysfunctional connections are the neuronal basis for the development of psychosocially induced mental disorders during later life. The aim of this review is to focus on the impact of perinatal stress on the neuronal and synaptic reorganization during brain development and possible implications for the etiology and therapy of mental disorders such as ADHD. Copyright © 2011 Elsevier B.V. All rights reserved.

The SOL-2/Neto Auxiliary Protein Modulates the Function of AMPA-Subtype Ionotropic Glutamate Receptors

PubMed Central

Wang, Rui; Mellem, Jerry E.; Jensen, Michael; Brockie, Penelope J.; Walker, Craig S.; Hoerndli, Frédéric J.; Madsen, David M.; Maricq, Andres V.

2012-01-01

Summary The neurotransmitter glutamate mediates excitatory synaptic transmission by gating ionotropic glutamate receptors (iGluRs). AMPA receptors (AMPARs), a subtype of iGluR, are strongly implicated in synaptic plasticity, learning and memory. We previously discovered two classes of AMPAR auxiliary proteins in C. elegans that modify receptor kinetics and thus change synaptic transmission. Here, we have identified another auxiliary protein, SOL-2, a CUB-domain protein that associates with both the related auxiliary subunit SOL-1 and with the GLR-1 AMPAR. In sol-2 mutants, behaviors dependent on glutamatergic transmission are disrupted, GLR-1-mediated currents are diminished, and GLR-1 desensitization and pharmacology are modified. Remarkably, a secreted variant of SOL-1 delivered in trans can rescue sol-1 mutants and this rescue depends on in cis expression of SOL-2. Finally, we demonstrate that SOL-1 and SOL-2 have an ongoing role in the adult nervous system to control AMPAR-mediated currents. PMID:22958824

The SOL-2/Neto auxiliary protein modulates the function of AMPA-subtype ionotropic glutamate receptors.

PubMed

Wang, Rui; Mellem, Jerry E; Jensen, Michael; Brockie, Penelope J; Walker, Craig S; Hoerndli, Frédéric J; Hauth, Linda; Madsen, David M; Maricq, Andres V

2012-09-06

The neurotransmitter glutamate mediates excitatory synaptic transmission by gating ionotropic glutamate receptors (iGluRs). AMPA receptors (AMPARs), a subtype of iGluR, are strongly implicated in synaptic plasticity, learning, and memory. We previously discovered two classes of AMPAR auxiliary proteins in C. elegans that modify receptor kinetics and thus change synaptic transmission. Here, we have identified another auxiliary protein, SOL-2, a CUB-domain protein that associates with both the related auxiliary subunit SOL-1 and with the GLR-1 AMPAR. In sol-2 mutants, behaviors dependent on glutamatergic transmission are disrupted, GLR-1-mediated currents are diminished, and GLR-1 desensitization and pharmacology are modified. Remarkably, a secreted variant of SOL-1 delivered in trans can rescue sol-1 mutants, and this rescue depends on in cis expression of SOL-2. Finally, we demonstrate that SOL-1 and SOL-2 have an ongoing role in the adult nervous system to control AMPAR-mediated currents. Copyright © 2012 Elsevier Inc. All rights reserved.

Network models of frequency modulated sweep detection.

PubMed

Skorheim, Steven; Razak, Khaleel; Bazhenov, Maxim

2014-01-01

Frequency modulated (FM) sweeps are common in species-specific vocalizations, including human speech. Auditory neurons selective for the direction and rate of frequency change in FM sweeps are present across species, but the synaptic mechanisms underlying such selectivity are only beginning to be understood. Even less is known about mechanisms of experience-dependent changes in FM sweep selectivity. We present three network models of synaptic mechanisms of FM sweep direction and rate selectivity that explains experimental data: (1) The 'facilitation' model contains frequency selective cells operating as coincidence detectors, summing up multiple excitatory inputs with different time delays. (2) The 'duration tuned' model depends on interactions between delayed excitation and early inhibition. The strength of delayed excitation determines the preferred duration. Inhibitory rebound can reinforce the delayed excitation. (3) The 'inhibitory sideband' model uses frequency selective inputs to a network of excitatory and inhibitory cells. The strength and asymmetry of these connections results in neurons responsive to sweeps in a single direction of sufficient sweep rate. Variations of these properties, can explain the diversity of rate-dependent direction selectivity seen across species. We show that the inhibitory sideband model can be trained using spike timing dependent plasticity (STDP) to develop direction selectivity from a non-selective network. These models provide a means to compare the proposed synaptic and spectrotemporal mechanisms of FM sweep processing and can be utilized to explore cellular mechanisms underlying experience- or training-dependent changes in spectrotemporal processing across animal models. Given the analogy between FM sweeps and visual motion, these models can serve a broader function in studying stimulus movement across sensory epithelia.

Model-Free Reconstruction of Excitatory Neuronal Connectivity from Calcium Imaging Signals

PubMed Central

Stetter, Olav; Battaglia, Demian; Soriano, Jordi; Geisel, Theo

2012-01-01

A systematic assessment of global neural network connectivity through direct electrophysiological assays has remained technically infeasible, even in simpler systems like dissociated neuronal cultures. We introduce an improved algorithmic approach based on Transfer Entropy to reconstruct structural connectivity from network activity monitored through calcium imaging. We focus in this study on the inference of excitatory synaptic links. Based on information theory, our method requires no prior assumptions on the statistics of neuronal firing and neuronal connections. The performance of our algorithm is benchmarked on surrogate time series of calcium fluorescence generated by the simulated dynamics of a network with known ground-truth topology. We find that the functional network topology revealed by Transfer Entropy depends qualitatively on the time-dependent dynamic state of the network (bursting or non-bursting). Thus by conditioning with respect to the global mean activity, we improve the performance of our method. This allows us to focus the analysis to specific dynamical regimes of the network in which the inferred functional connectivity is shaped by monosynaptic excitatory connections, rather than by collective synchrony. Our method can discriminate between actual causal influences between neurons and spurious non-causal correlations due to light scattering artifacts, which inherently affect the quality of fluorescence imaging. Compared to other reconstruction strategies such as cross-correlation or Granger Causality methods, our method based on improved Transfer Entropy is remarkably more accurate. In particular, it provides a good estimation of the excitatory network clustering coefficient, allowing for discrimination between weakly and strongly clustered topologies. Finally, we demonstrate the applicability of our method to analyses of real recordings of in vitro disinhibited cortical cultures where we suggest that excitatory connections are characterized by an elevated level of clustering compared to a random graph (although not extreme) and can be markedly non-local. PMID:22927808

Differences in spike train variability in rat vasopressin and oxytocin neurons and their relationship to synaptic activity

PubMed Central

Li, Chunyan; Tripathi, Pradeep K; Armstrong, William E

2007-01-01

The firing pattern of magnocellular neurosecretory neurons is intimately related to hormone release, but the relative contribution of synaptic versus intrinsic factors to the temporal dispersion of spikes is unknown. In the present study, we examined the firing patterns of vasopressin (VP) and oxytocin (OT) supraoptic neurons in coronal slices from virgin female rats, with and without blockade of inhibitory and excitatory synaptic currents. Inhibitory postsynaptic currents (IPSCs) were twice as prevalent as their excitatory counterparts (EPSCs), and both were more prevalent in OT compared with VP neurons. Oxytocin neurons fired more slowly and irregularly than VP neurons near threshold. Blockade of Cl− currents (including tonic and synaptic currents) with picrotoxin reduced interspike interval (ISI) variability of continuously firing OT and VP neurons without altering input resistance or firing rate. Blockade of EPSCs did not affect firing pattern. Phasic bursting neurons (putative VP neurons) were inconsistently affected by broad synaptic blockade, suggesting that intrinsic factors may dominate the ISI distribution during this mode in the slice. Specific blockade of synaptic IPSCs with gabazine also reduced ISI variability, but only in OT neurons. In all cases, the effect of inhibitory blockade on firing pattern was independent of any consistent change in input resistance or firing rate. Since the great majority of IPSCs are randomly distributed, miniature events (mIPSCs) in the coronal slice, these findings imply that even mIPSCs can impart irregularity to the firing pattern of OT neurons in particular, and could be important in regulating spike patterning in vivo. For example, the increased firing variability that precedes bursting in OT neurons during lactation could be related to significant changes in synaptic activity. PMID:17332000

Postnatal Ablation of Synaptic Retinoic Acid Signaling Impairs Cortical Information Processing and Sensory Discrimination in Mice.

PubMed

Park, Esther; Tjia, Michelle; Zuo, Yi; Chen, Lu

2018-06-06

Retinoic acid (RA) and its receptors (RARs) are well established essential transcriptional regulators during embryonic development. Recent findings in cultured neurons identified an independent and critical post-transcriptional role of RA and RARα in the homeostatic regulation of excitatory and inhibitory synaptic transmission in mature neurons. However, the functional relevance of synaptic RA signaling in vivo has not been established. Here, using somatosensory cortex as a model system and the RARα conditional knock-out mouse as a tool, we applied multiple genetic manipulations to delete RARα postnatally in specific populations of cortical neurons, and asked whether synaptic RA signaling observed in cultured neurons is involved in cortical information processing in vivo Indeed, conditional ablation of RARα in mice via a CaMKIIα-Cre or a layer 5-Cre driver line or via somatosensory cortex-specific viral expression of Cre-recombinase impaired whisker-dependent texture discrimination, suggesting a critical requirement of RARα expression in L5 pyramidal neurons of somatosensory cortex for normal tactile sensory processing. Transcranial two-photon imaging revealed a significant increase in dendritic spine elimination on apical dendrites of somatosensory cortical layer 5 pyramidal neurons in these mice. Interestingly, the enhancement of spine elimination is whisker experience-dependent as whisker trimming rescued the spine elimination phenotype. Additionally, experiencing an enriched environment improved texture discrimination in RARα-deficient mice and reduced excessive spine pruning. Thus, RA signaling is essential for normal experience-dependent cortical circuit remodeling and sensory processing. SIGNIFICANCE STATEMENT The importance of synaptic RA signaling has been demonstrated in in vitro studies. However, whether RA signaling mediated by RARα contributes to neural circuit functions in vivo remains largely unknown. In this study, using a RARα conditional knock-out mouse, we performed multiple regional/cell-type-specific manipulation of RARα expression in the postnatal brain, and show that RARα signaling contributes to normal whisker-dependent texture discrimination as well as regulating spine dynamics of apical dendrites from layer (L5) pyramidal neurons in S1. Deletion of RARα in excitatory neurons in the forebrain induces elevated spine elimination and impaired sensory discrimination. Our study provides novel insights into the role of RARα signaling in cortical processing and experience-dependent spine maturation. Copyright © 2018 the authors 0270-6474/18/385277-12$15.00/0.

Brain Transcriptome Profiles in Mouse Model Simulating Features of Post-traumatic Stress Disorder

DTIC Science & Technology

2015-02-28

comorbid-related signaling pathways indicate the pervasive and multisystem effects of aggressor exposure in mice, potentially mirroring the pathologic...11,12]. Impaired extinction of fear- potentiated startle and en- hanced cue conditioning in these brain regions (of trau- matized patients and animal...lead to either a long-term synap- tic potentiation (LTP) increase in synaptic strength and in- crease in excitatory post-synaptic potential

Gamma Rhythm Simulations in Alzheimer's Disease

NASA Astrophysics Data System (ADS)

Montgomery, Samuel; Perez, Carlos; Ullah, Ghanim

The different neural rhythms that occur during the sleep-wake cycle regulate the brain's multiple functions. Memory acquisition occurs during fast gamma rhythms during consciousness, while slow oscillations mediate memory consolidation and erasure during sleep. At the neural network level, these rhythms are generated by the finely timed activity within excitatory and inhibitory neurons. In Alzheimer's Disease (AD) the function of inhibitory neurons is compromised due to an increase in amyloid beta (A β) leading to elevated sodium leakage from extracellular space in the hippocampus. Using a Hodgkin-Huxley formalism, heightened sodium leakage current into inhibitory neurons is observed to compromise functionality. Using a simple two neuron system it was observed that as the conductance of the sodium leakage current is increased in inhibitory neurons there is a significant decrease in spiking frequency regarding the membrane potential. This triggers a significant increase in excitatory spiking leading to aberrant network behavior similar to that seen in AD patients. The next step is to extend this model to a larger neuronal system with varying synaptic densities and conductance strengths as well as deterministic and stochastic drives.

Long-Term Plasticity of Neurotransmitter Release: Emerging Mechanisms and Contributions to Brain Function and Disease.

PubMed

Monday, Hannah R; Younts, Thomas J; Castillo, Pablo E

2018-04-25

Long-lasting changes of brain function in response to experience rely on diverse forms of activity-dependent synaptic plasticity. Chief among them are long-term potentiation and long-term depression of neurotransmitter release, which are widely expressed by excitatory and inhibitory synapses throughout the central nervous system and can dynamically regulate information flow in neural circuits. This review article explores recent advances in presynaptic long-term plasticity mechanisms and contributions to circuit function. Growing evidence indicates that presynaptic plasticity may involve structural changes, presynaptic protein synthesis, and transsynaptic signaling. Presynaptic long-term plasticity can alter the short-term dynamics of neurotransmitter release, thereby contributing to circuit computations such as novelty detection, modifications of the excitatory/inhibitory balance, and sensory adaptation. In addition, presynaptic long-term plasticity underlies forms of learning and its dysregulation participates in several neuropsychiatric conditions, including schizophrenia, autism, intellectual disabilities, neurodegenerative diseases, and drug abuse. Expected final online publication date for the Annual Review of Neuroscience Volume 41 is July 8, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Bisphenol A Impairs Synaptic Plasticity by Both Pre‐ and Postsynaptic Mechanisms

PubMed Central

Li, Tingting; Gong, Huarui; Chen, Zhi; Jin, Yan; Xu, Guangwei

2017-01-01

Bisphenol A (BPA), an environmental xenoestrogen, has been reported to induce learning and memory impairments in rodent animals. However, effects of BPA exposure on synaptic plasticity and the underlying physiological mechanisms remain elusive. Our behavioral and electrophysiological analyses show that BPA obviously perturbs hippocampal spatial memory of juvenile Sprague–Dawley rats after four weeks exposure, with significantly impaired long‐term potentiation (LTP) in the hippocampus. These effects involve decreased spine density of pyramidal neurons, especially the apical dendritic spine. Further presynaptic findings show an overt inhibition of pulse‐paired facilitation during electrophysiological recording, which suggest the decrease of presynaptic transmitter release and is consistent with reduced production of presynaptic glutamate after BPA exposure. Meanwhile, LTP‐related glutamate receptors, NMDA receptor 2A (NR2A) and AMPA receptor 1 (GluR1), are significantly downregulated in BPA‐exposed rats. Excitatory postsynaptic currents (EPSCs) results also show that EPSCNMDA, but not EPSCAMPA, is declined by 40% compared to the baseline in BPA‐perfused brain slices. Taken together, these findings reveal that juvenile BPA exposure has negative effects on synaptic plasticity, which result from decreases in dendritic spine density and excitatory synaptic transmission. Importantly, this study also provides new insights into the dynamics of BPA‐induced memory deterioration during the whole life of rats. PMID:28852612

Hyperconnectivity and slow synapses during early development of medial prefrontal cortex in a mouse model for mental retardation and autism.

PubMed

Testa-Silva, Guilherme; Loebel, Alex; Giugliano, Michele; de Kock, Christiaan P J; Mansvelder, Huibert D; Meredith, Rhiannon M

2012-06-01

Neuronal theories of neurodevelopmental disorders (NDDs) of autism and mental retardation propose that abnormal connectivity underlies deficits in attentional processing. We tested this theory by studying unitary synaptic connections between layer 5 pyramidal neurons within medial prefrontal cortex (mPFC) networks in the Fmr1-KO mouse model for mental retardation and autism. In line with predictions from neurocognitive theory, we found that neighboring pyramidal neurons were hyperconnected during a critical period in early mPFC development. Surprisingly, excitatory synaptic connections between Fmr1-KO pyramidal neurons were significantly slower and failed to recover from short-term depression as quickly as wild type (WT) synapses. By 4-5 weeks of mPFC development, connectivity rates were identical for both KO and WT pyramidal neurons and synapse dynamics changed from depressing to facilitating responses with similar properties in both groups. We propose that the early alteration in connectivity and synaptic recovery are tightly linked: using a network model, we show that slower synapses are essential to counterbalance hyperconnectivity in order to maintain a dynamic range of excitatory activity. However, the slow synaptic time constants induce decreased responsiveness to low-frequency stimulation, which may explain deficits in integration and early information processing in attentional neuronal networks in NDDs.

Hyperconnectivity and Slow Synapses during Early Development of Medial Prefrontal Cortex in a Mouse Model for Mental Retardation and Autism

PubMed Central

Testa-Silva, Guilherme; Loebel, Alex; Giugliano, Michele; de Kock, Christiaan P.J.; Mansvelder, Huibert D.; Meredith, Rhiannon M.

2013-01-01

Neuronal theories of neurodevelopmental disorders (NDDs) of autism and mental retardation propose that abnormal connectivity underlies deficits in attentional processing. We tested this theory by studying unitary synaptic connections between layer 5 pyramidal neurons within medial prefrontal cortex (mPFC) networks in the Fmr1-KO mouse model for mental retardation and autism. In line with predictions from neurocognitive theory, we found that neighboring pyramidal neurons were hyperconnected during a critical period in early mPFC development. Surprisingly, excitatory synaptic connections between Fmr1-KO pyramidal neurons were significantly slower and failed to recover from short-term depression as quickly as wild type (WT) synapses. By 4--5 weeks of mPFC development, connectivity rates were identical for both KO and WT pyramidal neurons and synapse dynamics changed from depressing to facilitating responses with similar properties in both groups. We propose that the early alteration in connectivity and synaptic recovery are tightly linked: using a network model, we show that slower synapses are essential to counterbalance hyperconnectivity in order to maintain a dynamic range of excitatory activity. However, the slow synaptic time constants induce decreased responsiveness to low-frequency stimulation, which may explain deficits in integration and early information processing in attentional neuronal networks in NDDs. PMID:21856714

Characterization of the zinc-induced Shank3 interactome of mouse synaptosome.

PubMed

Lee, Yeunkum; Ryu, Jae Ryun; Kang, Hyojin; Kim, Yoonhee; Kim, Shinhyun; Zhang, Yinhua; Jin, Chunmei; Cho, Hyo Min; Kim, Won-Ki; Sun, Woong; Han, Kihoon

2017-12-16

Variants of the SHANK3 gene, which encodes a core scaffold protein of the postsynaptic density of excitatory synapses, have been causally associated with numerous brain disorders. Shank3 proteins directly bind zinc ions through their C-terminal sterile α motif domain, which enhances the multimerization and synaptic localization of Shank3, to regulate excitatory synaptic strength. However, no studies have explored whether zinc affects the protein interactions of Shank3, which might contribute to the synaptic changes observed after zinc application. To examine this, we first purified Shank3 protein complexes from mouse brain synaptosomal lysates that were incubated with different concentrations of ZnCl 2 , and analyzed them with mass spectrometry. We used strict criteria to identify 71 proteins that specifically interacted with Shank3 when extra ZnCl 2 was added to the lysate. To characterize the zinc-induced Shank3 interactome, we performed various bioinformatic analyses that revealed significant associations of the interactome with subcellular compartments, including mitochondria, and brain disorders, such as bipolar disorder and schizophrenia. Together, our results showing that zinc affected the Shank3 protein interactions of in vitro mouse synaptosomes provided an additional link between zinc and core synaptic proteins that have been implicated in multiple brain disorders. Copyright © 2017 Elsevier Inc. All rights reserved.

Axonal synapse sorting in medial entorhinal cortex

NASA Astrophysics Data System (ADS)

Schmidt, Helene; Gour, Anjali; Straehle, Jakob; Boergens, Kevin M.; Brecht, Michael; Helmstaedter, Moritz

2017-09-01

Research on neuronal connectivity in the cerebral cortex has focused on the existence and strength of synapses between neurons, and their location on the cell bodies and dendrites of postsynaptic neurons. The synaptic architecture of individual presynaptic axonal trees, however, remains largely unknown. Here we used dense reconstructions from three-dimensional electron microscopy in rats to study the synaptic organization of local presynaptic axons in layer 2 of the medial entorhinal cortex, the site of grid-like spatial representations. We observe path-length-dependent axonal synapse sorting, such that axons of excitatory neurons sequentially target inhibitory neurons followed by excitatory neurons. Connectivity analysis revealed a cellular feedforward inhibition circuit involving wide, myelinated inhibitory axons and dendritic synapse clustering. Simulations show that this high-precision circuit can control the propagation of synchronized activity in the medial entorhinal cortex, which is known for temporally precise discharges.

Identification of the kainate receptor subunits underlying modulation of excitatory synaptic transmission in the CA3 region of the hippocampus.

PubMed

Contractor, A; Swanson, G T; Sailer, A; O'Gorman, S; Heinemann, S F

2000-11-15

To understand the physiological role of kainate receptors and their participation in seizure induction in animal models of epilepsy, it will be necessary to develop a comprehensive description of their action in the CA3 region of the hippocampus. Activation of presynaptic kainate receptors depresses excitatory synaptic transmission at mossy fiber and associational-commissural inputs to CA3 pyramidal neurons (Vignes et al., 1998; Bortolotto et al., 1999; Kamiya and Ozawa, 2000). In this study, we use gene-targeted mice lacking glutamate receptor 5 (GluR5) or GluR6 kainate receptor subunits to identify the receptor subunits that comprise the kainate receptors responsible for presynaptic modulation of CA3 transmission. We found that bath application of kainate (3 microm) profoundly reduced EPSCs at mossy fiber and collateral synapses in neurons from wild-type and GluR5(-/-) mice but had no effect on EPSCs in neurons from GluR6(-/-) mice. These results therefore contrast with previous studies that supported a role for GluR5-containing receptors at mossy fiber and associational-commissural synapses (Vignes et al., 1998; Bortolotto et al., 1999). Surprisingly, at perforant path synapses kainate receptor activation enhanced transmission; this potentiation was abolished in both GluR5 and GluR6 knock-out mice. Kainate receptors thus play multiple and complex roles to modulate excitatory synaptic transmission in the CA3 region of the hippocampus.

Expression of SHANK3 in the Temporal Neocortex of Patients with Intractable Temporal Epilepsy and Epilepsy Rat Models.

PubMed

Zhang, Yanke; Gao, Baobing; Xiong, Yan; Zheng, Fangshuo; Xu, Xin; Yang, Yong; Hu, Yida; Wang, Xuefeng

2017-07-01

SH3 and multiple ankyrin (ANK) repeat domain 3 (SHANK3) is a synaptic scaffolding protein enriched in the postsynaptic density of excitatory synapses. SHANK3 plays an important role in the formation and maturation of excitatory synapses. In the brain, SHANK3 directly or indirectly interacts with various synaptic molecules including N-methyl-D-aspartate receptor, the metabotropic glutamate receptor (mGluR), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor. Previous studies have shown that Autism spectrum disorder is a result of mutations of the main SHANK3 isoforms, which may be due to deficit in excitatory synaptic transmission and plasticity. Recently, accumulating evidence has demonstrated that overexpression of SHANK3 could induce seizures in vivo. However, little is known about the role of SHANK3 in refractory temporal lobe epilepsy (TLE). Therefore, we investigated the expression pattern of SHANK3 in patients with intractable temporal lobe epilepsy and in pilocarpine-induced models of epilepsy. Immunofluorescence, immunohistochemistry, and western blot analysis were used to locate and determine the expression of SHANK3 in the temporal neocortex of patients with epilepsy, and in the hippocampus and temporal lobe cortex of rats in a pilocarpine-induced epilepsy model. Double-labeled immunofluorescence showed that SHANK3 was mainly expressed in neurons. Western blot analysis confirmed that SHANK3 expression was increased in the neocortex of TLE patients and rats. These results indicate that SHANK3 participates in the pathology of epilepsy.

An intracellular characterization of neurones and neural connexions within the left coeliac ganglion of cats.

PubMed Central

Decktor, D L; Weems, W A

1983-01-01

Intracellular recordings were made in vitro from neurones located within the left coeliac ganglion of the cat solar plexus. Thirty percent of the neurones within left coeliac ganglia were identified as efferent neurones. Within this neuronal population, splenic-efferent and renal-efferent neurones were identified specifically. Neurones within left coeliac ganglia were characterized as either phasic (fast adapting) neurones or tonic (slowly adapting) neurones depending upon their prolonged firing behaviour. Electrophysiological properties of neurones varied considerably. The wide range of values obtained for both input resistance and input capacitance suggest that sizeable differences in either specific membrane resistance or cell geometry exist within the over-all neurone population. Frequency distributions of input resistance, time constant, input capacitance and current threshold for tonic and phasic neurones were found to be significantly different. Compound excitatory post-synaptic potentials were produced by stimulation of the ipsilateral splanchnic nerves in 69% of the neurones tested and in 3% of the neurones tested upon stimulation of the contralateral splanchnic nerves. Electrical stimulation of nerve fibres located in the coeliac plexus, the superior mesenteric plexus or the left renal nerves generated excitatory synaptic potentials in neurones located within left coeliac ganglia. It is concluded that neurones within the left coeliac ganglion are innervated by splanchnic nerve fibres primarily contained within the left splanchnic nerves, receive excitatory synaptic input from splenic, renal and other peripheral preganglionic fibres and have extremely varied electrophysiological properties. PMID:6620179

Nootropic agents enhance the recruitment of fast GABAA inhibition in rat neocortex.

PubMed

Ling, Douglas S F; Benardo, Larry S

2005-07-01

It is widely believed that nootropic (cognition-enhancing) agents produce their therapeutic effects by augmenting excitatory synaptic transmission in cortical circuits, primarily through positive modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate receptors (AMPARs). However, GABA-mediated inhibition is also critical for cognition, and enhanced GABA function may be likewise therapeutic for cognitive disorders. Could nootropics act through such a mechanism as well? To address this question, we examined the effects of nootropic agents on excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs) recorded from layer V pyramidal cells in acute slices of somatosensory cortex. Aniracetam, a positive modulator of AMPA/kainate receptors, increased the peak amplitude of evoked EPSCs and the amplitude and duration of polysynaptic fast IPSCs, manifested as a greater total charge carried by IPSCs. As a result, the EPSC/IPSC ratio of total charge was decreased, representing a shift in the excitation-inhibition balance that favors inhibition. Aniracetam did not affect the magnitude of either monosynaptic IPSCs (mono-IPSCs) recorded in the presence of excitatory amino acid receptor antagonists, or miniature IPSCs (mIPSCs) recorded in the presence of tetrodotoxin. However, the duration of both mono-IPSCs and mIPSCs was prolonged, suggesting that aniracetam also directly modulates GABAergic transmission. Cyclothiazide, a preferential modulator of AMPAR function, enhanced the magnitude and duration of polysynaptic IPSCs, similar to aniracetam, but did not affect mono-IPSCs. Concanavalin A, a kainate receptor modulator, had little effect on EPSCs or IPSCs, suggesting there was no contribution from kainate receptor activity. These findings indicate that AMPAR modulators strengthen inhibition in neocortical pyramidal cells, most likely by altering the kinetics of AMPARs on synaptically connected interneurons and possibly by modulating GABA(A) receptor responses in pyramidal cells. This suggests that the therapeutic actions of nootropic agents may be partly mediated through enhanced cortical GABAergic inhibition, and not solely through the direct modification of excitation, as previously thought.

A computational study of astrocytic glutamate influence on post-synaptic neuronal excitability.

PubMed

Flanagan, Bronac; McDaid, Liam; Wade, John; Wong-Lin, KongFatt; Harkin, Jim

2018-04-01

The ability of astrocytes to rapidly clear synaptic glutamate and purposefully release the excitatory transmitter is critical in the functioning of synapses and neuronal circuits. Dysfunctions of these homeostatic functions have been implicated in the pathology of brain disorders such as mesial temporal lobe epilepsy. However, the reasons for these dysfunctions are not clear from experimental data and computational models have been developed to provide further understanding of the implications of glutamate clearance from the extracellular space, as a result of EAAT2 downregulation: although they only partially account for the glutamate clearance process. In this work, we develop an explicit model of the astrocytic glutamate transporters, providing a more complete description of the glutamate chemical potential across the astrocytic membrane and its contribution to glutamate transporter driving force based on thermodynamic principles and experimental data. Analysis of our model demonstrates that increased astrocytic glutamate content due to glutamine synthetase downregulation also results in increased postsynaptic quantal size due to gliotransmission. Moreover, the proposed model demonstrates that increased astrocytic glutamate could prolong the time course of glutamate in the synaptic cleft and enhances astrocyte-induced slow inward currents, causing a disruption to the clarity of synaptic signalling and the occurrence of intervals of higher frequency postsynaptic firing. Overall, our work distilled the necessity of a low astrocytic glutamate concentration for reliable synaptic transmission of information and the possible implications of enhanced glutamate levels as in epilepsy.

Amino acid neurotransmitters and new approaches to anticonvulsant drug action.

PubMed

Meldrum, B

1984-01-01

Amino acids provide the most universal and important inhibitory (gamma-aminobutyric acid (GABA), glycine) and excitatory (glutamate, aspartate, cysteic acid, cysteine sulphinic acid) neurotransmitters in the brain. An anticonvulsant action may be produced (1) by enhancing inhibitory (GABAergic) processes, and (2) by diminishing excitatory transmission. Possible pharmacological mechanisms for enhancing GABA-mediated inhibition include (1) GABA agonist action, (2) GABA prodrugs, (3) drugs facilitating GABA release from terminals, (4) inhibition of GABA-transaminase, (5) allosteric enhancement of the efficacy of GABA at the receptor complex, (6) direction action on the chloride ionophore, and (7) inhibition of GABA reuptake. Examples of these approaches include the use of irreversible GABA-transaminase inhibitors, such as gamma-vinyl GABA, and the development of anticonvulsant beta-carbolines that interact with the "benzodiazepine receptor." Pharmacological mechanisms for diminishing excitatory transmission include (1) enzyme inhibitors that decrease the maximal rate of synthesis of glutamate or aspartate, (2) drugs that decrease the synaptic release of glutamate or aspartate, and (3) drugs that block the post-synaptic action of excitatory amino acids. Compounds that selectively antagonise excitation due to dicarboxylic amino acids have recently been developed. Those that selectively block excitation produced by N-methyl-D-aspartate (and aspartate) have proved to be potent anticonvulsants in many animal models of epilepsy. This provides a novel approach to the design of anticonvulsant drugs.

Zinc at glutamatergic synapses.

PubMed

Paoletti, P; Vergnano, A M; Barbour, B; Casado, M

2009-01-12

It has long been known that the mammalian forebrain contains a subset of glutamatergic neurons that sequester zinc in their synaptic vesicles. This zinc may be released into the synaptic cleft upon neuronal activity. Extracellular zinc has the potential to interact with and modulate many different synaptic targets, including glutamate receptors and transporters. Among these targets, NMDA receptors appear particularly interesting because certain NMDA receptor subtypes (those containing the NR2A subunit) contain allosteric sites exquisitely sensitive to extracellular zinc. The existence of these high-affinity zinc binding sites raises the possibility that zinc may act both in a phasic and tonic mode. Changes in zinc concentration and subcellular zinc distribution have also been described in several pathological conditions linked to glutamatergic transmission dysfunctions. However, despite intense investigation, the functional significance of vesicular zinc remains largely a mystery. In this review, we present the anatomy and the physiology of the glutamatergic zinc-containing synapse. Particular emphasis is put on the molecular and cellular mechanisms underlying the putative roles of zinc as a messenger involved in excitatory synaptic transmission and plasticity. We also highlight the many controversial issues and unanswered questions. Finally, we present and compare two widely used zinc chelators, CaEDTA and tricine, and show why tricine should be preferred to CaEDTA when studying fast transient zinc elevations as may occur during synaptic activity.

GABA regulates synaptic integration of newly generated neurons in the adult brain

NASA Astrophysics Data System (ADS)

Ge, Shaoyu; Goh, Eyleen L. K.; Sailor, Kurt A.; Kitabatake, Yasuji; Ming, Guo-Li; Song, Hongjun

2006-02-01

Adult neurogenesis, the birth and integration of new neurons from adult neural stem cells, is a striking form of structural plasticity and highlights the regenerative capacity of the adult mammalian brain. Accumulating evidence suggests that neuronal activity regulates adult neurogenesis and that new neurons contribute to specific brain functions. The mechanism that regulates the integration of newly generated neurons into the pre-existing functional circuitry in the adult brain is unknown. Here we show that newborn granule cells in the dentate gyrus of the adult hippocampus are tonically activated by ambient GABA (γ-aminobutyric acid) before being sequentially innervated by GABA- and glutamate-mediated synaptic inputs. GABA, the major inhibitory neurotransmitter in the adult brain, initially exerts an excitatory action on newborn neurons owing to their high cytoplasmic chloride ion content. Conversion of GABA-induced depolarization (excitation) into hyperpolarization (inhibition) in newborn neurons leads to marked defects in their synapse formation and dendritic development in vivo. Our study identifies an essential role for GABA in the synaptic integration of newly generated neurons in the adult brain, and suggests an unexpected mechanism for activity-dependent regulation of adult neurogenesis, in which newborn neurons may sense neuronal network activity through tonic and phasic GABA activation.

Wavelet Analysis of Nonstationary Fluctuations of Monte Carlo-Simulated Excitatory Postsynaptic Currents

PubMed Central

Aristizabal, F.; Glavinovic, M. I.

2003-01-01

Tracking spectral changes of rapidly varying signals is a demanding task. In this study, we explore on Monte Carlo-simulated glutamate-activated AMPA patch and synaptic currents whether a wavelet analysis offers such a possibility. Unlike Fourier methods that determine only the frequency content of a signal, the wavelet analysis determines both the frequency and the time. This is owing to the nature of the basis functions, which are infinite for Fourier transforms (sines and cosines are infinite), but are finite for wavelet analysis (wavelets are localized waves). In agreement with previous reports, the frequency of the stationary patch current fluctuations is higher for larger currents, whereas the mean-variance plots are parabolic. The spectra of the current fluctuations and mean-variance plots are close to the theoretically predicted values. The median frequency of the synaptic and nonstationary patch currents is, however, time dependent, though at the peak of synaptic currents, the median frequency is insensitive to the number of glutamate molecules released. Such time dependence demonstrates that the “composite spectra” of the current fluctuations gathered over the whole duration of synaptic currents cannot be used to assess the mean open time or effective mean open time of AMPA channels. The current (patch or synaptic) versus median frequency plots show hysteresis. The median frequency is thus not a simple reflection of the overall receptor saturation levels and is greater during the rise phase for the same saturation level. The hysteresis is due to the higher occupancy of the doubly bound state during the rise phase and not due to the spatial spread of the saturation disk, which remains remarkably constant. Albeit time dependent, the variance of the synaptic and nonstationary patch currents can be accurately determined. Nevertheless the evaluation of the number of AMPA channels and their single current from the mean-variance plots of patch or synaptic currents is not highly accurate owing to the varying number of the activatable AMPA channels caused by desensitization. The spatial nonuniformity of open, bound, and desensitized AMPA channels, and the time dependence and spatial nonuniformity of the glutamate concentration in the synaptic cleft, further reduce the accuracy of estimates of the number of AMPA channels from synaptic currents. In conclusion, wavelet analysis of nonstationary fluctuations of patch and synaptic currents expands our ability to determine accurately the variance and frequency of current fluctuations, demonstrates the limits of applicability of techniques currently used to evaluate the single channel current and number of AMPA channels, and offers new insights into the mechanisms involved in the generation of unitary quantal events at excitatory central synapses. PMID:14507683

Wavelet analysis of nonstationary fluctuations of Monte Carlo-simulated excitatory postsynaptic currents.

PubMed

Aristizabal, F; Glavinovic, M I

2003-10-01

Tracking spectral changes of rapidly varying signals is a demanding task. In this study, we explore on Monte Carlo-simulated glutamate-activated AMPA patch and synaptic currents whether a wavelet analysis offers such a possibility. Unlike Fourier methods that determine only the frequency content of a signal, the wavelet analysis determines both the frequency and the time. This is owing to the nature of the basis functions, which are infinite for Fourier transforms (sines and cosines are infinite), but are finite for wavelet analysis (wavelets are localized waves). In agreement with previous reports, the frequency of the stationary patch current fluctuations is higher for larger currents, whereas the mean-variance plots are parabolic. The spectra of the current fluctuations and mean-variance plots are close to the theoretically predicted values. The median frequency of the synaptic and nonstationary patch currents is, however, time dependent, though at the peak of synaptic currents, the median frequency is insensitive to the number of glutamate molecules released. Such time dependence demonstrates that the "composite spectra" of the current fluctuations gathered over the whole duration of synaptic currents cannot be used to assess the mean open time or effective mean open time of AMPA channels. The current (patch or synaptic) versus median frequency plots show hysteresis. The median frequency is thus not a simple reflection of the overall receptor saturation levels and is greater during the rise phase for the same saturation level. The hysteresis is due to the higher occupancy of the doubly bound state during the rise phase and not due to the spatial spread of the saturation disk, which remains remarkably constant. Albeit time dependent, the variance of the synaptic and nonstationary patch currents can be accurately determined. Nevertheless the evaluation of the number of AMPA channels and their single current from the mean-variance plots of patch or synaptic currents is not highly accurate owing to the varying number of the activatable AMPA channels caused by desensitization. The spatial nonuniformity of open, bound, and desensitized AMPA channels, and the time dependence and spatial nonuniformity of the glutamate concentration in the synaptic cleft, further reduce the accuracy of estimates of the number of AMPA channels from synaptic currents. In conclusion, wavelet analysis of nonstationary fluctuations of patch and synaptic currents expands our ability to determine accurately the variance and frequency of current fluctuations, demonstrates the limits of applicability of techniques currently used to evaluate the single channel current and number of AMPA channels, and offers new insights into the mechanisms involved in the generation of unitary quantal events at excitatory central synapses.

Electric Dipole Theory of Chemical Synaptic Transmission

PubMed Central

Wei, Ling Y.

1968-01-01

In this paper we propose that chemicals such as acetylcholine are electric dipoles which when oriented and arranged in a large array could produce an electric field strong enough to drive positive ions over the junction barrier of the post-synaptic membrane and thus initiate excitation or produce depolarization. This theory is able to explain a great number of facts such as cleft size, synaptic delay, nonregeneration, subthreshold integration, facilitation with repetition, and the calcium and magnesium effects. It also shows why and how acetylcholine could act as excitatory or inhibitory transmitters under different circumstances. Our conclusion is that the nature of synaptic transmission is essentially electrical, be it mediated by electrical or chemical transmitters. PMID:4296121

Homeostatic regulation of excitatory synapses on striatal medium spiny neurons expressing the D2 dopamine receptor.

PubMed

Thibault, Dominic; Giguère, Nicolas; Loustalot, Fabien; Bourque, Marie-Josée; Ducrot, Charles; El Mestikawy, Salah; Trudeau, Louis-Éric

2016-05-01

Striatal medium spiny neurons (MSNs) are contacted by glutamatergic axon terminals originating from cortex, thalamus and other regions. The striatum is also innervated by dopaminergic (DAergic) terminals, some of which release glutamate as a co-transmitter. Despite evidence for functional DA release at birth in the striatum, the role of DA in the establishment of striatal circuitry is unclear. In light of recent work suggesting activity-dependent homeostatic regulation of glutamatergic terminals on MSNs expressing the D2 DA receptor (D2-MSNs), we used primary co-cultures to test the hypothesis that stimulation of DA and glutamate receptors regulates the homeostasis of glutamatergic synapses on MSNs. Co-culture of D2-MSNs with mesencephalic DA neurons or with cortical neurons produced an increase in spines and functional glutamate synapses expressing VGLUT2 or VGLUT1, respectively. The density of VGLUT2-positive terminals was reduced by the conditional knockout of this gene from DA neurons. In the presence of both mesencephalic and cortical neurons, the density of synapses reached the same total, compatible with the possibility of a homeostatic mechanism capping excitatory synaptic density. Blockade of D2 receptors increased the density of cortical and mesencephalic glutamatergic terminals, without changing MSN spine density or mEPSC frequency. Combined blockade of AMPA and NMDA glutamate receptors increased the density of cortical terminals and decreased that of mesencephalic VGLUT2-positive terminals, with no net change in total excitatory terminal density or in mEPSC frequency. These results suggest that DA and glutamate signaling regulate excitatory inputs to striatal D2-MSNs at both the pre- and postsynaptic level, under the influence of a homeostatic mechanism controlling functional output of the circuit.

Correlating Fluorescence and High-Resolution Scanning Electron Microscopy (HRSEM) for the study of GABAA receptor clustering induced by inhibitory synaptic plasticity.

PubMed

Orlando, Marta; Ravasenga, Tiziana; Petrini, Enrica Maria; Falqui, Andrea; Marotta, Roberto; Barberis, Andrea

2017-10-23

Both excitatory and inhibitory synaptic contacts display activity dependent dynamic changes in their efficacy that are globally termed synaptic plasticity. Although the molecular mechanisms underlying glutamatergic synaptic plasticity have been extensively investigated and described, those responsible for inhibitory synaptic plasticity are only beginning to be unveiled. In this framework, the ultrastructural changes of the inhibitory synapses during plasticity have been poorly investigated. Here we combined confocal fluorescence microscopy (CFM) with high resolution scanning electron microscopy (HRSEM) to characterize the fine structural rearrangements of post-synaptic GABA A Receptors (GABA A Rs) at the nanometric scale during the induction of inhibitory long-term potentiation (iLTP). Additional electron tomography (ET) experiments on immunolabelled hippocampal neurons allowed the visualization of synaptic contacts and confirmed the reorganization of post-synaptic GABA A R clusters in response to chemical iLTP inducing protocol. Altogether, these approaches revealed that, following the induction of inhibitory synaptic potentiation, GABA A R clusters increase in size and number at the post-synaptic membrane with no other major structural changes of the pre- and post-synaptic elements.

Flexible Ionic-Electronic Hybrid Oxide Synaptic TFTs with Programmable Dynamic Plasticity for Brain-Inspired Neuromorphic Computing.

PubMed

John, Rohit Abraham; Ko, Jieun; Kulkarni, Mohit R; Tiwari, Naveen; Chien, Nguyen Anh; Ing, Ng Geok; Leong, Wei Lin; Mathews, Nripan

2017-08-01

Emulation of biological synapses is necessary for future brain-inspired neuromorphic computational systems that could look beyond the standard von Neuman architecture. Here, artificial synapses based on ionic-electronic hybrid oxide-based transistors on rigid and flexible substrates are demonstrated. The flexible transistors reported here depict a high field-effect mobility of ≈9 cm 2 V -1 s -1 with good mechanical performance. Comprehensive learning abilities/synaptic rules like paired-pulse facilitation, excitatory and inhibitory postsynaptic currents, spike-time-dependent plasticity, consolidation, superlinear amplification, and dynamic logic are successfully established depicting concurrent processing and memory functionalities with spatiotemporal correlation. The results present a fully solution processable approach to fabricate artificial synapses for next-generation transparent neural circuits. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Synaptic structure and function are altered by the neddylation inhibitor MLN4924

PubMed Central

Scudder, Samantha L.; Patrick, Gentry N.

2015-01-01

The posttranslational modification of proteins by the ubiquitin-like small molecule NEDD8 has previously been shown to be vital in a number of cell signaling pathways. In particular, conjugation of NEDD8 (neddylation) serves to regulate protein ubiquitination through modifications to E3 ubiquitin ligases. Despite the prevalence of NEDD8 in neurons, very little work has been done to characterize the role of this modifier in these cells. Here, we use the recently developed NEDD8 Activating Enzyme (NAE) inhibitor MLN4924 and report evidence of a role for NEDD8 in regulating mammalian excitatory synapses. Application of this drug to dissociated rat hippocampal neurons caused reductions in synaptic strength, surface glutamate receptor levels, dendritic spine width, and spine density, suggesting that neddylation is involved in the maintenance of synapses. PMID:25701678

Age- and Sex-Dependent Impact of Repeated Social Stress on Intrinsic and Synaptic Excitability of the Rat Prefrontal Cortex

PubMed Central

Urban, Kimberly R.; Valentino, Rita J.

2017-01-01

Abstract Stress is implicated in psychiatric illnesses that are characterized by impairments in cognitive functions that are mediated by the medial prefrontal cortex (mPFC). Because sex and age determine stress vulnerability, the effects of repeated social stress occurring during early adolescence, mid-adolescence, or adulthood on the cellular properties of male and female rat mPFC Layer V neurons in vitro were examined. Repeated resident–intruder stress produced age- and sex-specific effects on mPFC intrinsic and synaptic excitability. Mid-adolescents were particularly vulnerable to effects on intrinsic excitability. The maximum number of action potentials (APs) evoked by increasing current intensity was robustly decreased in stressed male and female mid-adolescent rats compared with age-matched controls. These effects were associated with stress-induced changes in AP half-width, amplitude, threshold, and input resistance. Social stress at all ages generally decreased synaptic excitability by decreasing the amplitude of spontaneous excitatory postsynaptic potentials. The results suggest that whereas social stress throughout life can diminish the influence of afferents driving the mPFC, social stress during mid-adolescence additionally affects intrinsic characteristics of mPFC neurons that determine excitability. The depressant effects of social stress on intrinsic and synaptic mPFC neurons may underlie its ability to affect executive functions and emotional responses, particularly during adolescence. PMID:28013234

Age- and Sex-Dependent Impact of Repeated Social Stress on Intrinsic and Synaptic Excitability of the Rat Prefrontal Cortex.

PubMed

Urban, Kimberly R; Valentino, Rita J

2017-01-01

Stress is implicated in psychiatric illnesses that are characterized by impairments in cognitive functions that are mediated by the medial prefrontal cortex (mPFC). Because sex and age determine stress vulnerability, the effects of repeated social stress occurring during early adolescence, mid-adolescence, or adulthood on the cellular properties of male and female rat mPFC Layer V neurons in vitro were examined. Repeated resident-intruder stress produced age- and sex-specific effects on mPFC intrinsic and synaptic excitability. Mid-adolescents were particularly vulnerable to effects on intrinsic excitability. The maximum number of action potentials (APs) evoked by increasing current intensity was robustly decreased in stressed male and female mid-adolescent rats compared with age-matched controls. These effects were associated with stress-induced changes in AP half-width, amplitude, threshold, and input resistance. Social stress at all ages generally decreased synaptic excitability by decreasing the amplitude of spontaneous excitatory postsynaptic potentials. The results suggest that whereas social stress throughout life can diminish the influence of afferents driving the mPFC, social stress during mid-adolescence additionally affects intrinsic characteristics of mPFC neurons that determine excitability. The depressant effects of social stress on intrinsic and synaptic mPFC neurons may underlie its ability to affect executive functions and emotional responses, particularly during adolescence. © The Author 2016. Published by Oxford University Press.

Establishment of high reciprocal connectivity between clonal cortical neurons is regulated by the Dnmt3b DNA methyltransferase and clustered protocadherins.

PubMed

Tarusawa, Etsuko; Sanbo, Makoto; Okayama, Atsushi; Miyashita, Toshio; Kitsukawa, Takashi; Hirayama, Teruyoshi; Hirabayashi, Takahiro; Hasegawa, Sonoko; Kaneko, Ryosuke; Toyoda, Shunsuke; Kobayashi, Toshihiro; Kato-Itoh, Megumi; Nakauchi, Hiromitsu; Hirabayashi, Masumi; Yagi, Takeshi; Yoshimura, Yumiko

2016-12-02

The specificity of synaptic connections is fundamental for proper neural circuit function. Specific neuronal connections that underlie information processing in the sensory cortex are initially established without sensory experiences to a considerable extent, and then the connections are individually refined through sensory experiences. Excitatory neurons arising from the same single progenitor cell are preferentially connected in the postnatal cortex, suggesting that cell lineage contributes to the initial wiring of neurons. However, the postnatal developmental process of lineage-dependent connection specificity is not known, nor how clonal neurons, which are derived from the same neural stem cell, are stamped with the identity of their common neural stem cell and guided to form synaptic connections. We show that cortical excitatory neurons that arise from the same neural stem cell and reside within the same layer preferentially establish reciprocal synaptic connections in the mouse barrel cortex. We observed a transient increase in synaptic connections between clonal but not nonclonal neuron pairs during postnatal development, followed by selective stabilization of the reciprocal connections between clonal neuron pairs. Furthermore, we demonstrate that selective stabilization of the reciprocal connections between clonal neuron pairs is impaired by the deficiency of DNA methyltransferase 3b (Dnmt3b), which determines DNA-methylation patterns of genes in stem cells during early corticogenesis. Dnmt3b regulates the postnatal expression of clustered protocadherin (cPcdh) isoforms, a family of adhesion molecules. We found that cPcdh deficiency in clonal neuron pairs impairs the whole process of the formation and stabilization of connections to establish lineage-specific connection reciprocity. Our results demonstrate that local, reciprocal neural connections are selectively formed and retained between clonal neurons in layer 4 of the barrel cortex during postnatal development, and that Dnmt3b and cPcdhs are required for the establishment of lineage-specific reciprocal connections. These findings indicate that lineage-specific connection reciprocity is predetermined by Dnmt3b during embryonic development, and that the cPcdhs contribute to postnatal cortical neuron identification to guide lineage-dependent synaptic connections in the neocortex.

Netrin-G1 regulates fear-like and anxiety-like behaviors in dissociable neural circuits.

PubMed

Zhang, Qi; Sano, Chie; Masuda, Akira; Ando, Reiko; Tanaka, Mika; Itohara, Shigeyoshi

2016-06-27

In vertebrate mammals, distributed neural circuits in the brain are involved in emotion-related behavior. Netrin-G1 is a glycosyl-phosphatidylinositol-anchored synaptic adhesion molecule whose deficiency results in impaired fear-like and anxiety-like behaviors under specific circumstances. To understand the cell type and circuit specificity of these responses, we generated netrin-G1 conditional knockout mice with loss of expression in cortical excitatory neurons, inhibitory neurons, or thalamic neurons. Genetic deletion of netrin-G1 in cortical excitatory neurons resulted in altered anxiety-like behavior, but intact fear-like behavior, whereas loss of netrin-G1 in inhibitory neurons resulted in attenuated fear-like behavior, but intact anxiety-like behavior. These data indicate a remarkable double dissociation of fear-like and anxiety-like behaviors involving netrin-G1 in excitatory and inhibitory neurons, respectively. Our findings support a crucial role for netrin-G1 in dissociable neural circuits for the modulation of emotion-related behaviors, and provide genetic models for investigating the mechanisms underlying the dissociation. The results also suggest the involvement of glycosyl-phosphatidylinositol-anchored synaptic adhesion molecules in the development and pathogenesis of emotion-related behavior.

Towards a general theory of neural computation based on prediction by single neurons.

PubMed

Fiorillo, Christopher D

2008-10-01

Although there has been tremendous progress in understanding the mechanics of the nervous system, there has not been a general theory of its computational function. Here I present a theory that relates the established biophysical properties of single generic neurons to principles of Bayesian probability theory, reinforcement learning and efficient coding. I suggest that this theory addresses the general computational problem facing the nervous system. Each neuron is proposed to mirror the function of the whole system in learning to predict aspects of the world related to future reward. According to the model, a typical neuron receives current information about the state of the world from a subset of its excitatory synaptic inputs, and prior information from its other inputs. Prior information would be contributed by synaptic inputs representing distinct regions of space, and by different types of non-synaptic, voltage-regulated channels representing distinct periods of the past. The neuron's membrane voltage is proposed to signal the difference between current and prior information ("prediction error" or "surprise"). A neuron would apply a Hebbian plasticity rule to select those excitatory inputs that are the most closely correlated with reward but are the least predictable, since unpredictable inputs provide the neuron with the most "new" information about future reward. To minimize the error in its predictions and to respond only when excitation is "new and surprising," the neuron selects amongst its prior information sources through an anti-Hebbian rule. The unique inputs of a mature neuron would therefore result from learning about spatial and temporal patterns in its local environment, and by extension, the external world. Thus the theory describes how the structure of the mature nervous system could reflect the structure of the external world, and how the complexity and intelligence of the system might develop from a population of undifferentiated neurons, each implementing similar learning algorithms.

Synapse-specific astrocyte gating of amygdala-related behavior.

PubMed

Martin-Fernandez, Mario; Jamison, Stephanie; Robin, Laurie M; Zhao, Zhe; Martin, Eduardo D; Aguilar, Juan; Benneyworth, Michael A; Marsicano, Giovanni; Araque, Alfonso

2017-11-01

The amygdala plays key roles in fear and anxiety. Studies of the amygdala have largely focused on neuronal function and connectivity. Astrocytes functionally interact with neurons, but their role in the amygdala remains largely unknown. We show that astrocytes in the medial subdivision of the central amygdala (CeM) determine the synaptic and behavioral outputs of amygdala circuits. To investigate the role of astrocytes in amygdala-related behavior and identify the underlying synaptic mechanisms, we used exogenous or endogenous signaling to selectively activate CeM astrocytes. Astrocytes depressed excitatory synapses from basolateral amygdala via A 1 adenosine receptor activation and enhanced inhibitory synapses from the lateral subdivision of the central amygdala via A 2A receptor activation. Furthermore, astrocytic activation decreased the firing rate of CeM neurons and reduced fear expression in a fear-conditioning paradigm. Therefore, we conclude that astrocyte activity determines fear responses by selectively regulating specific synapses, which indicates that animal behavior results from the coordinated activity of neurons and astrocytes.

Input-Specific NMDAR-Dependent Potentiation of Dendritic GABAergic Inhibition.

PubMed

Chiu, Chiayu Q; Martenson, James S; Yamazaki, Maya; Natsume, Rie; Sakimura, Kenji; Tomita, Susumu; Tavalin, Steven J; Higley, Michael J

2018-01-17

Preservation of a balance between synaptic excitation and inhibition is critical for normal brain function. A number of homeostatic cellular mechanisms have been suggested to play a role in maintaining this balance, including long-term plasticity of GABAergic inhibitory synapses. Many previous studies have demonstrated a coupling of postsynaptic spiking with modification of perisomatic inhibition. Here, we demonstrate that activation of NMDA-type glutamate receptors leads to input-specific long-term potentiation of dendritic inhibition mediated by somatostatin-expressing interneurons. This form of plasticity is expressed postsynaptically and requires both CaMKIIα and the β2 subunit of the GABA-A receptor. Importantly, this process may function to preserve dendritic inhibition, as genetic deletion of NMDAR signaling results in a selective weakening of dendritic inhibition. Overall, our results reveal a new mechanism for linking excitatory and inhibitory input in neuronal dendrites and provide novel insight into the homeostatic regulation of synaptic transmission in cortical circuits. Copyright © 2017 Elsevier Inc. All rights reserved.

Structural and Functional Architecture of AMPA-Type Glutamate Receptors and Their Auxiliary Proteins.

PubMed

Greger, Ingo H; Watson, Jake F; Cull-Candy, Stuart G

2017-05-17

AMPA receptors (AMPARs) are tetrameric ion channels that together with other ionotropic glutamate receptors (iGluRs), the NMDA and kainate receptors, mediate a majority of excitatory neurotransmission in the central nervous system. Whereas NMDA receptors gate channels with slow kinetics, responsible primarily for generating long-term synaptic potentiation and depression, AMPARs are the main fast transduction elements at synapses and are critical for the expression of plasticity. The kinetic and conductance properties of AMPARs are laid down during their biogenesis and are regulated by post-transcriptional RNA editing, splice variation, post-translational modification, and subunit composition. Furthermore, AMPAR assembly, trafficking, and functional heterogeneity depends on a large repertoire of auxiliary subunits-a feature that is particularly striking for this type of iGluR. Here, we discuss how the subunit structure, stoichiometry, and auxiliary subunits generate a heterogeneous plethora of receptors, each tailored to fulfill a vital role in fast synaptic signaling and plasticity. Copyright © 2017 Elsevier Inc. All rights reserved.

Clustered Dynamics of Inhibitory Synapses and Dendritic Spines in the Adult Neocortex

PubMed Central

Chen, Jerry L.; Villa, Katherine L; Cha, Jae Won; So, Peter T.C.; Kubota, Yoshiyuki; Nedivi, Elly

2012-01-01

A key feature of the mammalian brain is its capacity to adapt in response to experience, in part by remodeling of synaptic connections between neurons. Excitatory synapse rearrangements have been monitored in vivo by observation of dendritic spine dynamics, but lack of a vital marker for inhibitory synapses has precluded their observation. Here, we simultaneously monitor in vivo inhibitory synapse and dendritic spine dynamics across the entire dendritic arbor of pyramidal neurons in the adult mammalian cortex using large volume high-resolution dual color two-photon microscopy. We find that inhibitory synapses on dendritic shafts and spines differ in their distribution across the arbor and in their remodeling kinetics during normal and altered sensory experience. Further, we find inhibitory synapse and dendritic spine remodeling to be spatially clustered, and that clustering is influenced by sensory input. Our findings provide in vivo evidence for local coordination of inhibitory and excitatory synaptic rearrangements. PMID:22542188

Mechanisms of Nicotine Addiction

DOE Office of Scientific and Technical Information (OSTI.GOV)

McGehee, Daniel

Nicotine reinforces the use of tobacco products primarily through its interaction with specific receptor proteins within the brain’s reward centers. A critical step in the process of addiction for many drugs, including nicotine, is the release of the neurotransmitter dopamine. A single nicotine exposure will enhance dopamine levels for hours, however, nicotinic receptors undergo both activation and then desensitization in minutes, which presents an important problem. How does the time course of receptor activity lead to the prolonged release of dopamine? We have found that persistent modulation of both inhibitory and excitatory synaptic connections by nicotine underlies the sustained increasemore » in dopamine release. Because these inputs express different types of nicotinic receptors there is a coordinated shift in the balance of synaptic inputs toward excitation of the dopamine neurons. Excitatory inputs are turned on while inhibitory inputs are depressed, thereby boosting the brain’s reward system.« less

Characterization and Modeling of Nonfilamentary Ta/TaOx/TiO2/Ti Analog Synaptic Device

PubMed Central

Wang, Yu-Fen; Lin, Yen-Chuan; Wang, I-Ting; Lin, Tzu-Ping; Hou, Tuo-Hung

2015-01-01

A two-terminal analog synaptic device that precisely emulates biological synaptic features is expected to be a critical component for future hardware-based neuromorphic computing. Typical synaptic devices based on filamentary resistive switching face severe limitations on the implementation of concurrent inhibitory and excitatory synapses with low conductance and state fluctuation. For overcoming these limitations, we propose a Ta/TaOx/TiO2/Ti device with superior analog synaptic features. A physical simulation based on the homogeneous (nonfilamentary) barrier modulation induced by oxygen ion migration accurately reproduces various DC and AC evolutions of synaptic states, including the spike-timing-dependent plasticity and paired-pulse facilitation. Furthermore, a physics-based compact model for facilitating circuit-level design is proposed on the basis of the general definition of memristor devices. This comprehensive experimental and theoretical study of the promising electronic synapse can facilitate realizing large-scale neuromorphic systems. PMID:25955658

CHRONIC HYPERTENSION ENHANCES PRE-SYNAPTIC INHIBITION BY BACLOFEN IN THE NUCLEUS OF THE SOLITARY TRACT

PubMed Central

Zhang, Weirong; Mifflin, Steve

2010-01-01

The selective γ-aminobutyric acid B-subtype receptor agonist baclofen activates both pre- and post-synaptic receptors in the brain. Microinjection of baclofen into the nucleus of the solitary tract increases arterial pressure, heart rate and sympathetic nerve discharge consistent with inhibition of the arterial baroreflex. The magnitude of these responses is enhanced in hypertension and is associated with increased post-synaptic GABAB receptor function. We tested whether a pre-synaptic mechanism contributes to the enhanced baclofen inhibition in hypertension. Whole-cell recordings of second-order baroreceptor neurons, identified by 4-(4-(dihexadecylamino)styryl)-N-methylpyridinium iodide labeling of aortic nerve, were obtained in brainstem slices from normotensive control and renal-wrap hypertensive rats. After 4 weeks, arterial blood pressure was 162±9 mmHg in hypertensive (n=6) and 107±3 mmHg in control rats (n=6/11, p<0.001). Baclofen reduced the amplitude of excitatory post-synaptic currents evoked by solitary tract stimulation and the EC50 of this inhibition was greater in control (1.5±0.5 µmol/L, n=6) than hypertensive cells (0.6±0.1 µmol/L, n=9, p<0.05). Baclofen (1 µmol/L) elicited greater inhibition on evoked response in hypertensive (58±6%, n=9) than control cells (40±6%, n=8, p<0.05). Another index of pre-synaptic inhibition, the paired-pulse ratio (ratio of second to first evoked response amplitudes at stimulus intervals of 40 ms), was greater in hypertensive (0.60±0.08, n=8) than control cells (0.48±0.06. n=5, p<0.05). The results suggest that in renal-wrap hypertensive rats, baclofen causes an enhanced pre-synaptic inhibition of glutamate release from baroreceptor afferent terminals to second-order neurons in the nucleus of the solitary tract. This enhanced pre-synaptic inhibition could contribute to altered baroreflex function in hypertension. PMID:20038748

Impaired neurogenesis of the dentate gyrus is associated with pattern separation deficits: A computational study.

PubMed

Faghihi, Faramarz; Moustafa, Ahmed A

2016-09-01

The separation of input patterns received from the entorhinal cortex (EC) by the dentate gyrus (DG) is a well-known critical step of information processing in the hippocampus. Although the role of interneurons in separation pattern efficiency of the DG has been theoretically known, the balance of neurogenesis of excitatory neurons and interneurons as well as its potential role in information processing in the DG is not fully understood. In this work, we study separation efficiency of the DG for different rates of neurogenesis of interneurons and excitatory neurons using a novel computational model in which we assume an increase in the synaptic efficacy between excitatory neurons and interneurons and then its decay over time. Information processing in the EC and DG was simulated as information flow in a two layer feed-forward neural network. The neurogenesis rate was modeled as the percentage of new born neurons added to the neuronal population in each time bin. The results show an important role of an optimal neurogenesis rate of interneurons and excitatory neurons in the DG in efficient separation of inputs from the EC in pattern separation tasks. The model predicts that any deviation of the optimal values of neurogenesis rates leads to different decreased levels of the separation deficits of the DG which influences its function to encode memory.

Visual Receptive Field Structure of Cortical Inhibitory Neurons Revealed by Two-Photon Imaging Guided Recording

PubMed Central

Liu, Bao-hua; Li, Pingyang; Li, Ya-tang; Sun, Yujiao J.; Yanagawa, Yuchio; Obata, Kunihiko; Zhang, Li I.; Tao, Huizhong W.

2009-01-01

Synaptic inhibition plays an important role in shaping receptive field (RF) properties in the visual cortex. However, the underlying mechanisms remain not well understood, partly due to difficulties in systematically studying functional properties of cortical inhibitory neurons in vivo. Here, we established two-photon imaging guided cell-attached recordings from genetically labelled inhibitory neurons and nearby “shadowed” excitatory neurons in the primary visual cortex of adult mice. Our results revealed that in layer 2/3, the majority of excitatory neurons exhibited both On and Off spike subfields, with their spatial arrangement varying from being completely segregated to overlapped. On the other hand, most layer 4 excitatory neurons exhibited only one discernable subfield. Interestingly, no RF structure with significantly segregated On and Off subfields was observed for layer 2/3 inhibitory neurons of either the fast-spike or regular-spike type. They predominantly possessed overlapped On and Off subfields with a significantly larger size than the excitatory neurons, and exhibited much weaker orientation tuning. These results from the mouse visual cortex suggest that different from the push-pull model proposed for simple cells, layer 2/3 simple-type neurons with segregated spike On and Off subfields likely receive spatially overlapped inhibitory On and Off inputs. We propose that the phase-insensitive inhibition can enhance the spatial distinctiveness of On and Off subfields through a gain control mechanism. PMID:19710305

PSD-95 family MAGUKs are essential for anchoring AMPA and NMDA receptor complexes at the postsynaptic density

PubMed Central

Chen, Xiaobing; Levy, Jonathan M.; Hou, Austin; Winters, Christine; Azzam, Rita; Sousa, Alioscka A.; Leapman, Richard D.; Nicoll, Roger A.; Reese, Thomas S.

2015-01-01

The postsynaptic density (PSD)-95 family of membrane-associated guanylate kinases (MAGUKs) are major scaffolding proteins at the PSD in glutamatergic excitatory synapses, where they maintain and modulate synaptic strength. How MAGUKs underlie synaptic strength at the molecular level is still not well understood. Here, we explore the structural and functional roles of MAGUKs at hippocampal excitatory synapses by simultaneous knocking down PSD-95, PSD-93, and synapse-associated protein (SAP)102 and combining electrophysiology and transmission electron microscopic (TEM) tomography imaging to analyze the resulting changes. Acute MAGUK knockdown greatly reduces synaptic transmission mediated by α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPARs) and N-methyl-d-aspartate receptors (NMDARs). This knockdown leads to a significant rise in the number of silent synapses, diminishes the size of PSDs without changes in pre- or postsynaptic membrane, and depletes the number of membrane-associated PSD-95–like vertical filaments and transmembrane structures, identified as AMPARs and NMDARs by EM tomography. The differential distribution of these receptor-like structures and dependence of their abundance on PSD size matches that of AMPARs and NMDARs in the hippocampal synapses. The loss of these structures following MAGUK knockdown tracks the reduction in postsynaptic AMPAR and NMDAR transmission, confirming the structural identities of these two types of receptors. These results demonstrate that MAGUKs are required for anchoring both types of glutamate receptors at the PSD and are consistent with a structural model where MAGUKs, corresponding to membrane-associated vertical filaments, are the essential structural proteins that anchor and organize both types of glutamate receptors and govern the overall molecular organization of the PSD. PMID:26604311

PSD-95 family MAGUKs are essential for anchoring AMPA and NMDA receptor complexes at the postsynaptic density.

PubMed

Chen, Xiaobing; Levy, Jonathan M; Hou, Austin; Winters, Christine; Azzam, Rita; Sousa, Alioscka A; Leapman, Richard D; Nicoll, Roger A; Reese, Thomas S

2015-12-15

The postsynaptic density (PSD)-95 family of membrane-associated guanylate kinases (MAGUKs) are major scaffolding proteins at the PSD in glutamatergic excitatory synapses, where they maintain and modulate synaptic strength. How MAGUKs underlie synaptic strength at the molecular level is still not well understood. Here, we explore the structural and functional roles of MAGUKs at hippocampal excitatory synapses by simultaneous knocking down PSD-95, PSD-93, and synapse-associated protein (SAP)102 and combining electrophysiology and transmission electron microscopic (TEM) tomography imaging to analyze the resulting changes. Acute MAGUK knockdown greatly reduces synaptic transmission mediated by α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPARs) and N-methyl-d-aspartate receptors (NMDARs). This knockdown leads to a significant rise in the number of silent synapses, diminishes the size of PSDs without changes in pre- or postsynaptic membrane, and depletes the number of membrane-associated PSD-95-like vertical filaments and transmembrane structures, identified as AMPARs and NMDARs by EM tomography. The differential distribution of these receptor-like structures and dependence of their abundance on PSD size matches that of AMPARs and NMDARs in the hippocampal synapses. The loss of these structures following MAGUK knockdown tracks the reduction in postsynaptic AMPAR and NMDAR transmission, confirming the structural identities of these two types of receptors. These results demonstrate that MAGUKs are required for anchoring both types of glutamate receptors at the PSD and are consistent with a structural model where MAGUKs, corresponding to membrane-associated vertical filaments, are the essential structural proteins that anchor and organize both types of glutamate receptors and govern the overall molecular organization of the PSD.

Neuroligin-1 overexpression in newborn granule cells in vivo.

PubMed

Schnell, Eric; Bensen, Aesoon L; Washburn, Eric K; Westbrook, Gary L

2012-01-01

Adult-born dentate granule cells integrate into the hippocampal network, extend neurites and form synapses in otherwise mature tissue. Excitatory and inhibitory inputs innervate these new granule cells in a stereotyped, temporally segregated manner, which presents a unique opportunity to study synapse development in the adult brain. To examine the role of neuroligins as synapse-inducing molecules in vivo, we infected dividing neural precursors in adult mice with a retroviral construct that increased neuroligin-1 levels during granule cell differentiation. By 21 days post-mitosis, exogenous neuroligin-1 was expressed at the tips of dendritic spines and increased the number of dendritic spines. Neuroligin-1-overexpressing cells showed a selective increase in functional excitatory synapses and connection multiplicity by single afferent fibers, as well as an increase in the synaptic AMPA/NMDA receptor ratio. In contrast to its synapse-inducing ability in vitro, neuroligin-1 overexpression did not induce precocious synapse formation in adult-born neurons. However, the dendrites of neuroligin-1-overexpressing cells did have more thin protrusions during an early period of dendritic outgrowth, suggesting enhanced filopodium formation or stabilization. Our results indicate that neuroligin-1 expression selectively increases the degree, but not the onset, of excitatory synapse formation in adult-born neurons.

Dynamics of networks of excitatory and inhibitory neurons in response to time-dependent inputs.

PubMed

Ledoux, Erwan; Brunel, Nicolas

2011-01-01

We investigate the dynamics of recurrent networks of excitatory (E) and inhibitory (I) neurons in the presence of time-dependent inputs. The dynamics is characterized by the network dynamical transfer function, i.e., how the population firing rate is modulated by sinusoidal inputs at arbitrary frequencies. Two types of networks are studied and compared: (i) a Wilson-Cowan type firing rate model; and (ii) a fully connected network of leaky integrate-and-fire (LIF) neurons, in a strong noise regime. We first characterize the region of stability of the "asynchronous state" (a state in which population activity is constant in time when external inputs are constant) in the space of parameters characterizing the connectivity of the network. We then systematically characterize the qualitative behaviors of the dynamical transfer function, as a function of the connectivity. We find that the transfer function can be either low-pass, or with a single or double resonance, depending on the connection strengths and synaptic time constants. Resonances appear when the system is close to Hopf bifurcations, that can be induced by two separate mechanisms: the I-I connectivity and the E-I connectivity. Double resonances can appear when excitatory delays are larger than inhibitory delays, due to the fact that two distinct instabilities exist with a finite gap between the corresponding frequencies. In networks of LIF neurons, changes in external inputs and external noise are shown to be able to change qualitatively the network transfer function. Firing rate models are shown to exhibit the same diversity of transfer functions as the LIF network, provided delays are present. They can also exhibit input-dependent changes of the transfer function, provided a suitable static non-linearity is incorporated.

Ultrastructure of identified fast excitatory, slow excitatory and inhibitory neuromuscular junctions in the locust.

PubMed

Titmus, M J

1981-06-01

The specialized jumping muscle of the locust, the metathoracic extensor tibiae (ETi), is innervated by four physiologically different motoneurons, including FETi, a phasic excitor, SETi, a tonic excitor, and CI, a tonic common inhibitor. FETi neuromuscular junctions were examined in three phasic ETi bundles innervated by FETi. FETi terminals were characterized by patchy contacts on to granular sarcoplasm. The ETi accessory extensor, innervated by both SETi and CI, contains two morphologically different types of axon ending. When this muscle was soaked in horseradish peroxidase, stimulation of SETi led to selective uptake in vesicles in terminals similar to those of FETi axons but containing smaller vesicles, while stimulation by CI caused increased uptake into terminals with more extensive contact directly on to fibrillar sarcoplasm. As has been observed in excitatory and inhibitory synapses in some crustacean and vertebrate nervous systems, the synaptic vesicles in the locust excitatory endings are round and electron-lucent while those in the inhibitory endings are more irregular in shape. The tonic neuromuscular junctions, SETi and CI, are more densely packed with vesicles, larger in cross-sectional area and appear to be of more complex shape than the smaller, vesicle-sparse, phasic FETi terminals. Following long duration stimulation at 10 Hz, the tonic neuromuscular junctions showed little morphological change. FETi endings, which fatigue within minutes at the same stimulation frequency, showed a 20% decrease in synaptic vesicle density and an increase in irregularly shaped membrane inclusions.

Cell Type–Specific Three-Dimensional Structure of Thalamocortical Circuits in a Column of Rat Vibrissal Cortex

PubMed Central

de Kock, Christiaan P. J.; Bruno, Randy M.; Ramirez, Alejandro; Meyer, Hanno S.; Dercksen, Vincent J.; Helmstaedter, Moritz; Sakmann, Bert

2012-01-01

Soma location, dendrite morphology, and synaptic innervation may represent key determinants of functional responses of individual neurons, such as sensory-evoked spiking. Here, we reconstruct the 3D circuits formed by thalamocortical afferents from the lemniscal pathway and excitatory neurons of an anatomically defined cortical column in rat vibrissal cortex. We objectively classify 9 cortical cell types and estimate the number and distribution of their somata, dendrites, and thalamocortical synapses. Somata and dendrites of most cell types intermingle, while thalamocortical connectivity depends strongly upon the cell type and the 3D soma location of the postsynaptic neuron. Correlating dendrite morphology and thalamocortical connectivity to functional responses revealed that the lemniscal afferents can account for some of the cell type- and location-specific subthreshold and spiking responses after passive whisker touch (e.g., in layer 4, but not for other cell types, e.g., in layer 5). Our data provides a quantitative 3D prediction of the cell type–specific lemniscal synaptic wiring diagram and elucidates structure–function relationships of this physiologically relevant pathway at single-cell resolution. PMID:22089425

Excitatory neuronal connectivity in the barrel cortex

PubMed Central

Feldmeyer, Dirk

2012-01-01

Neocortical areas are believed to be organized into vertical modules, the cortical columns, and the horizontal layers 1–6. In the somatosensory barrel cortex these columns are defined by the readily discernible barrel structure in layer 4. Information processing in the neocortex occurs along vertical and horizontal axes, thereby linking individual barrel-related columns via axons running through the different cortical layers of the barrel cortex. Long-range signaling occurs within the neocortical layers but also through axons projecting through the white matter to other neocortical areas and subcortical brain regions. Because of the ease of identification of barrel-related columns, the rodent barrel cortex has become a prototypical system to study the interactions between different neuronal connections within a sensory cortical area and between this area and other cortical as well subcortical regions. Such interactions will be discussed specifically for the feed-forward and feedback loops between the somatosensory and the somatomotor cortices as well as the different thalamic nuclei. In addition, recent advances concerning the morphological characteristics of excitatory neurons and their impact on the synaptic connectivity patterns and signaling properties of neuronal microcircuits in the whisker-related somatosensory cortex will be reviewed. In this context, their relationship between the structural properties of barrel-related columns and their function as a module in vertical synaptic signaling in the whisker-related cortical areas will be discussed. PMID:22798946

Olfactory bulb short axon cell release of GABA and dopamine produces a temporally biphasic inhibition-excitation response in external tufted cells.

PubMed

Liu, Shaolin; Plachez, Celine; Shao, Zuoyi; Puche, Adam; Shipley, Michael T

2013-02-13

Evidence for coexpression of two or more classic neurotransmitters in neurons has increased, but less is known about cotransmission. Ventral tegmental area (VTA) neurons corelease dopamine (DA), the excitatory transmitter glutamate, and the inhibitory transmitter GABA onto target cells in the striatum. Olfactory bulb (OB) short axon cells (SACs) form interglomerular connections and coexpress markers for DA and GABA. Using an optogenetic approach, we provide evidence that mouse OB SACs release both GABA and DA onto external tufted cells (ETCs) in other glomeruli. Optical activation of channelrhodopsin specifically expressed in DAergic SACs produced a GABA(A) receptor-mediated monosynaptic inhibitory response, followed by DA-D(1)-like receptor-mediated excitatory response in ETCs. The GABA(A) receptor-mediated hyperpolarization activates I(h) current in ETCs; synaptically released DA increases I(h), which enhances postinhibitory rebound spiking. Thus, the opposing actions of synaptically released GABA and DA are functionally integrated by I(h) to generate an inhibition-to-excitation "switch" in ETCs. Consistent with the established role of I(h) in ETC burst firing, we show that endogenous DA release increases ETC spontaneous bursting frequency. ETCs transmit sensory signals to mitral/tufted output neurons and drive intraglomerular inhibition to shape glomerulus output to downstream olfactory networks. GABA and DA cotransmission from SACs to ETCs may play a key role in regulating output coding across the glomerular array.

The hippocampo-amygdala control of contextual fear expression is affected in a model of intellectual disability.

PubMed

Zhang, Chun-Lei; Houbaert, Xander; Lepleux, Marilyn; Deshors, Melissa; Normand, Elisabeth; Gambino, Frédéric; Herzog, Etienne; Humeau, Yann

2015-11-01

The process of learning mainly depends on the ability to store new information, while the ability to retrieve this information and express appropriate behaviors are also crucial for the adaptation of individuals to environmental cues. Thereby, all three components contribute to the cognitive fitness of an individual. While a lack of behavioral adaptation is a recurrent trait of intellectually disabled patients, discriminating between memory formation, memory retrieval or behavioral expression deficits is not easy to establish. Here, we report some deficits in contextual fear behavior in knockout mice for the intellectual disability gene Il1rapl1. Functional in vivo experiments revealed that the lack of conditioned response resulted from a local inhibitory to excitatory (I/E) imbalance in basolateral amygdala (BLA) consecutive to a loss of excitatory drive onto BLA principal cells by caudal hippocampus axonal projections. A normalization of the fear behavior was obtained in adult mutant mice following opsin-based in vivo synaptic priming of hippocampo-BLA synapses in adult il1rapl1 knockout mice, indicating that synaptic efficacy at hippocampo-BLA projections is crucial for contextual fear memory expression. Importantly, because this restoration was obtained after the learning phase, our results suggest that some of the genetically encoded cognitive deficits in humans may originate from a lack of restitution of genuinely formed memories rather than an exclusive inability to store new memories.

Unbalance between Excitation and Inhibition in Phenylketonuria, a Genetic Metabolic Disease Associated with Autism

PubMed Central

De Jaco, Antonella; Mango, Dalila; De Angelis, Federica; Favaloro, Flores Lietta; Andolina, Diego; Nisticò, Robert; Fiori, Elena; Colamartino, Marco; Pascucci, Tiziana

2017-01-01

Phenylketonuria (PKU) is the most common genetic metabolic disease with a well-documented association with autism spectrum disorders. It is characterized by the deficiency of the phenylalanine hydroxylase activity, causing plasmatic hyperphenylalaninemia and variable neurological and cognitive impairments. Among the potential pathophysiological mechanisms implicated in autism spectrum disorders is the excitation/inhibition (E/I) imbalance which might result from alterations in excitatory/inhibitory synapse development, synaptic transmission and plasticity, downstream signalling pathways, and intrinsic neuronal excitability. Here, we investigated functional and molecular alterations in the prefrontal cortex (pFC) of BTBR-Pahenu2 (ENU2) mice, the animal model of PKU. Our data show higher frequency of inhibitory transmissions and significant reduced frequency of excitatory transmissions in the PKU-affected mice in comparison to wild type. Moreover, in the pFC of ENU2 mice, we reported higher levels of the post-synaptic cell-adhesion proteins neuroligin1 and 2. Altogether, our data point toward an imbalance in the E/I neurotransmission favouring inhibition in the pFC of ENU2 mice, along with alterations of the molecular components involved in the organization of cortical synapse. In addition to being the first evidence of E/I imbalance within cortical areas of a mouse model of PKU, our study provides further evidence of E/I imbalance in animal models of pathology associated with autism spectrum disorders. PMID:28468253

Lead Exposure Impairs Hippocampus Related Learning and Memory by Altering Synaptic Plasticity and Morphology During Juvenile Period.

PubMed

Wang, Tao; Guan, Rui-Li; Liu, Ming-Chao; Shen, Xue-Feng; Chen, Jing Yuan; Zhao, Ming-Gao; Luo, Wen-Jing

2016-08-01

Lead (Pb) is an environmental neurotoxic metal. Pb exposure may cause neurobehavioral changes, such as learning and memory impairment, and adolescence violence among children. Previous animal models have largely focused on the effects of Pb exposure during early development (from gestation to lactation period) on neurobehavior. In this study, we exposed Sprague-Dawley rats during the juvenile stage (from juvenile period to adult period). We investigated the synaptic function and structural changes and the relationship of these changes to neurobehavioral deficits in adult rats. Our results showed that juvenile Pb exposure caused fear-conditioned memory impairment and anxiety-like behavior, but locomotion and pain behavior were indistinguishable from the controls. Electrophysiological studies showed that long-term potentiation induction was affected in Pb-exposed rats, and this was probably due to excitatory synaptic transmission impairment in Pb-exposed rats. We found that NMDA and AMPA receptor-mediated current was inhibited, whereas the GABA synaptic transmission was normal in Pb-exposed rats. NR2A and phosphorylated GluR1 expression decreased. Moreover, morphological studies showed that density of dendritic spines declined by about 20 % in the Pb-treated group. The spine showed an immature form in Pb-exposed rats, as indicated by spine size measurements. However, the length and arborization of dendrites were unchanged. Our results suggested that juvenile Pb exposure in rats is associated with alterations in the glutamate receptor, which caused synaptic functional and morphological changes in hippocampal CA1 pyramidal neurons, thereby leading to behavioral changes.

Long-term modifications of synaptic efficacy in the human inferior and middle temporal cortex

NASA Technical Reports Server (NTRS)

Chen, W. R.; Lee, S.; Kato, K.; Spencer, D. D.; Shepherd, G. M.; Williamson, A.

1996-01-01

The primate temporal cortex has been demonstrated to play an important role in visual memory and pattern recognition. It is of particular interest to investigate whether activity-dependent modification of synaptic efficacy, a presumptive mechanism for learning and memory, is present in this cortical region. Here we address this issue by examining the induction of synaptic plasticity in surgically resected human inferior and middle temporal cortex. The results show that synaptic strength in the human temporal cortex could undergo bidirectional modifications, depending on the pattern of conditioning stimulation. High frequency stimulation (100 or 40 Hz) in layer IV induced long-term potentiation (LTP) of both intracellular excitatory postsynaptic potentials and evoked field potentials in layers II/III. The LTP induced by 100 Hz tetanus was blocked by 50-100 microM DL-2-amino-5-phosphonovaleric acid, suggesting that N-methyl-D-aspartate receptors were responsible for its induction. Long-term depression (LTD) was elicited by prolonged low frequency stimulation (1 Hz, 15 min). It was reduced, but not completely blocked, by DL-2-amino-5-phosphonovaleric acid, implying that some other mechanisms in addition to N-methyl-DL-aspartate receptors were involved in LTD induction. LTD was input-specific, i.e., low frequency stimulation of one pathway produced LTD of synaptic transmission in that pathway only. Finally, the LTP and LTD could reverse each other, suggesting that they can act cooperatively to modify the functional state of cortical network. These results suggest that LTP and LTD are possible mechanisms for the visual memory and pattern recognition functions performed in the human temporal cortex.

PTEN knockdown alters dendritic spine/protrusion morphology, not density

PubMed Central

Haws, Michael E.; Jaramillo, Thomas C.; Espinosa-Becerra, Felipe; Widman, Allie; Stuber, Garret D.; Sparta, Dennis R.; Tye, Kay M.; Russo, Scott J.; Parada, Luis F.; Kaplitt, Michael; Bonci, Antonello; Powell, Craig M.

2014-01-01

Mutations in phosphatase and tensin homolog deleted on chromosome ten (PTEN) are implicated in neuropsychiatric disorders including autism. Previous studies report that PTEN knockdown in neurons in vivo leads to increased spine density and synaptic activity. To better characterize synaptic changes in neurons lacking PTEN, we examined the effects of shRNA knockdown of PTEN in basolateral amygdala neurons on synaptic spine density and morphology using fluorescent dye confocal imaging. Contrary to previous studies in dentate gyrus, we find that knockdown of PTEN in basolateral amygdala leads to a significant decrease in total spine density in distal dendrites. Curiously, this decreased spine density is associated with increased miniature excitatory post-synaptic current frequency and amplitude, suggesting an increase in number and function of mature spines. These seemingly contradictory findings were reconciled by spine morphology analysis demonstrating increased mushroom spine density and size with correspondingly decreased thin protrusion density at more distal segments. The same analysis of PTEN conditional deletion in dentate gyrus demonstrated that loss of PTEN does not significantly alter total density of dendritic protrusions in the dentate gyrus, but does decrease thin protrusion density and increases density of more mature mushroom spines. These findings suggest that, contrary to previous reports, PTEN knockdown may not induce de novo spinogenesis, but instead may increase synaptic activity by inducing morphological and functional maturation of spines. Furthermore, behavioral analysis of basolateral amygdala PTEN knockdown suggests that these changes limited only to the basolateral amygdala complex may not be sufficient to induce increased anxiety-related behaviors. PMID:24264880

Transient Response in a Dendritic Neuron Model for Current Injected at One Branch

PubMed Central

Rinzel, John; Rall, Wilfrid

1974-01-01

Mathematical expressions are obtained for the response function corresponding to an instantaneous pulse of current injected to a single dendritic branch in a branched dendritic neuron model. The theoretical model assumes passive membrane properties and the equivalent cylinder constraint on branch diameters. The response function when used in a convolution formula enables one to compute the voltage transient at any specified point in the dendritic tree for an arbitrary current injection at a given input location. A particular numerical example, for a brief current injection at a branch terminal, illustrates the attenuation and delay characteristics of the depolarization peak as it spreads throughout the neuron model. In contrast to the severe attenuation of voltage transients from branch input sites to the soma, the fraction of total input charge actually delivered to the soma and other trees is calculated to be about one-half. This fraction is independent of the input time course. Other numerical examples, which compare a branch terminal input site with a soma input site, demonstrate that, for a given transient current injection, the peak depolarization is not proportional to the input resistance at the injection site and, for a given synaptic conductance transient, the effective synaptic driving potential can be significantly reduced, resulting in less synaptic current flow and charge, for a branch input site. Also, for the synaptic case, the two inputs are compared on the basis of the excitatory post-synaptic potential (EPSP) seen at the soma and the total charge delivered to the soma. PMID:4424185

Glutamate transporter GLAST controls synaptic wrapping by Bergmann glia and ensures proper wiring of Purkinje cells

PubMed Central

Miyazaki, Taisuke; Yamasaki, Miwako; Hashimoto, Kouichi; Kohda, Kazuhisa; Yuzaki, Michisuke; Shimamoto, Keiko; Tanaka, Kohichi; Kano, Masanobu; Watanabe, Masahiko

2017-01-01

Astrocytes regulate synaptic transmission through controlling neurotransmitter concentrations around synapses. Little is known, however, about their roles in neural circuit development. Here we report that Bergmann glia (BG), specialized cerebellar astrocytes that thoroughly enwrap Purkinje cells (PCs), are essential for synaptic organization in PCs through the action of the l-glutamate/l-aspartate transporter (GLAST). In GLAST-knockout mice, dendritic innervation by the main ascending climbing fiber (CF) branch was significantly weakened, whereas the transverse branch, which is thin and nonsynaptogenic in control mice, was transformed into thick and synaptogenic branches. Both types of CF branches frequently produced aberrant wiring to proximal and distal dendrites, causing multiple CF–PC innervation. Our electrophysiological analysis revealed that slow and small CF-evoked excitatory postsynaptic currents (EPSCs) were recorded from almost all PCs in GLAST-knockout mice. These atypical CF-EPSCs were far more numerous and had significantly faster 10–90% rise time than those elicited by glutamate spillover under pharmacological blockade of glial glutamate transporters. Innervation by parallel fibers (PFs) was also affected. PF synapses were robustly increased in the entire dendritic trees, leading to impaired segregation of CF and PF territories. Furthermore, lamellate BG processes were retracted from PC dendrites and synapses, leading to the exposure of these neuronal elements to the extracellular milieus. These synaptic and glial phenotypes were reproduced in wild-type mice after functional blockade of glial glutamate transporters. These findings highlight that glutamate transporter function by GLAST on BG plays important roles in development and maintenance of proper synaptic wiring and wrapping in PCs. PMID:28655840

Integrated plasticity at inhibitory and excitatory synapses in the cerebellar circuit.

PubMed

Mapelli, Lisa; Pagani, Martina; Garrido, Jesus A; D'Angelo, Egidio

2015-01-01

The way long-term potentiation (LTP) and depression (LTD) are integrated within the different synapses of brain neuronal circuits is poorly understood. In order to progress beyond the identification of specific molecular mechanisms, a system in which multiple forms of plasticity can be correlated with large-scale neural processing is required. In this paper we take as an example the cerebellar network, in which extensive investigations have revealed LTP and LTD at several excitatory and inhibitory synapses. Cerebellar LTP and LTD occur in all three main cerebellar subcircuits (granular layer, molecular layer, deep cerebellar nuclei) and correspondingly regulate the function of their three main neurons: granule cells (GrCs), Purkinje cells (PCs) and deep cerebellar nuclear (DCN) cells. All these neurons, in addition to be excited, are reached by feed-forward and feed-back inhibitory connections, in which LTP and LTD may either operate synergistically or homeostatically in order to control information flow through the circuit. Although the investigation of individual synaptic plasticities in vitro is essential to prove their existence and mechanisms, it is insufficient to generate a coherent view of their impact on network functioning in vivo. Recent computational models and cell-specific genetic mutations in mice are shedding light on how plasticity at multiple excitatory and inhibitory synapses might regulate neuronal activities in the cerebellar circuit and contribute to learning and memory and behavioral control.

Laminar-specific Scaling Down of Balanced Excitation and Inhibition in Auditory Cortex by Active Behavioral States

PubMed Central

Zhou, Mu; Liang, Feixue; Xiong, Xiaorui R.; Li, Lu; Li, Haifu; Xiao, Zhongju; Tao, Huizhong W.; Zhang, Li I.

2014-01-01

Cortical sensory processing is modulated by behavioral and cognitive states. How the modulation is achieved through impacting synaptic circuits remains largely unknown. In awake mouse auditory cortex, we reported that sensory-evoked spike responses of layer 2/3 (L2/3) excitatory cells were scaled down with preserved sensory tuning when animals transitioned from quiescence to active behaviors, while L4 and thalamic responses were unchanged. Whole-cell voltage-clamp recordings further revealed that tone-evoked synaptic excitation and inhibition exhibited a robust functional balance. Changes of behavioral state caused scaling down of excitation and inhibition at an approximately equal level in L2/3 cells, but no synaptic changes in L4 cells. This laminar-specific gain control could be attributed to an enhancement of L1–mediated inhibitory tone, with L2/3 parvalbumin inhibitory neurons suppressed as well. Thus, L2/3 circuits can adjust the salience of output in accordance with momentary behavioral demands while maintaining the sensitivity and quality of sensory processing. PMID:24747575

Diversity of bilateral synaptic assemblies for binaural computation in midbrain single neurons.

PubMed

He, Na; Kong, Lingzhi; Lin, Tao; Wang, Shaohui; Liu, Xiuping; Qi, Jiyao; Yan, Jun

2017-11-01

Binaural hearing confers many beneficial functions but our understanding of its underlying neural substrates is limited. This study examines the bilateral synaptic assemblies and binaural computation (or integration) in the central nucleus of the inferior colliculus (ICc) of the auditory midbrain, a key convergent center. Using in-vivo whole-cell patch-clamp, the excitatory and inhibitory postsynaptic potentials (EPSPs/IPSPs) of single ICc neurons to contralateral, ipsilateral and bilateral stimulation were recorded. According to the contralateral and ipsilateral EPSP/IPSP, 7 types of bilateral synaptic assemblies were identified. These include EPSP-EPSP (EE), E-IPSP (EI), E-no response (EO), II, IE, IO and complex-mode (CM) neurons. The CM neurons showed frequency- and/or amplitude-dependent EPSPs/IPSPs to contralateral or ipsilateral stimulation. Bilateral stimulation induced EPSPs/IPSPs that could be larger than (facilitation), similar to (ineffectiveness) or smaller than (suppression) those induced by contralateral stimulation. Our findings have allowed our group to characterize novel neural circuitry for binaural computation in the midbrain. Copyright © 2017 Elsevier B.V. All rights reserved.

The role of ionotropic glutamate receptors in childhood neurodevelopmental disorders: autism spectrum disorders and fragile x syndrome.

PubMed

Uzunova, Genoveva; Hollander, Eric; Shepherd, Jason

2014-01-01

Autism spectrum disorder (ASD) and Fragile X syndrome (FXS) are relatively common childhood neurodevelopmental disorders with increasing incidence in recent years. They are currently accepted as disorders of the synapse with alterations in different forms of synaptic communication and neuronal network connectivity. The major excitatory neurotransmitter system in brain, the glutamatergic system, is implicated in learning and memory, synaptic plasticity, neuronal development. While much attention is attributed to the role of metabotropic glutamate receptors in ASD and FXS, studies indicate that the ionotropic glutamate receptors (iGluRs) and their regulatory proteins are also altered in several brain regions. Role of iGluRs in the neurobiology of ASD and FXS is supported by a weight of evidence that ranges from human genetics to in vitro cultured neurons. In this review we will discuss clinical, molecular, cellular and functional changes in NMDA, AMPA and kainate receptors and the synaptic proteins that regulate them in the context of ASD and FXS. We will also discuss the significance for the development of translational biomarkers and treatments for the core symptoms of ASD and FXS.

Leaky synapses: Regulation of spontaneous neurotransmission in central synapses

PubMed Central

Wasser, Catherine R.; Kavalali, Ege T.

2009-01-01

The mechanisms underlying spontaneous neurotransmitter release are not well understood. Under physiological as well as pathophysiological circumstances, spontaneous fusion events can set the concentration of ambient levels of neurotransmitter within the synaptic cleft and in the extracellular milieu. In the brain, unregulated release of excitatory neurotransmitters, exacerbated during pathological conditions such as stroke, can lead to neuronal damage and death. In addition, recent findings suggest that under physiological circumstances spontaneous release events can trigger postsynaptic signaling events independent of evoked neurotransmitter release. Therefore, elucidation of mechanisms underlying spontaneous neurotransmission may help us better understand the functional significance of this form of release and provide tools for its selective manipulation. For instance, our recent investigations indicate that the level of cholesterol in the synapse plays a critical role in limiting spontaneous synaptic vesicle fusion. Therefore, alterations in synaptic cholesterol metabolism can be a critical determinant of glutamatergic neurotransmission at rest. This article aims to provide a closer look into our current understanding of the mechanisms underlying spontaneous neurotransmission and the signaling triggered by these unitary release events. PMID:18434032

Emergence of network structure due to spike-timing-dependent plasticity in recurrent neuronal networks IV: structuring synaptic pathways among recurrent connections.

PubMed

Gilson, Matthieu; Burkitt, Anthony N; Grayden, David B; Thomas, Doreen A; van Hemmen, J Leo

2009-12-01

In neuronal networks, the changes of synaptic strength (or weight) performed by spike-timing-dependent plasticity (STDP) are hypothesized to give rise to functional network structure. This article investigates how this phenomenon occurs for the excitatory recurrent connections of a network with fixed input weights that is stimulated by external spike trains. We develop a theoretical framework based on the Poisson neuron model to analyze the interplay between the neuronal activity (firing rates and the spike-time correlations) and the learning dynamics, when the network is stimulated by correlated pools of homogeneous Poisson spike trains. STDP can lead to both a stabilization of all the neuron firing rates (homeostatic equilibrium) and a robust weight specialization. The pattern of specialization for the recurrent weights is determined by a relationship between the input firing-rate and correlation structures, the network topology, the STDP parameters and the synaptic response properties. We find conditions for feed-forward pathways or areas with strengthened self-feedback to emerge in an initially homogeneous recurrent network.

Dynamic Control of Excitatory Synapse Development by a Rac1 GEF/GAP Regulatory Complex

PubMed Central

Um, Kyongmi; Niu, Sanyong; Duman, Joseph G.; Cheng, Jinxuan; Tu, Yen-Kuei; Schwechter, Brandon; Liu, Feng; Hiles, Laura; Narayanan, Anjana; Ash, Ryan T.; Mulherkar, Shalaka; Alpadi, Kannan; Smirnakis, Stelios M.; Tolias, Kimberley F.

2014-01-01

SUMMARY The small GTPase Rac1 orchestrates actin-dependent remodeling essential for numerous cellular processes including synapse development. While precise spatiotemporal regulation of Rac1 is necessary for its function, little is known about the mechanisms that enable Rac1 activators (GEFs) and inhibitors (GAPs) to act in concert to regulate Rac1 signaling. Here we identify a regulatory complex composed of a Rac-GEF (Tiam1) and a Rac-GAP (Bcr) that cooperate to control excitatory synapse development. Disruption of Bcr function within this complex increases Rac1 activity and dendritic spine remodeling, resulting in excessive synaptic growth that is rescued by Tiam1 inhibition. Notably, EphB receptors utilize the Tiam1-Bcr complex to control synaptogenesis. Following EphB activation, Tiam1 induces Rac1-dependent spine formation, whereas Bcr prevents Rac1-mediated receptor internalization, promoting spine growth over retraction. The finding that a Rac-specific GEF/GAP complex is required to maintain optimal levels of Rac1 signaling provides an important insight into the regulation of small GTPases. PMID:24960694

Neurotrophin and FGF Signaling Adapter Proteins, FRS2 and FRS3, Regulate Dentate Granule Cell Maturation and Excitatory Synaptogenesis.

PubMed

Nandi, Sayan; Alviña, Karina; Lituma, Pablo J; Castillo, Pablo E; Hébert, Jean M

2018-01-15

Dentate granule cells (DGCs) play important roles in cognitive processes. Knowledge about how growth factors such as FGFs and neurotrophins contribute to the maturation and synaptogenesis of DGCs is limited. Here, using brain-specific and germline mouse mutants we show that a module of neurotrophin and FGF signaling, the FGF Receptor Substrate (FRS) family of intracellular adapters, FRS2 and FRS3, are together required for postnatal brain development. In the hippocampus, FRS promotes dentate gyrus morphogenesis and DGC maturation during developmental neurogenesis, similar to previously published functions for both neurotrophins and FGFs. Consistent with a role in DGC maturation, two-photon imaging revealed that Frs2,3-double mutants have reduced numbers of dendritic branches and spines in DGCs. Functional analysis further showed that double-mutant mice exhibit fewer excitatory synaptic inputs onto DGCs. These observations reveal roles for FRS adapters in DGC maturation and synaptogenesis and suggest that FRS proteins may act as an important node for FGF and neurotrophin signaling in postnatal hippocampal development. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Ablation of the presynaptic organizer Bassoon in excitatory neurons retards dentate gyrus maturation and enhances learning performance.

PubMed

Annamneedi, Anil; Caliskan, Gürsel; Müller, Sabrina; Montag, Dirk; Budinger, Eike; Angenstein, Frank; Fejtova, Anna; Tischmeyer, Wolfgang; Gundelfinger, Eckart D; Stork, Oliver

2018-06-18

Bassoon is a large scaffolding protein of the presynaptic active zone involved in the development of presynaptic terminals and in the regulation of neurotransmitter release at both excitatory and inhibitory brain synapses. Mice with constitutive ablation of the Bassoon (Bsn) gene display impaired presynaptic function, show sensory deficits and develop severe seizures. To specifically study the role of Bassoon at excitatory forebrain synapses and its relevance for control of behavior, we generated conditional knockout (Bsn cKO) mice by gene ablation through an Emx1 promoter-driven Cre recombinase. In these animals, we confirm selective loss of Bassoon from glutamatergic neurons of the forebrain. Behavioral assessment revealed that, in comparison to wild-type littermates, Bsn cKO mice display selectively enhanced contextual fear memory and increased novelty preference in a spatial discrimination/pattern separation task. These changes are accompanied by an augmentation of baseline synaptic transmission at medial perforant path to dentate gyrus (DG) synapses, as indicated by increased ratios of field excitatory postsynaptic potential slope to fiber volley amplitude. At the structural level, an increased complexity of apical dendrites of DG granule cells can be detected in Bsn cKO mice. In addition, alterations in the expression of cellular maturation markers and a lack of age-dependent decrease in excitability between juvenile and adult Bsn cKO mice are observed. Our data suggest that expression of Bassoon in excitatory forebrain neurons is required for the normal maturation of the DG and important for spatial and contextual memory.

Orientation selectivity of synaptic input to neurons in mouse and cat primary visual cortex.

PubMed

Tan, Andrew Y Y; Brown, Brandon D; Scholl, Benjamin; Mohanty, Deepankar; Priebe, Nicholas J

2011-08-24

Primary visual cortex (V1) is the site at which orientation selectivity emerges in mammals: visual thalamus afferents to V1 respond equally to all stimulus orientations, whereas their target V1 neurons respond selectively to stimulus orientation. The emergence of orientation selectivity in V1 has long served as a model for investigating cortical computation. Recent evidence for orientation selectivity in mouse V1 opens cortical computation to dissection by genetic and imaging tools, but also raises two essential questions: (1) How does orientation selectivity in mouse V1 neurons compare with that in previously described species? (2) What is the synaptic basis for orientation selectivity in mouse V1? A comparison of orientation selectivity in mouse and in cat, where such measures have traditionally been made, reveals that orientation selectivity in mouse V1 is weaker than in cat V1, but that spike threshold plays a similar role in narrowing selectivity between membrane potential and spike rate. To uncover the synaptic basis for orientation selectivity, we made whole-cell recordings in vivo from mouse V1 neurons, comparing neuronal input selectivity-based on membrane potential, synaptic excitation, and synaptic inhibition-to output selectivity based on spiking. We found that a neuron's excitatory and inhibitory inputs are selective for the same stimulus orientations as is its membrane potential response, and that inhibitory selectivity is not broader than excitatory selectivity. Inhibition has different dynamics than excitation, adapting more rapidly. In neurons with temporally modulated responses, the timing of excitation and inhibition was different in mice and cats.

Orientation Selectivity of Synaptic Input to Neurons in Mouse and Cat Primary Visual Cortex

PubMed Central

Tan (陈勇毅), Andrew Y. Y.; Brown, Brandon D.; Scholl, Benjamin; Mohanty, Deepankar; Priebe, Nicholas J.

2011-01-01

Primary visual cortex (V1) is the site at which orientation selectivity emerges in mammals: visual thalamus afferents to V1 respond equally to all stimulus orientations whereas their target V1 neurons respond selectively to stimulus orientation. The emergence of orientation selectivity in V1 has long served as a model for investigating cortical computation. Recent evidence for orientation selectivity in mouse V1 opens cortical computation to dissection by genetic and imaging tools, but also raises two essential questions: 1) how does orientation selectivity in mouse V1 neurons compare with that in previously described species? 2) what is the synaptic basis for orientation selectivity in mouse V1? A comparison of orientation selectivity in mouse and in cat, where such measures have traditionally been made, reveals that orientation selectivity in mouse V1 is weaker than in cat V1, but that spike threshold plays a similar role in narrowing selectivity between membrane potential and spike rate. To uncover the synaptic basis for orientation selectivity, we made whole-cell recordings in vivo from mouse V1 neurons, comparing neuronal input selectivity - based on membrane potential, synaptic excitation, and synaptic inhibition - to output selectivity based on spiking. We found that a neuron's excitatory and inhibitory inputs are selective for the same stimulus orientations as is its membrane potential response, and that inhibitory selectivity is not broader than excitatory selectivity. Inhibition has different dynamics than excitation, adapting more rapidly. In neurons with temporally modulated responses, the timing of excitation and inhibition was different in mice and cats. PMID:21865476

Dendritic Spine Instability in a Mouse Model of CDKL5 Disorder Is Rescued by Insulin-like Growth Factor 1.

PubMed

Della Sala, Grazia; Putignano, Elena; Chelini, Gabriele; Melani, Riccardo; Calcagno, Eleonora; Michele Ratto, Gian; Amendola, Elena; Gross, Cornelius T; Giustetto, Maurizio; Pizzorusso, Tommaso

2016-08-15

CDKL5 (cyclin-dependent kinase-like 5) is mutated in many severe neurodevelopmental disorders, including atypical Rett syndrome. CDKL5 was shown to interact with synaptic proteins, but an in vivo analysis of the role of CDKL5 in dendritic spine dynamics and synaptic molecular organization is still lacking. In vivo two-photon microscopy of the somatosensory cortex of Cdkl5(-/y) mice was applied to monitor structural dynamics of dendritic spines. Synaptic function and plasticity were measured using electrophysiological recordings of excitatory postsynaptic currents and long-term potentiation in brain slices and assessing the expression of synaptic postsynaptic density protein 95 (PSD-95). Finally, we studied the impact of insulin-like growth factor 1 (IGF-1) treatment on CDKL5 null mice to restore the synaptic deficits. Adult mutant mice showed a significant reduction in spine density and PSD-95-positive synaptic puncta, a reduction of persistent spines, and impaired long-term potentiation. In juvenile mutants, short-term spine elimination, but not formation, was dramatically increased. Exogenous administration of IGF-1 rescued defective rpS6 phosphorylation, spine density, and PSD-95 expression. Endogenous cortical IGF-1 levels were unaffected by CDKL5 deletion. These data demonstrate that dendritic spine stabilization is strongly regulated by CDKL5. Moreover, our data suggest that IGF-1 treatment could be a promising candidate for clinical trials in CDKL5 patients. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Bilinearity in Spatiotemporal Integration of Synaptic Inputs

PubMed Central

Li, Songting; Liu, Nan; Zhang, Xiao-hui; Zhou, Douglas; Cai, David

2014-01-01

Neurons process information via integration of synaptic inputs from dendrites. Many experimental results demonstrate dendritic integration could be highly nonlinear, yet few theoretical analyses have been performed to obtain a precise quantitative characterization analytically. Based on asymptotic analysis of a two-compartment passive cable model, given a pair of time-dependent synaptic conductance inputs, we derive a bilinear spatiotemporal dendritic integration rule. The summed somatic potential can be well approximated by the linear summation of the two postsynaptic potentials elicited separately, plus a third additional bilinear term proportional to their product with a proportionality coefficient . The rule is valid for a pair of synaptic inputs of all types, including excitation-inhibition, excitation-excitation, and inhibition-inhibition. In addition, the rule is valid during the whole dendritic integration process for a pair of synaptic inputs with arbitrary input time differences and input locations. The coefficient is demonstrated to be nearly independent of the input strengths but is dependent on input times and input locations. This rule is then verified through simulation of a realistic pyramidal neuron model and in electrophysiological experiments of rat hippocampal CA1 neurons. The rule is further generalized to describe the spatiotemporal dendritic integration of multiple excitatory and inhibitory synaptic inputs. The integration of multiple inputs can be decomposed into the sum of all possible pairwise integration, where each paired integration obeys the bilinear rule. This decomposition leads to a graph representation of dendritic integration, which can be viewed as functionally sparse. PMID:25521832

Transgenic FingRs for Live Mapping of Synaptic Dynamics in Genetically-Defined Neurons

PubMed Central

Son, Jong-Hyun; Keefe, Matthew D.; Stevenson, Tamara J.; Barrios, Joshua P.; Anjewierden, Scott; Newton, James B.; Douglass, Adam D.; Bonkowsky, Joshua L.

2016-01-01

Tools for genetically-determined visualization of synaptic circuits and interactions are necessary to build connectomics of the vertebrate brain and to screen synaptic properties in neurological disease models. Here we develop a transgenic FingR (fibronectin intrabodies generated by mRNA display) technology for monitoring synapses in live zebrafish. We demonstrate FingR labeling of defined excitatory and inhibitory synapses, and show FingR applicability for dissecting synapse dynamics in normal and disease states. Using our system we show that chronic hypoxia, associated with neurological defects in preterm birth, affects dopaminergic neuron synapse number depending on the developmental timing of hypoxia. PMID:26728131

Activation of Muscarinic M1 Acetylcholine Receptors Induces Long-Term Potentiation in the Hippocampus

PubMed Central

Dennis, Siobhan H.; Pasqui, Francesca; Colvin, Ellen M.; Sanger, Helen; Mogg, Adrian J.; Felder, Christian C.; Broad, Lisa M.; Fitzjohn, Steve M.; Isaac, John T.R.; Mellor, Jack R.

2016-01-01

Muscarinic M1 acetylcholine receptors (M1Rs) are highly expressed in the hippocampus, and their inhibition or ablation disrupts the encoding of spatial memory. It has been hypothesized that the principal mechanism by which M1Rs influence spatial memory is by the regulation of hippocampal synaptic plasticity. Here, we use a combination of recently developed, well characterized, selective M1R agonists and M1R knock-out mice to define the roles of M1Rs in the regulation of hippocampal neuronal and synaptic function. We confirm that M1R activation increases input resistance and depolarizes hippocampal CA1 pyramidal neurons and show that this profoundly increases excitatory postsynaptic potential-spike coupling. Consistent with a critical role for M1Rs in synaptic plasticity, we now show that M1R activation produces a robust potentiation of glutamatergic synaptic transmission onto CA1 pyramidal neurons that has all the hallmarks of long-term potentiation (LTP): The potentiation requires NMDA receptor activity and bi-directionally occludes with synaptically induced LTP. Thus, we describe synergistic mechanisms by which acetylcholine acting through M1Rs excites CA1 pyramidal neurons and induces LTP, to profoundly increase activation of CA1 pyramidal neurons. These features are predicted to make a major contribution to the pro-cognitive effects of cholinergic transmission in rodents and humans. PMID:26472558

Cell-Specific Activity-Dependent Fractionation of Layer 2/3→5B Excitatory Signaling in Mouse Auditory Cortex

PubMed Central

Joshi, Ankur; Middleton, Jason W.; Anderson, Charles T.; Borges, Katharine; Suter, Benjamin A.; Shepherd, Gordon M. G.

2015-01-01

Auditory cortex (AC) layer 5B (L5B) contains both corticocollicular neurons, a type of pyramidal-tract neuron projecting to the inferior colliculus, and corticocallosal neurons, a type of intratelencephalic neuron projecting to contralateral AC. Although it is known that these neuronal types have distinct roles in auditory processing and different response properties to sound, the synaptic and intrinsic mechanisms shaping their input–output functions remain less understood. Here, we recorded in brain slices of mouse AC from retrogradely labeled corticocollicular and neighboring corticocallosal neurons in L5B. Corticocollicular neurons had, on average, lower input resistance, greater hyperpolarization-activated current (Ih), depolarized resting membrane potential, faster action potentials, initial spike doublets, and less spike-frequency adaptation. In paired recordings between single L2/3 and labeled L5B neurons, the probabilities of connection, amplitude, latency, rise time, and decay time constant of the unitary EPSC were not different for L2/3→corticocollicular and L2/3→corticocallosal connections. However, short trains of unitary EPSCs showed no synaptic depression in L2/3→corticocollicular connections, but substantial depression in L2/3→corticocallosal connections. Synaptic potentials in L2/3→corticocollicular connections decayed faster and showed less temporal summation, consistent with increased Ih in corticocollicular neurons, whereas synaptic potentials in L2/3→corticocallosal connections showed more temporal summation. Extracellular L2/3 stimulation at two different rates resulted in spiking in L5B neurons; for corticocallosal neurons the spike rate was frequency dependent, but for corticocollicular neurons it was not. Together, these findings identify cell-specific intrinsic and synaptic mechanisms that divide intracortical synaptic excitation from L2/3 to L5B into two functionally distinct pathways with different input–output functions. PMID:25698747

Electrical coupling regulates layer 1 interneuron microcircuit formation in the neocortex

PubMed Central

Yao, Xing-Hua; Wang, Min; He, Xiang-Nan; He, Fei; Zhang, Shu-Qing; Lu, Wenlian; Qiu, Zi-Long; Yu, Yong-Chun

2016-01-01

The coexistence of electrical and chemical synapses among interneurons is essential for interneuron function in the neocortex. However, it remains largely unclear whether electrical coupling between interneurons influences chemical synapse formation and microcircuit assembly during development. Here, we show that electrical and GABAergic chemical connections robustly develop between interneurons in neocortical layer 1 over a similar time course. Electrical coupling promotes action potential generation and synchronous firing between layer 1 interneurons. Furthermore, electrically coupled interneurons exhibit strong GABA-A receptor-mediated synchronous synaptic activity. Disruption of electrical coupling leads to a loss of bidirectional, but not unidirectional, GABAergic connections. Moreover, a reduction in electrical coupling induces an increase in excitatory synaptic inputs to layer 1 interneurons. Together, these findings strongly suggest that electrical coupling between neocortical interneurons plays a critical role in regulating chemical synapse development and precise formation of circuits. PMID:27510304

VGLUTs and Glutamate Synthesis—Focus on DRG Neurons and Pain

PubMed Central

Malet, Mariana; Brumovsky, Pablo R.

2015-01-01

The amino acid glutamate is the principal excitatory transmitter in the nervous system, including in sensory neurons that convey pain sensation from the periphery to the brain. It is now well established that a family of membrane proteins, termed vesicular glutamate transporters (VGLUTs), serve a critical function in these neurons: they incorporate glutamate into synaptic vesicles. VGLUTs have a central role both under normal neurotransmission and pathological conditions, such as neuropathic or inflammatory pain. In the present short review, we will address VGLUTs in the context of primary afferent neurons. We will focus on the role of VGLUTs in pain triggered by noxious stimuli, peripheral nerve injury, and tissue inflammation, as mostly explored in transgenic mice. The possible interplay between glutamate biosynthesis and VGLUT-dependent packaging in synaptic vesicles, and its potential impact in various pain states will be presented. PMID:26633536

The dynamics of GABA signaling: Revelations from the circadian pacemaker in the suprachiasmatic nucleus

PubMed Central

Albers, H. Elliott; Walton, James C.; Gamble, Karen L.; McNeill, John K.; Hummer, Daniel L.

2016-01-01

Virtually every neuron within the suprachiasmatic nucleus (SCN) communicates via GABAergic signaling. The extracellular levels of GABA within the SCN are determined by a complex interaction of synthesis and transport, as well as synaptic and non-synaptic release. The response to GABA is mediated by GABAA receptors that respond to both phasic and tonic GABA release and that can produce excitatory as well as inhibitory cellular responses. GABA also influences circadian control through the exclusively inhibitory effects of GABAB receptors. Both GABA and neuropeptide signaling occur within the SCN, although the functional consequences of the interactions of these signals are not well understood. This review considers the role of GABA in the circadian pacemaker, in the mechanisms responsible for the generation of circadian rhythms, in the ability of non-photic stimuli to reset the phase of the pacemaker, and in the ability of the day-night cycle to entrain the pacemaker. PMID:27894927

Role of GABAergic inhibition in hippocampal network oscillations.

PubMed

Mann, Edward O; Paulsen, Ole

2007-07-01

Physiological rhythmic activity in cortical circuits relies on GABAergic inhibition to balance excitation and control spike timing. With a focus on recent experimental progress in the hippocampus, here we review the mechanisms by which synaptic inhibition can control the precise timing of spike generation, by way of effects of GABAergic events on membrane conductance ('shunting' inhibition) and membrane potential ('hyperpolarizing' inhibition). Synaptic inhibition itself can be synchronized by way of interactions within networks of GABAergic neurons, and by excitatory neurons. The importance of GABAergic mechanisms for generation of cortical rhythms is now well established. What remains to be resolved is how such inhibitory control of spike timing can be harnessed for long-range fast synchronization, and the relevance of these mechanisms to network function. This review is part of the INMED/TINS special issue Physiogenic and pathogenic oscillations: the beauty and the beast, based on presentations at the annual INMED/TINS symposium (http://inmednet.com).

Distinct cortical circuit mechanisms for complex forelimb movement and motor map topography.

PubMed

Harrison, Thomas C; Ayling, Oliver G S; Murphy, Timothy H

2012-04-26

Cortical motor maps are the basis of voluntary movement, but they have proven difficult to understand in the context of their underlying neuronal circuits. We applied light-based motor mapping of Channelrhodopsin-2 mice to reveal a functional subdivision of the forelimb motor cortex based on the direction of movement evoked by brief (10 ms) pulses. Prolonged trains of electrical or optogenetic stimulation (100-500 ms) targeted to anterior or posterior subregions of motor cortex evoked reproducible complex movements of the forelimb to distinct positions in space. Blocking excitatory cortical synaptic transmission did not abolish basic motor map topography, but the site-specific expression of complex movements was lost. Our data suggest that the topography of movement maps arises from their segregated output projections, whereas complex movements evoked by prolonged stimulation require intracortical synaptic transmission. Copyright © 2012 Elsevier Inc. All rights reserved.

Synaptic structure and function are altered by the neddylation inhibitor MLN4924.

PubMed

Scudder, Samantha L; Patrick, Gentry N

2015-03-01

The posttranslational modification of proteins by the ubiquitin-like small molecule NEDD8 has previously been shown to be vital in a number of cell signaling pathways. In particular, conjugation of NEDD8 (neddylation) serves to regulate protein ubiquitination through modifications to E3 ubiquitin ligases. Despite the prevalence of NEDD8 in neurons, very little work has been done to characterize the role of this modifier in these cells. Here, we use the recently developed NEDD8 Activating Enzyme (NAE) inhibitor MLN4924 and report evidence of a role for NEDD8 in regulating mammalian excitatory synapses. Application of this drug to dissociated rat hippocampal neurons caused reductions in synaptic strength, surface glutamate receptor levels, dendritic spine width, and spine density, suggesting that neddylation is involved in the maintenance of synapses. Copyright © 2015 Elsevier Inc. All rights reserved.

The polarity protein partitioning-defective 1 (PAR-1) regulates dendritic spine morphogenesis through phosphorylating postsynaptic density protein 95 (PSD-95).

PubMed

Wu, Qian; DiBona, Victoria L; Bernard, Laura P; Zhang, Huaye

2012-08-31

The polarity protein PAR-1 plays an essential role in many cellular contexts, including embryogenesis, asymmetric cell division, directional migration, and epithelial morphogenesis. Despite its known importance in different cellular processes, the role of PAR-1 in neuronal morphogenesis is less well understood. In particular, its role in the morphogenesis of dendritic spines, which are sites of excitatory synaptic inputs, has been unclear. Here, we show that PAR-1 is required for normal spine morphogenesis in hippocampal neurons. We further show that PAR-1 functions through phosphorylating the synaptic scaffolding protein PSD-95 in this process. Phosphorylation at a conserved serine residue in the KXGS motif in PSD-95 regulates spine morphogenesis, and a phosphomimetic mutant of this site can rescue the defects of kinase-dead PAR-1. Together, our findings uncover a role of PAR-1 in spine morphogenesis in hippocampal neurons through phosphorylating PSD-95.

The presynaptic ribbon maintains vesicle populations at the hair cell afferent fiber synapse

PubMed Central

Becker, Lars; Schnee, Michael E; Niwa, Mamiko; Sun, Willy; Maxeiner, Stephan; Talaei, Sara; Kachar, Bechara; Rutherford, Mark A

2018-01-01

The ribbon is the structural hallmark of cochlear inner hair cell (IHC) afferent synapses, yet its role in information transfer to spiral ganglion neurons (SGNs) remains unclear. We investigated the ribbon’s contribution to IHC synapse formation and function using KO mice lacking RIBEYE. Despite loss of the entire ribbon structure, synapses retained their spatiotemporal development and KO mice had a mild hearing deficit. IHCs of KO had fewer synaptic vesicles and reduced exocytosis in response to brief depolarization; a high stimulus level rescued exocytosis in KO. SGNs exhibited a lack of sustained excitatory postsynaptic currents (EPSCs). We observed larger postsynaptic glutamate receptor plaques, potentially compensating for the reduced EPSC rate in KO. Surprisingly, large-amplitude EPSCs were maintained in KO, while a small population of low-amplitude slower EPSCs was increased in number. The ribbon facilitates signal transduction at physiological stimulus levels by retaining a larger residency pool of synaptic vesicles. PMID:29328021

Human limbic encephalitis serum enhances hippocampal mossy fiber-CA3 pyramidal cell synaptic transmission.

PubMed

Lalic, Tatjana; Pettingill, Philippa; Vincent, Angela; Capogna, Marco

2011-01-01

Limbic encephalitis (LE) is a central nervous system (CNS) disease characterized by subacute onset of memory loss and epileptic seizures. A well-recognized form of LE is associated with voltage-gated potassium channel complex antibodies (VGKC-Abs) in the patients' sera. We aimed to test the hypothesis that purified immunoglobulin G (IgG) from a VGKC-Ab LE serum would excite hippocampal CA3 pyramidal cells by reducing VGKC function at mossy-fiber (MF)-CA3 pyramidal cell synapses. We compared the effects of LE and healthy control IgG by whole-cell patch-clamp and extracellular recordings from CA3 pyramidal cells of rat hippocampal acute slices. We found that the LE IgG induced epileptiform activity at a population level, since synaptic stimulation elicited multiple population spikes extracellularly recorded in the CA3 area. Moreover, the LE IgG increased the rate of tonic firing and strengthened the MF-evoked synaptic responses. The synaptic failure of evoked excitatory postsynaptic currents (EPSCs) was significantly lower in the presence of the LE IgG compared to the control IgG. This suggests that the LE IgG increased the release probability on MF-CA3 pyramidal cell synapses compared to the control IgG. Interestingly, α-dendrotoxin (120 nm), a selective Kv1.1, 1.2, and 1.6 subunit antagonist of VGKC, mimicked the LE IgG-mediated effects. This is the first functional demonstration that LE IgGs reduce VGKC function at CNS synapses and increase cell excitability. Wiley Periodicals, Inc. © 2010 International League Against Epilepsy.

Anesthetic Agent-Specific Effects on Synaptic Inhibition

PubMed Central

MacIver, M. Bruce

2014-01-01

Background Anesthetics enhance gamma-aminobutyric acid (GABA)-mediated inhibition in the central nervous system. Different agents have been shown to act on tonic versus synaptic GABA receptors to different degrees, but it remains unknown whether different forms of synaptic inhibition are also differentially engaged. With this in mind, we tested the hypothesis that different types of GABA-mediated synapses exhibit different anesthetic sensitivities. The present study compared effects produced by isoflurane, halothane, pentobarbital, thiopental and propofol on paired pulse GABAA receptor-mediated synaptic inhibition. Effects on glutamate-mediated facilitation were also studied. Methods Synaptic responses were measured in rat hippocampal brain slices. Orthodromic paired pulse stimulation was used to assess anesthetic effects on either glutamate-mediated excitatory inputs or GABA-mediated inhibitory inputs to CA1 neurons. Antidromic stimulation was used to assess anesthetic effects on CA1 background excitability. Agents were studied at equi-effective concentrations for population spike depression to compare their relative degree of effect on synaptic inhibition. Results Differing degrees of anesthetic effect on paired pulse facilitation at excitatory glutamate synapses were evident, and blocking GABA inhibition revealed a previously unseen presynaptic action for pentobarbital. Although all five anesthetics depressed synaptically evoked excitation of CA1 neurons, the involvement of enhanced GABA-mediated inhibition differed considerably among agents. Single pulse inhibition was enhanced by propofol, thiopental and pentobarbital, but only marginally by halothane and isoflurane. In contrast, isoflurane enhanced paired pulse inhibition strongly, as did thiopental, but propofol, pentobarbital and halothane were less effective. Conclusions These observations support the idea that different GABA synapses use receptors with differing subunit compositions, and that anesthetics exhibit differing degrees of selectivity for these receptors. The differing anesthetic sensitivities seen in the present study, at glutamate and GABA synapses, help explain the unique behavioral/clinical profiles produced by different classes of anesthetics, and indicate that there are selective targets for new agent development. PMID:24977633

Anesthetic agent-specific effects on synaptic inhibition.

PubMed

MacIver, M Bruce

2014-09-01

Anesthetics enhance γ-aminobutyric acid (GABA)-mediated inhibition in the central nervous system. Different agents have been shown to act on tonic versus synaptic GABA receptors to different degrees, but it remains unknown whether different forms of synaptic inhibition are also differentially engaged. With this in mind, we tested the hypothesis that different types of GABA-mediated synapses exhibit different anesthetic sensitivities. The present study compared effects produced by isoflurane, halothane, pentobarbital, thiopental, and propofol on paired-pulse GABAA receptor-mediated synaptic inhibition. Effects on glutamate-mediated facilitation were also studied. Synaptic responses were measured in rat hippocampal brain slices. Orthodromic paired-pulse stimulation was used to assess anesthetic effects on either glutamate-mediated excitatory inputs or GABA-mediated inhibitory inputs to CA1 neurons. Antidromic stimulation was used to assess anesthetic effects on CA1 background excitability. Agents were studied at equieffective concentrations for population spike depression to compare their relative degree of effect on synaptic inhibition. Differing degrees of anesthetic effect on paired-pulse facilitation at excitatory glutamate synapses were evident, and blocking GABA inhibition revealed a previously unseen presynaptic action for pentobarbital. Although all 5 anesthetics depressed synaptically evoked excitation of CA1 neurons, the involvement of enhanced GABA-mediated inhibition differed considerably among agents. Single-pulse inhibition was enhanced by propofol, thiopental, and pentobarbital, but only marginally by halothane and isoflurane. In contrast, isoflurane enhanced paired-pulse inhibition strongly, as did thiopental, but propofol, pentobarbital, and halothane were less effective. These observations support the idea that different GABA synapses use receptors with differing subunit compositions and that anesthetics exhibit differing degrees of selectivity for these receptors. The differing anesthetic sensitivities seen in the present study, at glutamate and GABA synapses, help explain the unique behavioral/clinical profiles produced by different classes of anesthetics and indicate that there are selective targets for new agent development.

Inhibition linearizes firing rate responses in human motor units: implications for the role of persistent inward currents.

PubMed

Revill, Ann L; Fuglevand, Andrew J

2017-01-01

Motor neurons are the output neurons of the central nervous system and are responsible for controlling muscle contraction. When initially activated during voluntary contraction, firing rates of motor neurons increase steeply but then level out at modest rates. Activation of an intrinsic source of excitatory current at recruitment onset may underlie the initial steep increase in firing rate in motor neurons. We attempted to disable this intrinsic excitatory current by artificially activating an inhibitory reflex. When motor neuron activity was recorded while the inhibitory reflex was engaged, firing rates no longer increased steeply, suggesting that the intrinsic excitatory current was probably responsible for the initial sharp rise in motor neuron firing rate. During graded isometric contractions, motor unit (MU) firing rates increase steeply upon recruitment but then level off at modest rates even though muscle force continues to increase. The mechanisms underlying such firing behaviour are not known although activation of persistent inward currents (PICs) might be involved. PICs are intrinsic, voltage-dependent currents that activate strongly when motor neurons (MNs) are first recruited. Such activation might cause a sharp escalation in depolarizing current and underlie the steep initial rise in MU firing rate. Because PICs can be disabled with synaptic inhibition, we hypothesized that artificial activation of an inhibitory pathway might curb this initial steep rise in firing rate. To test this, human subjects performed slow triangular ramp contractions of the ankle dorsiflexors in the absence and presence of tonic synaptic inhibition delivered to tibialis anterior (TA) MNs by sural nerve stimulation. Firing rate profiles (expressed as a function of contraction force) of TA MUs recorded during these tasks were compared for control and stimulation conditions. Under control conditions, during the ascending phase of the triangular contractions, 93% of the firing rate profiles were best fitted by rising exponential functions. With stimulation, however, firing rate profiles were best fitted with linear functions or with less steeply rising exponentials. Firing rate profiles for the descending phases of the contractions were best fitted with linear functions for both control and stimulation conditions. These results seem consistent with the idea that PICs contribute to non-linear firing rate profiles during ascending but not descending phases of contractions. © 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.

Autism-like socio-communicative deficits and stereotypies in mice lacking heparan sulfate.

PubMed

Irie, Fumitoshi; Badie-Mahdavi, Hedieh; Yamaguchi, Yu

2012-03-27

Heparan sulfate regulates diverse cell-surface signaling events, and its roles in the development of the nervous system recently have been increasingly uncovered by studies using genetic models carrying mutations of genes encoding enzymes for its synthesis. On the other hand, the role of heparan sulfate in the physiological function of the adult brain has been poorly characterized, despite several pieces of evidence suggesting its role in the regulation of synaptic function. To address this issue, we eliminated heparan sulfate from postnatal neurons by conditionally inactivating Ext1, the gene encoding an enzyme essential for heparan sulfate synthesis. Resultant conditional mutant mice show no detectable morphological defects in the cytoarchitecture of the brain. Remarkably, these mutant mice recapitulate almost the full range of autistic symptoms, including impairments in social interaction, expression of stereotyped, repetitive behavior, and impairments in ultrasonic vocalization, as well as some associated features. Mapping of neuronal activation by c-Fos immunohistochemistry demonstrates that neuronal activation in response to social stimulation is attenuated in the amygdala in these mice. Electrophysiology in amygdala pyramidal neurons shows an attenuation of excitatory synaptic transmission, presumably because of the reduction in the level of synaptically localized AMPA-type glutamate receptors. Our results demonstrate that heparan sulfate is critical for normal functioning of glutamatergic synapses and that its deficiency mediates socio-communicative deficits and stereotypies characteristic for autism.

Autism-like socio-communicative deficits and stereotypies in mice lacking heparan sulfate

PubMed Central

Irie, Fumitoshi; Badie-Mahdavi, Hedieh; Yamaguchi, Yu

2012-01-01

Heparan sulfate regulates diverse cell-surface signaling events, and its roles in the development of the nervous system recently have been increasingly uncovered by studies using genetic models carrying mutations of genes encoding enzymes for its synthesis. On the other hand, the role of heparan sulfate in the physiological function of the adult brain has been poorly characterized, despite several pieces of evidence suggesting its role in the regulation of synaptic function. To address this issue, we eliminated heparan sulfate from postnatal neurons by conditionally inactivating Ext1, the gene encoding an enzyme essential for heparan sulfate synthesis. Resultant conditional mutant mice show no detectable morphological defects in the cytoarchitecture of the brain. Remarkably, these mutant mice recapitulate almost the full range of autistic symptoms, including impairments in social interaction, expression of stereotyped, repetitive behavior, and impairments in ultrasonic vocalization, as well as some associated features. Mapping of neuronal activation by c-Fos immunohistochemistry demonstrates that neuronal activation in response to social stimulation is attenuated in the amygdala in these mice. Electrophysiology in amygdala pyramidal neurons shows an attenuation of excitatory synaptic transmission, presumably because of the reduction in the level of synaptically localized AMPA-type glutamate receptors. Our results demonstrate that heparan sulfate is critical for normal functioning of glutamatergic synapses and that its deficiency mediates socio-communicative deficits and stereotypies characteristic for autism. PMID:22411800

Amplitude Normalization of Dendritic EPSPs at the Soma of Binaural Coincidence Detector Neurons of the Medial Superior Olive

PubMed Central

Winters, Bradley D.; Jin, Shan-Xue; Ledford, Kenneth R.

2017-01-01

The principal neurons of the medial superior olive (MSO) encode cues for horizontal sound localization through comparisons of the relative timing of EPSPs. To understand how the timing and amplitude of EPSPs are maintained during propagation in the dendrites, we made dendritic and somatic whole-cell recordings from MSO principal neurons in brain slices from Mongolian gerbils. In somatic recordings, EPSP amplitudes were largely uniform following minimal stimulation of excitatory synapses at visualized locations along the dendrites. Similar results were obtained when excitatory synaptic transmission was eliminated in a low calcium solution and then restored at specific dendritic sites by pairing input stimulation and focal application of a higher calcium solution. We performed dual dendritic and somatic whole-cell recordings to measure spontaneous EPSPs using a dual-channel template-matching algorithm to separate out those events initiated at or distal to the dendritic recording location. Local dendritic spontaneous EPSP amplitudes increased sharply in the dendrite with distance from the soma (length constant, 53.6 μm), but their attenuation during propagation resulted in a uniform amplitude of ∼0.2 mV at the soma. The amplitude gradient of dendritic EPSPs was also apparent in responses to injections of identical simulated excitatory synaptic currents in the dendrites. Compartmental models support the view that these results extensively reflect the influence of dendritic cable properties. With relatively few excitatory axons innervating MSO neurons, the normalization of dendritic EPSPs at the soma would increase the importance of input timing versus location during the processing of interaural time difference cues in vivo. SIGNIFICANCE STATEMENT The neurons of the medial superior olive analyze cues for sound localization by detecting the coincidence of binaural excitatory synaptic inputs distributed along the dendrites. Previous studies have shown that dendritic voltages undergo severe attenuation as they propagate to the soma, potentially reducing the influence of distal inputs. However, using dendritic and somatic patch recordings, we found that dendritic EPSP amplitude increased with distance from the soma, compensating for dendritic attenuation and normalizing EPSP amplitude at the soma. Much of this normalization reflected the influence of dendritic morphology. As different combinations of presynaptic axons may be active during consecutive cycles of sound stimuli, somatic EPSP normalization renders spike initiation more sensitive to synapse timing than dendritic location. PMID:28213442

Inhibition of 14-3-3 Proteins Leads to Schizophrenia-Related Behavioral Phenotypes and Synaptic Defects in Mice.

PubMed

Foote, Molly; Qiao, Haifa; Graham, Kourtney; Wu, Yuying; Zhou, Yi

2015-09-15

The 14-3-3 family of proteins is implicated in the regulation of several key neuronal processes. Previous human and animal studies suggested an association between 14-3-3 dysregulation and schizophrenia. We characterized behavioral and functional changes in transgenic mice that express an isoform-independent 14-3-3 inhibitor peptide in the brain. We recently showed that 14-3-3 functional knockout mice (FKO) exhibit impairments in associative learning and memory. We report here that these 14-3-3 FKO mice display other behavioral deficits that correspond to the core symptoms of schizophrenia. These behavioral deficits may be attributed to alterations in multiple neurotransmission systems in the 14-3-3 FKO mice. In particular, inhibition of 14-3-3 proteins results in a reduction of dendritic complexity and spine density in forebrain excitatory neurons, which may underlie the altered synaptic connectivity in the prefrontal cortical synapse of the 14-3-3 FKO mice. At the molecular level, this dendritic spine defect may stem from dysregulated actin dynamics secondary to a disruption of the 14-3-3-dependent regulation of phosphorylated cofilin. Collectively, our data provide a link between 14-3-3 dysfunction, synaptic alterations, and schizophrenia-associated behavioral deficits. Published by Elsevier Inc.

Focal adhesion kinase regulates neuronal growth, synaptic plasticity and hippocampus-dependent spatial learning and memory.

PubMed

Monje, Francisco J; Kim, Eun-Jung; Pollak, Daniela D; Cabatic, Maureen; Li, Lin; Baston, Arthur; Lubec, Gert

2012-01-01

The focal adhesion kinase (FAK) is a non-receptor tyrosine kinase abundantly expressed in the mammalian brain and highly enriched in neuronal growth cones. Inhibitory and facilitatory activities of FAK on neuronal growth have been reported and its role in neuritic outgrowth remains controversial. Unlike other tyrosine kinases, such as the neurotrophin receptors regulating neuronal growth and plasticity, the relevance of FAK for learning and memory in vivo has not been clearly defined yet. A comprehensive study aimed at determining the role of FAK in neuronal growth, neurotransmitter release and synaptic plasticity in hippocampal neurons and in hippocampus-dependent learning and memory was therefore undertaken using the mouse model. Gain- and loss-of-function experiments indicated that FAK is a critical regulator of hippocampal cell morphology. FAK mediated neurotrophin-induced neuritic outgrowth and FAK inhibition affected both miniature excitatory postsynaptic potentials and activity-dependent hippocampal long-term potentiation prompting us to explore the possible role of FAK in spatial learning and memory in vivo. Our data indicate that FAK has a growth-promoting effect, is importantly involved in the regulation of the synaptic function and mediates in vivo hippocampus-dependent spatial learning and memory. Copyright © 2011 S. Karger AG, Basel.

The role of the postsynaptic density in the pathology of the fragile X syndrome.

PubMed

Kindler, Stefan; Kreienkamp, Hans-Jürgen

2012-01-01

The protein repertoire of excitatory synapses controls dendritic spine morphology, synaptic plasticity and higher brain functions. In brain neurons, the RNA-associated fragile X mental retardation protein (FMRP) binds in vivo to various transcripts encoding key postsynaptic components and may thereby substantially regulate the molecular composition of dendritic spines. In agreement with this notion functional loss of FMRP in patients affected by the fragile X syndrome (FXS) causes cognitive impairment. Here we address our current understanding of the functional role of individual postsynaptic proteins. We discuss how FMRP controls the abundance of select proteins at postsynaptic sites, which signaling pathways regulate the local activity of FMRP at synapses, and how altered levels of postsynaptic proteins may contribute to FXS pathology.

Robust Working Memory in an Asynchronously Spiking Neural Network Realized with Neuromorphic VLSI

PubMed Central

Giulioni, Massimiliano; Camilleri, Patrick; Mattia, Maurizio; Dante, Vittorio; Braun, Jochen; Del Giudice, Paolo

2011-01-01

We demonstrate bistable attractor dynamics in a spiking neural network implemented with neuromorphic VLSI hardware. The on-chip network consists of three interacting populations (two excitatory, one inhibitory) of leaky integrate-and-fire (LIF) neurons. One excitatory population is distinguished by strong synaptic self-excitation, which sustains meta-stable states of “high” and “low”-firing activity. Depending on the overall excitability, transitions to the “high” state may be evoked by external stimulation, or may occur spontaneously due to random activity fluctuations. In the former case, the “high” state retains a “working memory” of a stimulus until well after its release. In the latter case, “high” states remain stable for seconds, three orders of magnitude longer than the largest time-scale implemented in the circuitry. Evoked and spontaneous transitions form a continuum and may exhibit a wide range of latencies, depending on the strength of external stimulation and of recurrent synaptic excitation. In addition, we investigated “corrupted” “high” states comprising neurons of both excitatory populations. Within a “basin of attraction,” the network dynamics “corrects” such states and re-establishes the prototypical “high” state. We conclude that, with effective theoretical guidance, full-fledged attractor dynamics can be realized with comparatively small populations of neuromorphic hardware neurons. PMID:22347151

Robust Working Memory in an Asynchronously Spiking Neural Network Realized with Neuromorphic VLSI.

PubMed

Giulioni, Massimiliano; Camilleri, Patrick; Mattia, Maurizio; Dante, Vittorio; Braun, Jochen; Del Giudice, Paolo

2011-01-01

We demonstrate bistable attractor dynamics in a spiking neural network implemented with neuromorphic VLSI hardware. The on-chip network consists of three interacting populations (two excitatory, one inhibitory) of leaky integrate-and-fire (LIF) neurons. One excitatory population is distinguished by strong synaptic self-excitation, which sustains meta-stable states of "high" and "low"-firing activity. Depending on the overall excitability, transitions to the "high" state may be evoked by external stimulation, or may occur spontaneously due to random activity fluctuations. In the former case, the "high" state retains a "working memory" of a stimulus until well after its release. In the latter case, "high" states remain stable for seconds, three orders of magnitude longer than the largest time-scale implemented in the circuitry. Evoked and spontaneous transitions form a continuum and may exhibit a wide range of latencies, depending on the strength of external stimulation and of recurrent synaptic excitation. In addition, we investigated "corrupted" "high" states comprising neurons of both excitatory populations. Within a "basin of attraction," the network dynamics "corrects" such states and re-establishes the prototypical "high" state. We conclude that, with effective theoretical guidance, full-fledged attractor dynamics can be realized with comparatively small populations of neuromorphic hardware neurons.

Dendritic nonlinearities reduce network size requirements and mediate ON and OFF states of persistent activity in a PFC microcircuit model.

PubMed

Papoutsi, Athanasia; Sidiropoulou, Kyriaki; Poirazi, Panayiota

2014-07-01

Technological advances have unraveled the existence of small clusters of co-active neurons in the neocortex. The functional implications of these microcircuits are in large part unexplored. Using a heavily constrained biophysical model of a L5 PFC microcircuit, we recently showed that these structures act as tunable modules of persistent activity, the cellular correlate of working memory. Here, we investigate the mechanisms that underlie persistent activity emergence (ON) and termination (OFF) and search for the minimum network size required for expressing these states within physiological regimes. We show that (a) NMDA-mediated dendritic spikes gate the induction of persistent firing in the microcircuit. (b) The minimum network size required for persistent activity induction is inversely proportional to the synaptic drive of each excitatory neuron. (c) Relaxation of connectivity and synaptic delay constraints eliminates the gating effect of NMDA spikes, albeit at a cost of much larger networks. (d) Persistent activity termination by increased inhibition depends on the strength of the synaptic input and is negatively modulated by dADP. (e) Slow synaptic mechanisms and network activity contain predictive information regarding the ability of a given stimulus to turn ON and/or OFF persistent firing in the microcircuit model. Overall, this study zooms out from dendrites to cell assemblies and suggests a tight interaction between dendritic non-linearities and network properties (size/connectivity) that may facilitate the short-memory function of the PFC.

Ultrastructure of Dendritic Spines: Correlation Between Synaptic and Spine Morphologies

PubMed Central

Arellano, Jon I.; Benavides-Piccione, Ruth; DeFelipe, Javier; Yuste, Rafael

2007-01-01

Dendritic spines are critical elements of cortical circuits, since they establish most excitatory synapses. Recent studies have reported correlations between morphological and functional parameters of spines. Specifically, the spine head volume is correlated with the area of the postsynaptic density (PSD), the number of postsynaptic receptors and the ready-releasable pool of transmitter, whereas the length of the spine neck is proportional to the degree of biochemical and electrical isolation of the spine from its parent dendrite. Therefore, the morphology of a spine could determine its synaptic strength and learning rules. To better understand the natural variability of neocortical spine morphologies, we used a combination of gold-toned Golgi impregnations and serial thin-section electron microscopy and performed three-dimensional reconstructions of spines from layer 2/3 pyramidal cells from mouse visual cortex. We characterized the structure and synaptic features of 144 completed reconstructed spines, and analyzed their morphologies according to their positions. For all morphological parameters analyzed, spines exhibited a continuum of variability, without clearly distinguishable subtypes of spines or clear dependence of their morphologies on their distance to the soma. On average, the spine head volume was correlated strongly with PSD area and weakly with neck diameter, but not with neck length. The large morphological diversity suggests an equally large variability of synaptic strength and learning rules. PMID:18982124

Information processing occurs via critical avalanches in a model of the primary visual cortex

NASA Astrophysics Data System (ADS)

Bortolotto, G. S.; Girardi-Schappo, M.; Gonsalves, J. J.; Pinto, L. T.; Tragtenberg, M. H. R.

2016-01-01

We study a new biologically motivated model for the Macaque monkey primary visual cortex which presents power-law avalanches after a visual stimulus. The signal propagates through all the layers of the model via avalanches that depend on network structure and synaptic parameter. We identify four different avalanche profiles as a function of the excitatory postsynaptic potential. The avalanches follow a size-duration scaling relation and present critical exponents that match experiments. The structure of the network gives rise to a regime of two characteristic spatial scales, one of which vanishes in the thermodynamic limit.

Subunit-specific rules governing AMPA receptor trafficking to synapses in hippocampal pyramidal neurons.

PubMed

Shi, S; Hayashi, Y; Esteban, J A; Malinow, R

2001-05-04

AMPA-type glutamate receptors (AMPA-Rs) mediate a majority of excitatory synaptic transmission in the brain. In hippocampus, most AMPA-Rs are hetero-oligomers composed of GluR1/GluR2 or GluR2/GluR3 subunits. Here we show that these AMPA-R forms display different synaptic delivery mechanisms. GluR1/GluR2 receptors are added to synapses during plasticity; this requires interactions between GluR1 and group I PDZ domain proteins. In contrast, GluR2/GluR3 receptors replace existing synaptic receptors continuously; this occurs only at synapses that already have AMPA-Rs and requires interactions by GluR2 with NSF and group II PDZ domain proteins. The combination of regulated addition and continuous replacement of synaptic receptors can stabilize long-term changes in synaptic efficacy and may serve as a general model for how surface receptor number is established and maintained.

PTEN Loss Increases the Connectivity of Fast Synaptic Motifs and Functional Connectivity in a Developing Hippocampal Network.

PubMed

Barrows, Caitlynn M; McCabe, Matthew P; Chen, Hongmei; Swann, John W; Weston, Matthew C

2017-09-06

Changes in synaptic strength and connectivity are thought to be a major mechanism through which many gene variants cause neurological disease. Hyperactivation of the PI3K-mTOR signaling network, via loss of function of repressors such as PTEN, causes epilepsy in humans and animal models, and altered mTOR signaling may contribute to a broad range of neurological diseases. Changes in synaptic transmission have been reported in animal models of PTEN loss; however, the full extent of these changes, and their effect on network function, is still unknown. To better understand the scope of these changes, we recorded from pairs of mouse hippocampal neurons cultured in a two-neuron microcircuit configuration that allowed us to characterize all four major connection types within the hippocampus. Loss of PTEN caused changes in excitatory and inhibitory connectivity, and these changes were postsynaptic, presynaptic, and transynaptic, suggesting that disruption of PTEN has the potential to affect most connection types in the hippocampal circuit. Given the complexity of the changes at the synaptic level, we measured changes in network behavior after deleting Pten from neurons in an organotypic hippocampal slice network. Slices containing Pten -deleted neurons showed increased recruitment of neurons into network bursts. Importantly, these changes were not confined to Pten -deleted neurons, but involved the entire network, suggesting that the extensive changes in synaptic connectivity rewire the entire network in such a way that promotes a widespread increase in functional connectivity. SIGNIFICANCE STATEMENT Homozygous deletion of the Pten gene in neuronal subpopulations in the mouse serves as a valuable model of epilepsy caused by mTOR hyperactivation. To better understand how gene deletions lead to altered neuronal activity, we investigated the synaptic and network effects that occur 1 week after Pten deletion. PTEN loss increased the connectivity of all four types of hippocampal synaptic connections, including two forms of increased inhibition of inhibition, and increased network functional connectivity. These data suggest that single gene mutations that cause neurological diseases such as epilepsy may affect a surprising range of connection types. Moreover, given the robustness of homeostatic plasticity, these diverse effects on connection types may be necessary to cause network phenotypes such as increased synchrony. Copyright © 2017 the authors 0270-6474/17/378595-17$15.00/0.

PTEN Loss Increases the Connectivity of Fast Synaptic Motifs and Functional Connectivity in a Developing Hippocampal Network

PubMed Central

McCabe, Matthew P.; Chen, Hongmei; Swann, John W.

2017-01-01

Changes in synaptic strength and connectivity are thought to be a major mechanism through which many gene variants cause neurological disease. Hyperactivation of the PI3K-mTOR signaling network, via loss of function of repressors such as PTEN, causes epilepsy in humans and animal models, and altered mTOR signaling may contribute to a broad range of neurological diseases. Changes in synaptic transmission have been reported in animal models of PTEN loss; however, the full extent of these changes, and their effect on network function, is still unknown. To better understand the scope of these changes, we recorded from pairs of mouse hippocampal neurons cultured in a two-neuron microcircuit configuration that allowed us to characterize all four major connection types within the hippocampus. Loss of PTEN caused changes in excitatory and inhibitory connectivity, and these changes were postsynaptic, presynaptic, and transynaptic, suggesting that disruption of PTEN has the potential to affect most connection types in the hippocampal circuit. Given the complexity of the changes at the synaptic level, we measured changes in network behavior after deleting Pten from neurons in an organotypic hippocampal slice network. Slices containing Pten-deleted neurons showed increased recruitment of neurons into network bursts. Importantly, these changes were not confined to Pten-deleted neurons, but involved the entire network, suggesting that the extensive changes in synaptic connectivity rewire the entire network in such a way that promotes a widespread increase in functional connectivity. SIGNIFICANCE STATEMENT Homozygous deletion of the Pten gene in neuronal subpopulations in the mouse serves as a valuable model of epilepsy caused by mTOR hyperactivation. To better understand how gene deletions lead to altered neuronal activity, we investigated the synaptic and network effects that occur 1 week after Pten deletion. PTEN loss increased the connectivity of all four types of hippocampal synaptic connections, including two forms of increased inhibition of inhibition, and increased network functional connectivity. These data suggest that single gene mutations that cause neurological diseases such as epilepsy may affect a surprising range of connection types. Moreover, given the robustness of homeostatic plasticity, these diverse effects on connection types may be necessary to cause network phenotypes such as increased synchrony. PMID:28751459

Heterogeneity of Intrinsic and Synaptic Properties of Neurons in the Ventral and Dorsal Parts of the Ventral Nucleus of the Lateral Lemniscus

PubMed Central

Caspari, Franziska; Baumann, Veronika J.; Garcia-Pino, Elisabet; Koch, Ursula

2015-01-01

The ventral nucleus of the lateral lemniscus (VNLL) provides a major inhibitory projection to the inferior colliculus (IC). Neurons in the VNLL respond with various firing patterns and different temporal precision to acoustic stimulation. The present study investigates the underlying intrinsic and synaptic properties of various cell types in different regions of the VNLL, using in vitro electrophysiological recordings from acute brain slices of mice and immunohistochemistry. We show that the biophysical membrane properties and excitatory input characteristics differed between dorsal and ventral VNLL neurons. Neurons in the ventral VNLL displayed an onset-type firing pattern and little hyperpolarization-activated current (Ih). Stimulation of lemniscal inputs evoked a large all-or-none excitatory response similar to Calyx of Held synapses in neurons in the lateral part of the ventral VNLL. Neurons that were located within the fiber tract of the lateral lemniscus, received several and weak excitatory input fibers. In the dorsal VNLL onset-type and sustained firing neurons were intermingled. These neurons showed large Ih and were strongly immunopositive for the hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) subunit. Both neuron types received several excitatory inputs that were weaker and slower compared to ventrolateral VNLL neurons. Using a mouse model that expresses channelrhodopsin under the promotor of the vesicular GABA transporter (VGAT) suggests that dorsal and ventral neurons were inhibitory since they were all depolarized by light stimulation. The diverse membrane and input properties in dorsal and ventral VNLL neurons suggest differential roles of these neurons for sound processing. PMID:26635535

Changes in inhibitory CA1 network in dual pathology model of epilepsy.

PubMed

Ouardouz, Mohamed; Carmant, Lionel

2012-01-01

The combination of two precipitating factors appears to be more and more recognized in patients with temporal lobe epilepsy. Using a two-hit rat model, with a neonatal freeze lesion mimicking a focal cortical malformation combined with hyperthermia-induced seizures mimicking febrile seizures, we have previously reported an increase of inhibition in CA1 pyramidal cells at P20. Here, we investigated the changes affecting excitatory and inhibitory drive onto CA1 interneurons to better define the changes in CA1 inhibitory networks and their paradoxical role in epileptogenesis, using electrophysiological recordings in CA1 hippocampus from rat pups (16-20 d old). We investigated interneurons in CA1 hippocampal area located in stratum oriens (Or) and at the border of strata lacunosum and moleculare (L-M). Our results revealed an increase of the excitatory drive to both types of interneurons with no change in the inhibitory drive. The mechanisms underlying the increase of excitatory synaptic currents (EPSCs) in both types of interneurons are different. In Or interneurons, the amplitude of spontaneous and miniature EPSCs increased, while their frequency was not affected suggesting changes at the post-synaptic level. In L-M interneurons, the frequency of spontaneous EPSCs increases, but the amplitude is not affected. Analyses of miniature EPSCs showed no changes in both their frequency and amplitude. We concluded that L-M interneurons increase in excitatory drive is due to a change in Shaffer collateral axon excitability. The changes described here in CA1 inhibitory network may actually contribute to the epileptogenicity observed in this dual pathology model by increasing pyramidal cell synchronization.

Spatiotemporal discrimination in neural networks with short-term synaptic plasticity

NASA Astrophysics Data System (ADS)

Shlaer, Benjamin; Miller, Paul

2015-03-01

Cells in recurrently connected neural networks exhibit bistability, which allows for stimulus information to persist in a circuit even after stimulus offset, i.e. short-term memory. However, such a system does not have enough hysteresis to encode temporal information about the stimuli. The biophysically described phenomenon of synaptic depression decreases synaptic transmission strengths due to increased presynaptic activity. This short-term reduction in synaptic strengths can destabilize attractor states in excitatory recurrent neural networks, causing the network to move along stimulus dependent dynamical trajectories. Such a network can successfully separate amplitudes and durations of stimuli from the number of successive stimuli. Stimulus number, duration and intensity encoding in randomly connected attractor networks with synaptic depression. Front. Comput. Neurosci. 7:59., and so provides a strong candidate network for the encoding of spatiotemporal information. Here we explicitly demonstrate the capability of a recurrent neural network with short-term synaptic depression to discriminate between the temporal sequences in which spatial stimuli are presented.

Bidirectional synaptic structural plasticity after chronic cocaine administration occurs through Rap1 small GTPase signaling

PubMed Central

Cahill, Michael E.; Bagot, Rosemary C.; Gancarz, Amy M.; Walker, Deena M.; Sun, HaoSheng; Wang, Zi-Jun; Heller, Elizabeth A.; Feng, Jian; Kennedy, Pamela J.; Koo, Ja Wook; Cates, Hannah M.; Neve, Rachael L.; Shen, Li; Dietz, David M.

2016-01-01

Summary Dendritic spines are the sites of most excitatory synapses in the CNS, and opposing alterations in the synaptic structure of medium spiny neurons (MSNs) of the nucleus accumbens, a primary brain reward region, are seen at early vs. late time points after cocaine administration. Here we investigate the time-dependent molecular and biochemical processes that regulate this bidirectional synaptic structural plasticity of NAc MSNs and associated changes in cocaine reward in response to chronic cocaine exposure. Our findings reveal key roles for the bidirectional synaptic expression of the Rap1b small GTPase and an associated local-synaptic protein translation network in this process. The transcriptional mechanisms and pathway-specific inputs to NAc that regulate Rap1b expression are also characterized. Collectively, these findings provide a precise mechanism by which nuclear to synaptic interactions induce “metaplasticity” in NAc MSNs, and we reveal the specific effects of this plasticity on reward behavior in a brain circuit-specific manner. PMID:26844834

Nitric Oxide Is an Activity-Dependent Regulator of Target Neuron Intrinsic Excitability

PubMed Central

Steinert, Joern R.; Robinson, Susan W.; Tong, Huaxia; Haustein, Martin D.; Kopp-Scheinpflug, Cornelia; Forsythe, Ian D.

2011-01-01

Summary Activity-dependent changes in synaptic strength are well established as mediating long-term plasticity underlying learning and memory, but modulation of target neuron excitability could complement changes in synaptic strength and regulate network activity. It is thought that homeostatic mechanisms match intrinsic excitability to the incoming synaptic drive, but evidence for involvement of voltage-gated conductances is sparse. Here, we show that glutamatergic synaptic activity modulates target neuron excitability and switches the basis of action potential repolarization from Kv3 to Kv2 potassium channel dominance, thereby adjusting neuronal signaling between low and high activity states, respectively. This nitric oxide-mediated signaling dramatically increases Kv2 currents in both the auditory brain stem and hippocampus (>3-fold) transforming synaptic integration and information transmission but with only modest changes in action potential waveform. We conclude that nitric oxide is a homeostatic regulator, tuning neuronal excitability to the recent history of excitatory synaptic inputs over intervals of minutes to hours. PMID:21791288

Light-Stimulated Synaptic Devices Utilizing Interfacial Effect of Organic Field-Effect Transistors.

PubMed

Dai, Shilei; Wu, Xiaohan; Liu, Dapeng; Chu, Yingli; Wang, Kai; Yang, Ben; Huang, Jia

2018-06-14

Synaptic transistors stimulated by light waves or photons may offer advantages to the devices, such as wide bandwidth, ultrafast signal transmission, and robustness. However, previously reported light-stimulated synaptic devices generally require special photoelectric properties from the semiconductors and sophisticated device's architectures. In this work, a simple and effective strategy for fabricating light-stimulated synaptic transistors is provided by utilizing interface charge trapping effect of organic field-effect transistors (OFETs). Significantly, our devices exhibited highly synapselike behaviors, such as excitatory postsynaptic current (EPSC) and pair-pulse facilitation (PPF), and presented memory and learning ability. The EPSC decay, PPF curves, and forgetting behavior can be well expressed by mathematical equations for synaptic devices, indicating that interfacial charge trapping effect of OFETs can be utilized as a reliable strategy to realize organic light-stimulated synapses. Therefore, this work provides a simple and effective strategy for fabricating light-stimulated synaptic transistors with both memory and learning ability, which enlightens a new direction for developing neuromorphic devices.

A Novel Human CAMK2A Mutation Disrupts Dendritic Morphology and Synaptic Transmission, and Causes ASD-Related Behaviors.

PubMed

Stephenson, Jason R; Wang, Xiaohan; Perfitt, Tyler L; Parrish, Walker P; Shonesy, Brian C; Marks, Christian R; Mortlock, Douglas P; Nakagawa, Terunaga; Sutcliffe, James S; Colbran, Roger J

2017-02-22

Characterizing the functional impact of novel mutations linked to autism spectrum disorder (ASD) provides a deeper mechanistic understanding of the underlying pathophysiological mechanisms. Here we show that a de novo Glu183 to Val (E183V) mutation in the CaMKIIα catalytic domain, identified in a proband diagnosed with ASD, decreases both CaMKIIα substrate phosphorylation and regulatory autophosphorylation, and that the mutated kinase acts in a dominant-negative manner to reduce CaMKIIα-WT autophosphorylation. The E183V mutation also reduces CaMKIIα binding to established ASD-linked proteins, such as Shank3 and subunits of l-type calcium channels and NMDA receptors, and increases CaMKIIα turnover in intact cells. In cultured neurons, the E183V mutation reduces CaMKIIα targeting to dendritic spines. Moreover, neuronal expression of CaMKIIα-E183V increases dendritic arborization and decreases both dendritic spine density and excitatory synaptic transmission. Mice with a knock-in CaMKIIα-E183V mutation have lower total forebrain CaMKIIα levels, with reduced targeting to synaptic subcellular fractions. The CaMKIIα-E183V mice also display aberrant behavioral phenotypes, including hyperactivity, social interaction deficits, and increased repetitive behaviors. Together, these data suggest that CaMKIIα plays a previously unappreciated role in ASD-related synaptic and behavioral phenotypes. SIGNIFICANCE STATEMENT Many autism spectrum disorder (ASD)-linked mutations disrupt the function of synaptic proteins, but no single gene accounts for >1% of total ASD cases. The molecular networks and mechanisms that couple the primary deficits caused by these individual mutations to core behavioral symptoms of ASD remain poorly understood. Here, we provide the first characterization of a mutation in the gene encoding CaMKIIα linked to a specific neuropsychiatric disorder. Our findings demonstrate that this ASD-linked de novo CAMK2A mutation disrupts multiple CaMKII functions, induces synaptic deficits, and causes ASD-related behavioral alterations, providing novel insights into the synaptic mechanisms contributing to ASD. Copyright © 2017 the authors 0270-6474/17/372217-18$15.00/0.

A Million-Plus Neuron Model of the Hippocampal Dentate Gyrus: Critical Role for Topography in Determining Spatiotemporal Network Dynamics.

PubMed

Hendrickson, Phillip J; Yu, Gene J; Song, Dong; Berger, Theodore W

2016-01-01

This paper describes a million-plus granule cell compartmental model of the rat hippocampal dentate gyrus, including excitatory, perforant path input from the entorhinal cortex, and feedforward and feedback inhibitory input from dentate interneurons. The model includes experimentally determined morphological and biophysical properties of granule cells, together with glutamatergic AMPA-like EPSP and GABAergic GABAA-like IPSP synaptic excitatory and inhibitory inputs, respectively. Each granule cell was composed of approximately 200 compartments having passive and active conductances distributed throughout the somatic and dendritic regions. Modeling excitatory input from the entorhinal cortex was guided by axonal transport studies documenting the topographical organization of projections from subregions of the medial and lateral entorhinal cortex, plus other important details of the distribution of glutamatergic inputs to the dentate gyrus. Information contained within previously published maps of this major hippocampal afferent were systematically converted to scales that allowed the topographical distribution and relative synaptic densities of perforant path inputs to be quantitatively estimated for inclusion in the current model. Results showed that when medial and lateral entorhinal cortical neurons maintained Poisson random firing, dentate granule cells expressed, throughout the million-cell network, a robust nonrandom pattern of spiking best described as a spatiotemporal "clustering." To identify the network property or properties responsible for generating such firing "clusters," we progressively eliminated from the model key mechanisms, such as feedforward and feedback inhibition, intrinsic membrane properties underlying rhythmic burst firing, and/or topographical organization of entorhinal afferents. Findings conclusively identified topographical organization of inputs as the key element responsible for generating a spatiotemporal distribution of clustered firing. These results uncover a functional organization of perforant path afferents to the dentate gyrus not previously recognized: topography-dependent clusters of granule cell activity as "functional units" or "channels" that organize the processing of entorhinal signals. This modeling study also reveals for the first time how a global signal processing feature of a neural network can evolve from one of its underlying structural characteristics.

A Million-Plus Neuron Model of the Hippocampal Dentate Gyrus: Critical Role for Topography in Determining Spatio-Temporal Network Dynamics

PubMed Central

Hendrickson, Phillip J.; Yu, Gene J.; Song, Dong; Berger, Theodore W.

2016-01-01

Goal This manuscript describes a million-plus granule cell compartmental model of the rat hippocampal dentate gyrus, including excitatory, perforant path input from the entorhinal cortex, and feedforward and feedback inhibitory input from dentate interneurons. Methods The model includes experimentally determined morphological and biophysical properties of granule cells, together with glutamatergic AMPA-like EPSP and GABAergic GABAA-like IPSP synaptic excitatory and inhibitory inputs, respectively. Each granule cell was composed of approximately 200 compartments having passive and active conductances distributed throughout the somatic and dendritic regions. Modeling excitatory input from the entorhinal cortex was guided by axonal transport studies documenting the topographical organization of projections from subregions of the medial and lateral entorhinal cortex, plus other important details of the distribution of glutamatergic inputs to the dentate gyrus. Information contained within previously published maps of this major hippocampal afferent were systematically converted to scales that allowed the topographical distribution and relative synaptic densities of perforant path inputs to be quantitatively estimated for inclusion in the current model. Results Results showed that when medial and lateral entorhinal cortical neurons maintained Poisson random firing, dentate granule cells expressed, throughout the million-cell network, a robust, non-random pattern of spiking best described as spatio-temporal “clustering”. To identify the network property or properties responsible for generating such firing “clusters”, we progressively eliminated from the model key mechanisms such as feedforward and feedback inhibition, intrinsic membrane properties underlying rhythmic burst firing, and/or topographical organization of entorhinal afferents. Conclusion Findings conclusively identified topographical organization of inputs as the key element responsible for generating a spatio-temporal distribution of clustered firing. These results uncover a functional organization of perforant path afferents to the dentate gyrus not previously recognized: topography-dependent clusters of granule cell activity as “functional units” or “channels” that organize the processing of entorhinal signals. This modeling study also reveals for the first time how a global signal processing feature of a neural network can evolve from one of its underlying structural characteristics. PMID:26087482

CDKL5 ensures excitatory synapse stability by reinforcing NGL-1-PSD95 interaction in the postsynaptic compartment and is impaired in patient iPSC-derived neurons.

PubMed

Ricciardi, Sara; Ungaro, Federica; Hambrock, Melanie; Rademacher, Nils; Stefanelli, Gilda; Brambilla, Dario; Sessa, Alessandro; Magagnotti, Cinzia; Bachi, Angela; Giarda, Elisa; Verpelli, Chiara; Kilstrup-Nielsen, Charlotte; Sala, Carlo; Kalscheuer, Vera M; Broccoli, Vania

2012-09-01

Mutations of the cyclin-dependent kinase-like 5 (CDKL5) and netrin-G1 (NTNG1) genes cause a severe neurodevelopmental disorder with clinical features that are closely related to Rett syndrome, including intellectual disability, early-onset intractable epilepsy and autism. We report here that CDKL5 is localized at excitatory synapses and contributes to correct dendritic spine structure and synapse activity. To exert this role, CDKL5 binds and phosphorylates the cell adhesion molecule NGL-1. This phosphorylation event ensures a stable association between NGL-1 and PSD95. Accordingly, phospho-mutant NGL-1 is unable to induce synaptic contacts whereas its phospho-mimetic form binds PSD95 more efficiently and partially rescues the CDKL5-specific spine defects. Interestingly, similarly to rodent neurons, iPSC-derived neurons from patients with CDKL5 mutations exhibit aberrant dendritic spines, thus suggesting a common function of CDKL5 in mice and humans.

On the Role of Glutamate in Presynaptic Development: Possible Contributions of Presynaptic NMDA Receptors.

PubMed

Fedder, Karlie N; Sabo, Shasta L

2015-12-14

Proper formation and maturation of synapses during development is a crucial step in building the functional neural circuits that underlie perception and behavior. It is well established that experience modifies circuit development. Therefore, understanding how synapse formation is controlled by synaptic activity is a key question in neuroscience. In this review, we focus on the regulation of excitatory presynaptic terminal development by glutamate, the predominant excitatory neurotransmitter in the brain. We discuss the evidence that NMDA receptor activation mediates these effects of glutamate and present the hypothesis that local activation of presynaptic NMDA receptors (preNMDARs) contributes to glutamate-dependent control of presynaptic development. Abnormal glutamate signaling and aberrant synapse development are both thought to contribute to the pathogenesis of a variety of neurodevelopmental disorders, including autism spectrum disorders, intellectual disability, epilepsy, anxiety, depression, and schizophrenia. Therefore, understanding how glutamate signaling and synapse development are linked is important for understanding the etiology of these diseases.

Activity-dependent switch of GABAergic inhibition into glutamatergic excitation in astrocyte-neuron networks.

PubMed

Perea, Gertrudis; Gómez, Ricardo; Mederos, Sara; Covelo, Ana; Ballesteros, Jesús J; Schlosser, Laura; Hernández-Vivanco, Alicia; Martín-Fernández, Mario; Quintana, Ruth; Rayan, Abdelrahman; Díez, Adolfo; Fuenzalida, Marco; Agarwal, Amit; Bergles, Dwight E; Bettler, Bernhard; Manahan-Vaughan, Denise; Martín, Eduardo D; Kirchhoff, Frank; Araque, Alfonso

2016-12-24

Interneurons are critical for proper neural network function and can activate Ca 2+ signaling in astrocytes. However, the impact of the interneuron-astrocyte signaling into neuronal network operation remains unknown. Using the simplest hippocampal Astrocyte-Neuron network, i.e., GABAergic interneuron, pyramidal neuron, single CA3-CA1 glutamatergic synapse, and astrocytes, we found that interneuron-astrocyte signaling dynamically affected excitatory neurotransmission in an activity- and time-dependent manner, and determined the sign (inhibition vs potentiation) of the GABA-mediated effects. While synaptic inhibition was mediated by GABA A receptors, potentiation involved astrocyte GABA B receptors, astrocytic glutamate release, and presynaptic metabotropic glutamate receptors. Using conditional astrocyte-specific GABA B receptor ( Gabbr1 ) knockout mice, we confirmed the glial source of the interneuron-induced potentiation, and demonstrated the involvement of astrocytes in hippocampal theta and gamma oscillations in vivo. Therefore, astrocytes decode interneuron activity and transform inhibitory into excitatory signals, contributing to the emergence of novel network properties resulting from the interneuron-astrocyte interplay.

A circuit mechanism for the propagation of waves of muscle contraction in Drosophila

PubMed Central

Fushiki, Akira; Zwart, Maarten F; Kohsaka, Hiroshi; Fetter, Richard D; Cardona, Albert; Nose, Akinao

2016-01-01

Animals move by adaptively coordinating the sequential activation of muscles. The circuit mechanisms underlying coordinated locomotion are poorly understood. Here, we report on a novel circuit for the propagation of waves of muscle contraction, using the peristaltic locomotion of Drosophila larvae as a model system. We found an intersegmental chain of synaptically connected neurons, alternating excitatory and inhibitory, necessary for wave propagation and active in phase with the wave. The excitatory neurons (A27h) are premotor and necessary only for forward locomotion, and are modulated by stretch receptors and descending inputs. The inhibitory neurons (GDL) are necessary for both forward and backward locomotion, suggestive of different yet coupled central pattern generators, and its inhibition is necessary for wave propagation. The circuit structure and functional imaging indicated that the commands to contract one segment promote the relaxation of the next segment, revealing a mechanism for wave propagation in peristaltic locomotion. DOI: http://dx.doi.org/10.7554/eLife.13253.001 PMID:26880545

Nlgn4 knockout induces network hypo-excitability in juvenile mouse somatosensory cortex in vitro.

PubMed

Delattre, V; La Mendola, D; Meystre, J; Markram, H; Markram, K

2013-10-09

Neuroligins (Nlgns) are postsynaptic cell adhesion molecules that form transynaptic complexes with presynaptic neurexins and regulate synapse maturation and plasticity. We studied the impact of the loss of Nlgn4 on the excitatory and inhibitory circuits in somatosensory cortical slices of juvenile mice by electrically stimulating these circuits using a multi-electrode array and recording the synaptic input to single neurons using the patch-clamp technique. We detected a decreased network response to stimulation in both excitatory and inhibitory circuits of Nlgn4 knock-out animals as compared to wild-type controls, and a decreased excitation-inhibition ratio. These data indicate that Nlgn4 is involved in the regulation of excitatory and inhibitory circuits and contributes to a balanced circuit response to stimulation.

A Change in the Ion Selectivity of Ligand-Gated Ion Channels Provides a Mechanism to Switch Behavior.

PubMed

Pirri, Jennifer K; Rayes, Diego; Alkema, Mark J

2015-01-01

Behavioral output of neural networks depends on a delicate balance between excitatory and inhibitory synaptic connections. However, it is not known whether network formation and stability is constrained by the sign of synaptic connections between neurons within the network. Here we show that switching the sign of a synapse within a neural circuit can reverse the behavioral output. The inhibitory tyramine-gated chloride channel, LGC-55, induces head relaxation and inhibits forward locomotion during the Caenorhabditis elegans escape response. We switched the ion selectivity of an inhibitory LGC-55 anion channel to an excitatory LGC-55 cation channel. The engineered cation channel is properly trafficked in the native neural circuit and results in behavioral responses that are opposite to those produced by activation of the LGC-55 anion channel. Our findings indicate that switches in ion selectivity of ligand-gated ion channels (LGICs) do not affect network connectivity or stability and may provide an evolutionary and a synthetic mechanism to change behavior.

Circuit-specific intracortical hyperconnectivity in mice with deletion of the autism-associated Met receptor tyrosine kinase

PubMed Central

Qiu, Shenfeng; Anderson, Charles T.; Levitt, Pat; Shepherd, Gordon M. G.

2011-01-01

Local hyperconnectivity in the neocortex is a hypothesized pathophysiological state in autism spectrum disorder (ASD). MET, a receptor tyrosine kinase that regulates dendrite and spine morphogenesis, has been established as a risk gene for ASD. Here, we analyzed the synaptic circuit organization of identified pyramidal neurons in the anterior frontal cortex of mice with a dorsal pallium derived, conditional knockout (cKO) of Met. Synaptic mapping by glutamate uncaging identified layer 2/3 as the main source of local excitatory input to layer 5 projection neurons in controls. In both cKO and heterozygotes this pathway was stronger by a factor of ~2. This increase was both sub-layer and projection-class specific, restricted to corticostriatal neurons in upper layer 5B, and not neighboring corticopontine neurons. Paired recordings in cKO slices demonstrated increased unitary connectivity. We propose that excitatory hyperconnectivity in specific neocortical microcircuits constitutes a physiological basis for Met-mediated ASD risk. PMID:21490227

Circuit-specific intracortical hyperconnectivity in mice with deletion of the autism-associated Met receptor tyrosine kinase.

PubMed

Qiu, Shenfeng; Anderson, Charles T; Levitt, Pat; Shepherd, Gordon M G

2011-04-13

Local hyperconnectivity in the neocortex is a hypothesized pathophysiological state in autism spectrum disorder (ASD). MET, a receptor tyrosine kinase that regulates dendrite and spine morphogenesis, has been established as a risk gene for ASD. Here, we analyzed the synaptic circuit organization of identified pyramidal neurons in the anterior frontal cortex of mice with a dorsal pallium-derived, conditional knock-out (cKO) of Met. Synaptic mapping by glutamate uncaging identified layer 2/3 as the main source of local excitatory input to layer 5 projection neurons in controls. In both cKO and heterozygotes, this pathway was stronger by a factor of approximately 2. This increase was both sublayer and projection-class specific, restricted to corticostriatal neurons in upper layer 5B and not neighboring corticopontine neurons. Paired recordings in cKO slices demonstrated increased unitary connectivity. We propose that excitatory hyperconnectivity in specific neocortical microcircuits constitutes a physiological basis for Met-mediated ASD risk.

Structure and symmetry inform gating principles of ionotropic glutamate receptors.

PubMed

Zhu, Shujia; Gouaux, Eric

2017-01-01

Ionotropic glutamate receptors (iGluRs) transduce signals derived from release of the excitatory neurotransmitter glutamate from pre-synaptic neurons into excitation of post-synaptic neurons on a millisecond time-scale. In recent years, the elucidation of full-length iGluR structures of NMDA, AMPA and kainate receptors by X-ray crystallography and single particle cryo-electron microscopy has greatly enhanced our understanding of the interrelationships between receptor architecture and gating mechanism. Here we briefly review full-length iGluR structures and discuss the similarities and differences between NMDA receptors and non-NMDA iGluRs. We focus on distinct conformations, including ligand-free, agonist-bound active, agonist-bound desensitized and antagonist-bound conformations as well as modulator and auxiliary protein-bound states. These findings provide insights into structure-based mechanisms of iGluR gating and modulation which together shape the amplitude and time course of the excitatory postsynaptic potential. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'. Copyright © 2016 Elsevier Ltd. All rights reserved.

Differences in chloride gradients allow for three distinct types of synaptic modulation by endocannabinoids.

PubMed

Wang, Yanqing; Burrell, Brian D

2016-08-01

Endocannabinoids can elicit persistent depression of excitatory and inhibitory synapses, reducing or enhancing (disinhibiting) neural circuit output, respectively. In this study, we examined whether differences in Cl(-) gradients can regulate which synapses undergo endocannabinoid-mediated synaptic depression vs. disinhibition using the well-characterized central nervous system (CNS) of the medicinal leech, Hirudo verbana Exogenous application of endocannabinoids or capsaicin elicits potentiation of pressure (P) cell synapses and depression of both polymodal (Npoly) and mechanical (Nmech) nociceptive synapses. In P synapses, blocking Cl(-) export prevented endocannabinoid-mediated potentiation, consistent with a disinhibition process that has been indicated by previous experiments. In Nmech neurons, which are depolarized by GABA due to an elevated Cl(-) equilibrium potentials (ECl), endocannabinoid-mediated depression was prevented by blocking Cl(-) import, indicating that this decrease in synaptic signaling was due to depression of excitatory GABAergic input (disexcitation). Npoly neurons are also depolarized by GABA, but endocannabinoids elicit depression in these synapses directly and were only weakly affected by disruption of Cl(-) import. Consequently, the primary role of elevated ECl may be to protect Npoly synapses from disinhibition. All forms of endocannabinoid-mediated plasticity required activation of transient potential receptor vanilloid (TRPV) channels. Endocannabinoid/TRPV-dependent synaptic plasticity could also be elicited by distinct patterns of afferent stimulation with low-frequency stimulation (LFS) eliciting endocannabinoid-mediated depression of Npoly synapses and high-frequency stimulus (HFS) eliciting endocannabinoid-mediated potentiation of P synapses and depression of Nmech synapses. These findings demonstrate a critical role of differences in Cl(-) gradients between neurons in determining the sign, potentiation vs. depression, of synaptic modulation under normal physiological conditions. Copyright © 2016 the American Physiological Society.

Differences in chloride gradients allow for three distinct types of synaptic modulation by endocannabinoids

PubMed Central

Wang, Yanqing

2016-01-01

Endocannabinoids can elicit persistent depression of excitatory and inhibitory synapses, reducing or enhancing (disinhibiting) neural circuit output, respectively. In this study, we examined whether differences in Cl− gradients can regulate which synapses undergo endocannabinoid-mediated synaptic depression vs. disinhibition using the well-characterized central nervous system (CNS) of the medicinal leech, Hirudo verbana. Exogenous application of endocannabinoids or capsaicin elicits potentiation of pressure (P) cell synapses and depression of both polymodal (Npoly) and mechanical (Nmech) nociceptive synapses. In P synapses, blocking Cl− export prevented endocannabinoid-mediated potentiation, consistent with a disinhibition process that has been indicated by previous experiments. In Nmech neurons, which are depolarized by GABA due to an elevated Cl− equilibrium potentials (ECl), endocannabinoid-mediated depression was prevented by blocking Cl− import, indicating that this decrease in synaptic signaling was due to depression of excitatory GABAergic input (disexcitation). Npoly neurons are also depolarized by GABA, but endocannabinoids elicit depression in these synapses directly and were only weakly affected by disruption of Cl− import. Consequently, the primary role of elevated ECl may be to protect Npoly synapses from disinhibition. All forms of endocannabinoid-mediated plasticity required activation of transient potential receptor vanilloid (TRPV) channels. Endocannabinoid/TRPV-dependent synaptic plasticity could also be elicited by distinct patterns of afferent stimulation with low-frequency stimulation (LFS) eliciting endocannabinoid-mediated depression of Npoly synapses and high-frequency stimulus (HFS) eliciting endocannabinoid-mediated potentiation of P synapses and depression of Nmech synapses. These findings demonstrate a critical role of differences in Cl− gradients between neurons in determining the sign, potentiation vs. depression, of synaptic modulation under normal physiological conditions. PMID:27226449

Mouse VAP33 is associated with the endoplasmic reticulum and microtubules

PubMed Central

Skehel, P. A.; Fabian-Fine, R.; Kandel, E. R.

2000-01-01

VAMP/synaptobrevin is a synaptic vesicle protein that is essential for neurotransmitter release. Intracellular injection of antisera against the Aplysia californica VAMP/synaptobrevin-binding protein ApVAP33 inhibited evoked excitatory postsynaptic potentials (EPSPs) in cultured cells, suggesting that this association may regulate the function of VAMP/synaptobrevin. We have identified and characterized a mouse homologue of ApVAP33, mVAP33. The overall domain structure of the proteins is conserved, and they have similar biochemical properties. mVAP33 mRNA is detectable in all mouse tissues examined, in contrast to the more restricted expression seen in A. californica. We analyzed the cellular distribution of mVAP33 protein in brain slices and cultured cortical cells by light and electron microscopy. Although present at higher levels in neurons, immunoreactivity was detected throughout both neurons and glia in a reticular pattern similar to that of endoplasmic reticulum-resident proteins. mVAP33 does not colocalize with VAMP/synaptobrevin at synaptic structures, but expression overlaps with lower levels of VAMP/synaptobrevin in the soma. Ultrastructural analysis revealed mVAP33 associated with microtubules and intracellular vesicles of heterogeneous size. In primary neuronal cultures, large aggregates of mVAP33 are also detected in short filamentous structures, which are occasionally associated with intracellular membranes. There is no evidence for accumulation of mVAP33 on synaptic vesicles or at the plasma membrane. These data suggest that mVAP33 is an endoplasmic-reticulum–resident protein that associates with components of the cytoskeleton. Any functional interaction between mVAP33 and VAMP/synaptobrevin, therefore, most likely involves the delivery of components to synaptic terminals rather than a direct participation in synaptic vesicle exocytosis. PMID:10655491

Pharmacology of Glutamate Transport in the CNS: Substrates and Inhibitors of Excitatory Amino Acid Transporters (EAATs) and the Glutamate/Cystine Exchanger System x c -

NASA Astrophysics Data System (ADS)

Bridges, Richard J.; Patel, Sarjubhai A.

As the primary excitatory neurotransmitter in the mammalian CNS, l-glutamate participates not only in standard fast synaptic communication, but also contributes to higher order signal processing, as well as neuropathology. Given this variety of functional roles, interest has been growing as to how the extracellular concentrations of l-glutamate surrounding neurons are regulated by cellular transporter proteins. This review focuses on two prominent systems, each of which appears capable of influencing both the signaling and pathological actions of l-glutamate within the CNS: the sodium-dependent excitatory amino acid transporters (EAATs) and the glutamate/cystine exchanger, system x c - (Sx c -). While the family of EAAT subtypes limit access to glutamate receptors by rapidly and efficiently sequestering l-glutamate in neurons and glia, Sxc - provides a route for the export of glutamate from cells into the extracellular environment. The primary intent of this work is to provide an overview of the inhibitors and substrates that have been developed to delineate the pharmacological specificity of these transport systems, as well as be exploited as probes with which to selectively investigate function. Particular attention is paid to the development of small molecule templates that mimic the structural properties of the endogenous substrates, l-glutamate, l-aspartate and l-cystine and how strategic control of functional group position and/or the introduction of lipophilic R-groups can impact multiple aspects of the transport process, including: subtype selectivity, inhibitory potency, and substrate activity.

Cortical Dynamics in Presence of Assemblies of Densely Connected Weight-Hub Neurons

PubMed Central

Setareh, Hesam; Deger, Moritz; Petersen, Carl C. H.; Gerstner, Wulfram

2017-01-01

Experimental measurements of pairwise connection probability of pyramidal neurons together with the distribution of synaptic weights have been used to construct randomly connected model networks. However, several experimental studies suggest that both wiring and synaptic weight structure between neurons show statistics that differ from random networks. Here we study a network containing a subset of neurons which we call weight-hub neurons, that are characterized by strong inward synapses. We propose a connectivity structure for excitatory neurons that contain assemblies of densely connected weight-hub neurons, while the pairwise connection probability and synaptic weight distribution remain consistent with experimental data. Simulations of such a network with generalized integrate-and-fire neurons display regular and irregular slow oscillations akin to experimentally observed up/down state transitions in the activity of cortical neurons with a broad distribution of pairwise spike correlations. Moreover, stimulation of a model network in the presence or absence of assembly structure exhibits responses similar to light-evoked responses of cortical layers in optogenetically modified animals. We conclude that a high connection probability into and within assemblies of excitatory weight-hub neurons, as it likely is present in some but not all cortical layers, changes the dynamics of a layer of cortical microcircuitry significantly. PMID:28690508

Estradiol acutely suppresses inhibition in the hippocampus through a sex-specific endocannabinoid and mGluR dependent mechanism

PubMed Central

Huang, Guang Zhe; Woolley, Catherine S.

2012-01-01

SUMMARY The steroid, 17β-estradiol (E2), is well known to influence hippocampal functions such as memory, affective behaviors, and epilepsy. There is growing awareness that in addition to responding to ovarian E2, the hippocampus of both males and females synthesizes E2 as a neurosteroid that could acutely modulate synaptic function. Previous work on acute E2 actions in hippocampus has focused on excitatory synapses. Here, we show that E2 rapidly suppresses inhibitory synaptic transmission in hippocampal CA1. E2 acts through the α form of the estrogen receptor to stimulate postsynaptic mGluR1-dependent mobilization of the endocannabinoid, anandamide, which then retrogradely suppresses GABA release from CB1 receptor-containing inhibitory presynaptic boutons. Remarkably, this effect of E2 is sex-specific, occurring in females but not males. Acute E2 modulation of endocannabinoid tone and consequent suppression of inhibition provides a new mechanism by which neurosteroid E2 could modulate hippocampus-dependent behaviors in a sex-specific manner. PMID:22681685

Impaired inhibitory control of cortical synchronization in fragile X syndrome.

PubMed

Paluszkiewicz, Scott M; Olmos-Serrano, Jose Luis; Corbin, Joshua G; Huntsman, Molly M

2011-11-01

Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by severe cognitive impairments, sensory hypersensitivity, and comorbidities with autism and epilepsy. Fmr1 knockout (KO) mouse models of FXS exhibit alterations in excitatory and inhibitory neurotransmission, but it is largely unknown how aberrant function of specific neuronal subtypes contributes to these deficits. In this study we show specific inhibitory circuit dysfunction in layer II/III of somatosensory cortex of Fmr1 KO mice. We demonstrate reduced activation of somatostatin-expressing low-threshold-spiking (LTS) interneurons in response to the group I metabotropic glutamate receptor (mGluR) agonist 3,5-dihydroxyphenylglycine (DHPG) in Fmr1 KO mice, resulting in impaired synaptic inhibition. Paired recordings from pyramidal neurons revealed reductions in synchronized synaptic inhibition and coordinated spike synchrony in response to DHPG, indicating a weakened LTS interneuron network in Fmr1 KO mice. Together, these findings reveal a functional defect in a single subtype of cortical interneuron in Fmr1 KO mice. This defect is linked to altered activity of the cortical network in line with the FXS phenotype.

Minocycline enhances inhibitory transmission to substantia gelatinosa neurons of the rat spinal dorsal horn.

PubMed

Peng, H-Z; Ma, L-X; Lv, M-H; Hu, T; Liu, T

2016-04-05

Minocycline, a second-generation tetracycline, is well known for its antibiotic, anti-inflammatory, and antinociceptive effects. Modulation of synaptic transmission is one of the analgesic mechanisms of minocycline. Although it has been reported that minocycline may suppress excitatory glutamatergic synaptic transmission, it remains unclear whether it could affect inhibitory synaptic transmission, which also plays a key role in modulating pain signaling. To examine the effect of minocycline on synaptic transmission in rat spinal substantia gelatinosa (SG) neurons, we recorded spontaneous inhibitory postsynaptic currents (sIPSCs) using whole-cell patch-clamp recording at a holding potential of 0 mV. Bath application of minocycline significantly increased the frequency but not the amplitude of sIPSCs in a reversible and concentration-dependent manner with an EC50 of 85. The enhancement of inhibitory synaptic transmission produced by minocycline was not affected by the glutamate receptor antagonists CNQX and D-APV or by the voltage-gated sodium channel blocker tetrodotoxin (TTX). Moreover, the potency of minocycline for facilitating sIPSC frequency was the same in both glycinergic and GABAergic sIPSCs without changing their decay phases. However, the facilitatory effect of minocycline on sIPSCs was eliminated in a Ca(2+)-free Krebs solution or by co-administration with calcium channel blockers. In summary, our data demonstrate that baseline inhibitory synaptic transmission in SG neurons is markedly enhanced by minocycline. This may function to decrease the excitability of SG neurons, thus leading to a modulation of nociceptive transmission. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Effects of 17beta-estradiol on glutamate synaptic transmission and neuronal excitability in the rat medial vestibular nuclei.

PubMed

Grassi, S; Frondaroli, A; Scarduzio, M; Dutia, M B; Dieni, C; Pettorossi, V E

2010-02-17

We investigated the effects of the neurosteroid 17beta-estradiol (E(2)) on the evoked and spontaneous activity of rat medial vestibular nucleus (MVN) neurons in brainstem slices. E(2) enhances the synaptic response to vestibular nerve stimulation in type B neurons and depresses the spontaneous discharge in both type A and B neurons. The amplitude of the field potential, as well as the excitatory post-synaptic potential (EPSP) and current (EPSC), in type B neurons, are enhanced by E(2). Both effects are long-term phenomena since they outlast the drug washout. The enhancement of synaptic response is mainly due to facilitation of glutamate release mediated by pre-synaptic N-methyl-D-aspartate receptors (NMDARs), since the reduction of paired pulse ratio (PPR) and the increase of miniature EPSC frequency after E(2) are abolished under D-(-)-2-amino-5-phosphonopentanoic acid (AP-5). E(2) also facilitates post-synaptic NMDARs, but it does not affect directly alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and group I-metabotropic glutamate receptors (mGluRs-I). In contrast, the depression of the spontaneous discharge of type A and type B neurons appears to depend on E(2) modulation of intrinsic ion conductances, as the effect remains after blockade of glutamate, GABA and glycine receptors (GlyRs). The net effect of E(2) is to enhance the signal-to-noise ratio of the synaptic response in type B neurons, relative to resting activity of all MVN neurons. These findings provide evidence for a novel potential mechanism to modulate the responsiveness of vestibular neurons to afferent inputs, and so regulate vestibular function in vivo.

Activity and circadian rhythm influence synaptic Shank3 protein levels in mice.

PubMed

Sarowar, Tasnuva; Chhabra, Resham; Vilella, Antonietta; Boeckers, Tobias M; Zoli, Michele; Grabrucker, Andreas M

2016-09-01

Various recent studies revealed that the proteins of the Shank family act as major scaffold organizing elements in the post-synaptic density of excitatory synapses and that their expression level is able to influence synapse formation, maturation and ultimately brain plasticity. An imbalance in Shank3 protein levels has been associated with a variety of neuropsychological and neurodegenerative disorders including autism spectrum disorders and Phelan-McDermid syndrome. Given that sleep disorders and low melatonin levels are frequently observed in autism spectrum disorders, and that circadian rhythms may be able to modulate Shank3 signaling and thereby synaptic function, here, we performed in vivo studies on CBA mice using protein biochemistry to investigate the synaptic expression levels of Shank3α during the day in different brain regions. Our results show that synaptic Shank3 protein concentrations exhibit minor oscillations during the day in hippocampal and striatal brain regions that correlate with changes in serum melatonin levels. Furthermore, as circadian rhythms are tightly connected to activity levels in mice, we increased physical activity using running wheels. The expression of Shank3α increases rapidly by induced activity in thalamus and cortex, but decreases in striatum, superimposing the circadian rhythms of different brain regions. We conclude that synaptic Shank3 proteins build highly dynamic platforms that are modulated by the light:dark cycles but even more so driven by activity. Using wild-type CBA mice, we show that Shank3 is a highly dynamic and activity-regulated protein at synapses. In the hippocampus, changes in synaptic Shank3 levels are influenced by circadian rhythm/melatonin concentration, while running activity increases and decreases levels of Shank3 in the cortex and striatum respectively. © 2016 International Society for Neurochemistry.

Hippocampal LTP and contextual learning require surface diffusion of AMPA receptors.

PubMed

Penn, A C; Zhang, C L; Georges, F; Royer, L; Breillat, C; Hosy, E; Petersen, J D; Humeau, Y; Choquet, D

2017-09-21

Long-term potentiation (LTP) of excitatory synaptic transmission has long been considered a cellular correlate for learning and memory. Early LTP (less than 1 h) had initially been explained either by presynaptic increases in glutamate release or by direct modification of postsynaptic AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor function. Compelling models have more recently proposed that synaptic potentiation can occur by the recruitment of additional postsynaptic AMPA receptors (AMPARs), sourced either from an intracellular reserve pool by exocytosis or from nearby extra-synaptic receptors pre-existing on the neuronal surface. However, the exact mechanism through which synapses can rapidly recruit new AMPARs during early LTP remains unknown. In particular, direct evidence for a pivotal role of AMPAR surface diffusion as a trafficking mechanism in synaptic plasticity is still lacking. Here, using AMPAR immobilization approaches, we show that interfering with AMPAR surface diffusion markedly impairs synaptic potentiation of Schaffer collaterals and commissural inputs to the CA1 area of the mouse hippocampus in cultured slices, acute slices and in vivo. Our data also identify distinct contributions of various AMPAR trafficking routes to the temporal profile of synaptic potentiation. In addition, AMPAR immobilization in vivo in the dorsal hippocampus inhibited fear conditioning, indicating that AMPAR diffusion is important for the early phase of contextual learning. Therefore, our results provide a direct demonstration that the recruitment of new receptors to synapses by surface diffusion is a critical mechanism for the expression of LTP and hippocampal learning. Since AMPAR surface diffusion is dictated by weak Brownian forces that are readily perturbed by protein-protein interactions, we anticipate that this fundamental trafficking mechanism will be a key target for modulating synaptic potentiation and learning.

Olfactory bulb short axon cell release of GABA and dopamine produces a temporally biphasic inhibition-excitation response in external tufted cells

PubMed Central

Liu, Shaolin; Plachez, Celine; Shao, Zuoyi; Puche, Adam; Shipley, Michael T.

2013-01-01

Evidence for co-expression of two or more classic neurotransmitters in neurons has increased but less is known about co-transmission. Ventral tegmental area (VTA) neurons, co-release dopamine (DA), the excitatory transmitter glutamate and the inhibitory transmitter GABA onto target cells in the striatum. Olfactory bulb (OB) short axon cells (SACs) form interglomerular connections and co-express markers for dopamine (DA) and GABA. Using an optogenetic approach we provide evidence that mouse OB SACs release both GABA and DA onto external tufted cells (ETCs) in other glomeruli. Optical activation of channelrhodopsin specifically expressed in DAergic SACs produced a GABAA receptor-mediated monosynaptic inhibitory response followed by DA-D1-like receptor-mediated excitatory response in ETCs. The GABAA receptor-mediated hyperpolarization activates Ih current in ETCs; synaptically released DA increases Ih, which enhances post-inhibitory rebound spiking. Thus, the opposing actions of synaptically released GABA and DA are functionally integrated by Ih to generate an inhibition-to-excitation “switch” in ETCs. Consistent with the established role of Ih in ETC burst firing, we show that endogenous DA release increases ETC spontaneous bursting frequency. ETCs transmit sensory signals to mitral/tufted output neurons and drive intraglomerular inhibition to shape glomerulus output to downstream olfactory networks. GABA and DA co-transmission from SACs to ETCs may play a key role in regulating output coding across the glomerular array. PMID:23407950

Bidirectional control of social hierarchy by synaptic efficacy in medial prefrontal cortex.

PubMed

Wang, Fei; Zhu, Jun; Zhu, Hong; Zhang, Qi; Lin, Zhanmin; Hu, Hailan

2011-11-04

Dominance hierarchy has a profound impact on animals' survival, health, and reproductive success, but its neural circuit mechanism is virtually unknown. We found that dominance ranking in mice is transitive, relatively stable, and highly correlates among multiple behavior measures. Recording from layer V pyramidal neurons of the medial prefrontal cortex (mPFC) showed higher strength of excitatory synaptic inputs in mice with higher ranking, as compared with their subordinate cage mates. Furthermore, molecular manipulations that resulted in an increase and decrease in the synaptic efficacy in dorsal mPFC neurons caused an upward and downward movement in the social rank, respectively. These results provide direct evidence for mPFC's involvement in social hierarchy and suggest that social rank is plastic and can be tuned by altering synaptic strength in mPFC pyramidal cells.

Actin Out: Regulation of the Synaptic Cytoskeleton

PubMed Central

Spence, Erin F.; Soderling, Scott H.

2015-01-01

The small size of dendritic spines belies the elaborate role they play in excitatory synaptic transmission and ultimately complex behaviors. The cytoskeletal architecture of the spine is predominately composed of actin filaments. These filaments, which at first glance might appear simple, are also surprisingly complex. They dynamically assemble into different structures and serve as a platform for orchestrating the elaborate responses of the spine during spinogenesis and experience-dependent plasticity. Multiple mutations associated with human neurodevelopmental and psychiatric disorders involve genes that encode regulators of the synaptic cytoskeleton. A major, unresolved question is how the disruption of specific actin filament structures leads to the onset and progression of complex synaptic and behavioral phenotypes. This review will cover established and emerging mechanisms of actin cytoskeletal remodeling and how this influences specific aspects of spine biology that are implicated in disease. PMID:26453304

Pathway and Cell-Specific Kappa-Opioid Receptor Modulation of Excitatory-Inhibitory Balance Differentially Gates D1 and D2 Accumbens Neuron Activity

PubMed Central

Tejeda, Hugo A.; Wu, Jocelyn; Kornspun, Alana R.; Pignatelli, Marco; Kashtelyan, Vadim; Krashes, Michael J.; Lowell, Brad B.; Carlezon, William A.; Bonci, Antonello

2018-01-01

Endogenous dynorphin signaling via the kappa-opioid receptor (KOR) in the nucleus accumbens (NAcc) powerfully mediates negative affective states and stress reactivity. Excitatory inputs from the hippocampus and amygdala play a fundamental role in shaping the activity of both NAcc D1 and D2 MSNs, which encode positive and negative motivational valences, respectively. However, a circuit-based mechanism by which KOR modulation of excitation-inhibition balance modifies D1 and D2 MSN activity is lacking. Here, we provide a comprehensive synaptic framework wherein presynaptic KOR inhibition decreases excitatory drive of D1 MSN activity by the amygdala, but not hippocampus. Conversely, presynaptic inhibition by KORs of inhibitory synapses on D2 MSNs enhances integration of excitatory drive by the amygdala and hippocampus. In conclusion, we describe a circuit-based mechanism showing differential gating of afferent control of D1 and D2 MSN activity by KORs in a pathway specific manner. PMID:28056342

Emergence of Slow Collective Oscillations in Neural Networks with Spike-Timing Dependent Plasticity

NASA Astrophysics Data System (ADS)

Mikkelsen, Kaare; Imparato, Alberto; Torcini, Alessandro

2013-05-01

The collective dynamics of excitatory pulse coupled neurons with spike-timing dependent plasticity is studied. The introduction of spike-timing dependent plasticity induces persistent irregular oscillations between strongly and weakly synchronized states, reminiscent of brain activity during slow-wave sleep. We explain the oscillations by a mechanism, the Sisyphus Effect, caused by a continuous feedback between the synaptic adjustments and the coherence in the neural firing. Due to this effect, the synaptic weights have oscillating equilibrium values, and this prevents the system from relaxing into a stationary macroscopic state.

Emerging roles of the neurotrophin receptor TrkC in synapse organization.

PubMed

Naito, Yusuke; Lee, Alfred Kihoon; Takahashi, Hideto

2017-03-01

Tropomyosin-receptor-kinase (Trk) receptors have been extensively studied for their roles in kinase-dependent signaling cascades in nervous system development. Synapse organization is coordinated by trans-synaptic interactions of various cell adhesion proteins, a representative example of which is the neurexin-neuroligin complex. Recently, a novel role for TrkC as a synapse organizing protein has been established. Post-synaptic TrkC binds to pre-synaptic type-IIa receptor-type protein tyrosine phosphatase sigma (PTPσ). TrkC-PTPσ specifically induces excitatory synapses in a kinase domain-independent manner. TrkC has distinct extracellular domains for PTPσ- and NT-3-binding and thus may bind both ligands simultaneously. Indeed, NT-3 enhances the TrkC-PTPσ interaction, thus facilitating synapse induction at the pre-synaptic side and increasing pre-synaptic vesicle recycling in a kinase-independent fashion. A crystal structure study has revealed the detailed structure of the TrkC-PTPσ complex as well as competitive modulation of TrkC-mediated synaptogenesis by heparan sulfate proteoglycans (HSPGs), which bind the same domain of TrkC as PTPσ. Thus, there is strong evidence supporting a role for the TrkC-PTPσ complex in mechanisms underlying the fine turning of neural connectivity. Furthermore, disruption of the TrkC-PTPσ complex may be the underlying cause of certain psychiatric disorders caused by mutations in the gene encoding TrkC (NTRK3), supporting its role in cognitive functions. Copyright © 2016 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

Andrographolide reduces cognitive impairment in young and mature AβPPswe/PS-1 mice.

PubMed

Serrano, Felipe G; Tapia-Rojas, Cheril; Carvajal, Francisco J; Hancke, Juan; Cerpa, Waldo; Inestrosa, Nibaldo C

2014-12-18

Alzheimer's disease (AD) is a neurodegenerative disorder in which the amyloid-β (Aβ) oligomers are a key factor in synaptic impairment and in spatial memory decline associated with neuronal dysfunction. This impairment includes synaptic failure associated with the loss of synaptic proteins that contribute to AD progression. Interestingly, the use of natural compounds is an emergent conceptual strategy in the search for drugs with therapeutic potentials for treating neurodegenerative disorders. In the present study, we report that andrographolide (ANDRO), which is a labdane diterpene extracted from Andrographis paniculata, increases slope of field excitatory postsynaptic potentials (fEPSP) in the CA1 region of hippocampal slices and inhibits long-term depression (LTD), protecting the long-term potentiation (LTP) against the damage induced by Aβ oligomers in vitro, most likely by inhibiting glycogen synthase kinase-3β (GSK-3β). Additionally, ANDRO prevents changes in neuropathology in two different age groups (7- and 12-month-old mice) of an AβPPswe/PS-1 Alzheimer's model. ANDRO reduces the Aβ levels, changing the ontogeny of amyloid plaques in hippocampi and cortices in 7-month-old mice, and reduces tau phosphorylation around the Aβ oligomeric species in both age groups. Additionally, we observed that ANDRO recovers spatial memory functions that correlate with protecting synaptic plasticity and synaptic proteins in two different age groups. Our results suggest that ANDRO could be used in a potential preventive therapy during AD progression.

Pathological effect of homeostatic synaptic scaling on network dynamics in diseases of the cortex.

PubMed

Fröhlich, Flavio; Bazhenov, Maxim; Sejnowski, Terrence J

2008-02-13

Slow periodic EEG discharges are common in CNS disorders. The pathophysiology of this aberrant rhythmic activity is poorly understood. We used a computational model of a neocortical network with a dynamic homeostatic scaling rule to show that loss of input (partial deafferentation) can trigger network reorganization that results in pathological periodic discharges. The decrease in average firing rate in the network by deafferentation was compensated by homeostatic synaptic scaling of recurrent excitation among pyramidal cells. Synaptic scaling succeeded in recovering the network target firing rate for all degrees of deafferentation (fraction of deafferented cells), but there was a critical degree of deafferentation for pathological network reorganization. For deafferentation degrees below this value, homeostatic upregulation of recurrent excitation had minimal effect on the macroscopic network dynamics. For deafferentation above this threshold, however, a slow periodic oscillation appeared, patterns of activity were less sparse, and bursting occurred in individual neurons. Also, comparison of spike-triggered afferent and recurrent excitatory conductances revealed that information transmission was strongly impaired. These results suggest that homeostatic plasticity can lead to secondary functional impairment in case of cortical disorders associated with cell loss.

The Role of Ionotropic Glutamate Receptors in Childhood Neurodevelopmental Disorders: Autism Spectrum Disorders and Fragile X Syndrome

PubMed Central

Uzunova, Genoveva; Hollander, Eric; Shepherd, Jason

2014-01-01

Autism spectrum disorder (ASD) and Fragile X syndrome (FXS) are relatively common childhood neurodevelopmental disorders with increasing incidence in recent years. They are currently accepted as disorders of the synapse with alterations in different forms of synaptic communication and neuronal network connectivity. The major excitatory neurotransmitter system in brain, the glutamatergic system, is implicated in learning and memory, synaptic plasticity, neuronal development. While much attention is attributed to the role of metabotropic glutamate receptors in ASD and FXS, studies indicate that the ionotropic glutamate receptors (iGluRs) and their regulatory proteins are also altered in several brain regions. Role of iGluRs in the neurobiology of ASD and FXS is supported by a weight of evidence that ranges from human genetics to in vitro cultured neurons. In this review we will discuss clinical, molecular, cellular and functional changes in NMDA, AMPA and kainate receptors and the synaptic proteins that regulate them in the context of ASD and FXS. We will also discuss the significance for the development of translational biomarkers and treatments for the core symptoms of ASD and FXS. PMID:24533017

Genetically determined measures of striatal D2 signaling predict prefrontal activity during working memory performance.

PubMed

Bertolino, Alessandro; Taurisano, Paolo; Pisciotta, Nicola Marco; Blasi, Giuseppe; Fazio, Leonardo; Romano, Raffaella; Gelao, Barbara; Lo Bianco, Luciana; Lozupone, Madia; Di Giorgio, Annabella; Caforio, Grazia; Sambataro, Fabio; Niccoli-Asabella, Artor; Papp, Audrey; Ursini, Gianluca; Sinibaldi, Lorenzo; Popolizio, Teresa; Sadee, Wolfgang; Rubini, Giuseppe

2010-02-22

Variation of the gene coding for D2 receptors (DRD2) has been associated with risk for schizophrenia and with working memory deficits. A functional intronic SNP (rs1076560) predicts relative expression of the two D2 receptors isoforms, D2S (mainly pre-synaptic) and D2L (mainly post-synaptic). However, the effect of functional genetic variation of DRD2 on striatal dopamine D2 signaling and on its correlation with prefrontal activity during working memory in humans is not known. Thirty-seven healthy subjects were genotyped for rs1076560 (G>T) and underwent SPECT with [123I]IBZM (which binds primarily to post-synaptic D2 receptors) and with [123I]FP-CIT (which binds to pre-synaptic dopamine transporters, whose activity and density is also regulated by pre-synaptic D2 receptors), as well as BOLD fMRI during N-Back working memory. Subjects carrying the T allele (previously associated with reduced D2S expression) had striatal reductions of [123I]IBZM and of [123I]FP-CIT binding. DRD2 genotype also differentially predicted the correlation between striatal dopamine D2 signaling (as identified with factor analysis of the two radiotracers) and activity of the prefrontal cortex during working memory as measured with BOLD fMRI, which was positive in GG subjects and negative in GT. Our results demonstrate that this functional SNP within DRD2 predicts striatal binding of the two radiotracers to dopamine transporters and D2 receptors as well as the correlation between striatal D2 signaling with prefrontal cortex activity during performance of a working memory task. These data are consistent with the possibility that the balance of excitatory/inhibitory modulation of striatal neurons may also affect striatal outputs in relationship with prefrontal activity during working memory performance within the cortico-striatal-thalamic-cortical pathway.

Genetically Determined Measures of Striatal D2 Signaling Predict Prefrontal Activity during Working Memory Performance

PubMed Central

Bertolino, Alessandro; Taurisano, Paolo; Pisciotta, Nicola Marco; Blasi, Giuseppe; Fazio, Leonardo; Romano, Raffaella; Gelao, Barbara; Bianco, Luciana Lo; Lozupone, Madia; Di Giorgio, Annabella; Caforio, Grazia; Sambataro, Fabio; Niccoli-Asabella, Artor; Papp, Audrey; Ursini, Gianluca; Sinibaldi, Lorenzo; Popolizio, Teresa; Sadee, Wolfgang; Rubini, Giuseppe

2010-01-01

Background Variation of the gene coding for D2 receptors (DRD2) has been associated with risk for schizophrenia and with working memory deficits. A functional intronic SNP (rs1076560) predicts relative expression of the two D2 receptors isoforms, D2S (mainly pre-synaptic) and D2L (mainly post-synaptic). However, the effect of functional genetic variation of DRD2 on striatal dopamine D2 signaling and on its correlation with prefrontal activity during working memory in humans is not known. Methods Thirty-seven healthy subjects were genotyped for rs1076560 (G>T) and underwent SPECT with [123I]IBZM (which binds primarily to post-synaptic D2 receptors) and with [123I]FP-CIT (which binds to pre-synaptic dopamine transporters, whose activity and density is also regulated by pre-synaptic D2 receptors), as well as BOLD fMRI during N-Back working memory. Results Subjects carrying the T allele (previously associated with reduced D2S expression) had striatal reductions of [123I]IBZM and of [123I]FP-CIT binding. DRD2 genotype also differentially predicted the correlation between striatal dopamine D2 signaling (as identified with factor analysis of the two radiotracers) and activity of the prefrontal cortex during working memory as measured with BOLD fMRI, which was positive in GG subjects and negative in GT. Conclusions Our results demonstrate that this functional SNP within DRD2 predicts striatal binding of the two radiotracers to dopamine transporters and D2 receptors as well as the correlation between striatal D2 signaling with prefrontal cortex activity during performance of a working memory task. These data are consistent with the possibility that the balance of excitatory/inhibitory modulation of striatal neurons may also affect striatal outputs in relationship with prefrontal activity during working memory performance within the cortico-striatal-thalamic-cortical pathway. PMID:20179754

Effects of Neuromodulation on Excitatory-Inhibitory Neural Network Dynamics Depend on Network Connectivity Structure

NASA Astrophysics Data System (ADS)

Rich, Scott; Zochowski, Michal; Booth, Victoria

2018-01-01

Acetylcholine (ACh), one of the brain's most potent neuromodulators, can affect intrinsic neuron properties through blockade of an M-type potassium current. The effect of ACh on excitatory and inhibitory cells with this potassium channel modulates their membrane excitability, which in turn affects their tendency to synchronize in networks. Here, we study the resulting changes in dynamics in networks with inter-connected excitatory and inhibitory populations (E-I networks), which are ubiquitous in the brain. Utilizing biophysical models of E-I networks, we analyze how the network connectivity structure in terms of synaptic connectivity alters the influence of ACh on the generation of synchronous excitatory bursting. We investigate networks containing all combinations of excitatory and inhibitory cells with high (Type I properties) or low (Type II properties) modulatory tone. To vary network connectivity structure, we focus on the effects of the strengths of inter-connections between excitatory and inhibitory cells (E-I synapses and I-E synapses), and the strengths of intra-connections among excitatory cells (E-E synapses) and among inhibitory cells (I-I synapses). We show that the presence of ACh may or may not affect the generation of network synchrony depending on the network connectivity. Specifically, strong network inter-connectivity induces synchronous excitatory bursting regardless of the cellular propensity for synchronization, which aligns with predictions of the PING model. However, when a network's intra-connectivity dominates its inter-connectivity, the propensity for synchrony of either inhibitory or excitatory cells can determine the generation of network-wide bursting.

Reconstitution of Homomeric GluA2flop Receptors in Supported Lipid Membranes

PubMed Central

Baranovic, Jelena; Ramanujan, Chandra S.; Kasai, Nahoko; Midgett, Charles R.; Madden, Dean R.; Torimitsu, Keiichi; Ryan, John F.

2013-01-01

AMPA receptors (AMPARs) are glutamate-gated ion channels ubiquitous in the vertebrate central nervous system, where they mediate fast excitatory neurotransmission and act as molecular determinants of memory formation and learning. Together with detailed analyses of individual AMPAR domains, structural studies of full-length AMPARs by electron microscopy and x-ray crystallography have provided important insights into channel assembly and function. However, the correlation between the structure and functional states of the channel remains ambiguous particularly because these functional states can be assessed only with the receptor bound within an intact lipid bilayer. To provide a basis for investigating AMPAR structure in a membrane environment, we developed an optimized reconstitution protocol using a receptor whose structure has previously been characterized by electron microscopy. Single-channel recordings of reconstituted homomeric GluA2flop receptors recapitulate key electrophysiological parameters of the channels expressed in native cellular membranes. Atomic force microscopy studies of the reconstituted samples provide high-resolution images of membrane-embedded full-length AMPARs at densities comparable to those in postsynaptic membranes. The data demonstrate the effect of protein density on conformational flexibility and dimensions of the receptors and provide the first structural characterization of functional membrane-embedded AMPARs, thus laying the foundation for correlated structure-function analyses of the predominant mediators of excitatory synaptic signals in the brain. PMID:23382380

Differential temperature sensitivity of synaptic and firing processes in a neural mass model of epileptic discharges explains heterogeneous response of experimental epilepsy to focal brain cooling.

PubMed

Soriano, Jaymar; Kubo, Takatomi; Inoue, Takao; Kida, Hiroyuki; Yamakawa, Toshitaka; Suzuki, Michiyasu; Ikeda, Kazushi

2017-10-01

Experiments with drug-induced epilepsy in rat brains and epileptic human brain region reveal that focal cooling can suppress epileptic discharges without affecting the brain's normal neurological function. Findings suggest a viable treatment for intractable epilepsy cases via an implantable cooling device. However, precise mechanisms by which cooling suppresses epileptic discharges are still not clearly understood. Cooling experiments in vitro presented evidence of reduction in neurotransmitter release from presynaptic terminals and loss of dendritic spines at post-synaptic terminals offering a possible synaptic mechanism. We show that termination of epileptic discharges is possible by introducing a homogeneous temperature factor in a neural mass model which attenuates the post-synaptic impulse responses of the neuronal populations. This result however may be expected since such attenuation leads to reduced post-synaptic potential and when the effect on inhibitory interneurons is less than on excitatory interneurons, frequency of firing of pyramidal cells is consequently reduced. While this is observed in cooling experiments in vitro, experiments in vivo exhibit persistent discharges during cooling but suppressed in magnitude. This leads us to conjecture that reduction in the frequency of discharges may be compensated through intrinsic excitability mechanisms. Such compensatory mechanism is modelled using a reciprocal temperature factor in the firing response function in the neural mass model. We demonstrate that the complete model can reproduce attenuation of both magnitude and frequency of epileptic discharges during cooling. The compensatory mechanism suggests that cooling lowers the average and the variance of the distribution of threshold potential of firing across the population. Bifurcation study with respect to the temperature parameters of the model reveals how heterogeneous response of epileptic discharges to cooling (termination or suppression only) is exhibited. Possibility of differential temperature effects on post-synaptic potential generation of different populations is also explored.

Differential temperature sensitivity of synaptic and firing processes in a neural mass model of epileptic discharges explains heterogeneous response of experimental epilepsy to focal brain cooling

PubMed Central

Inoue, Takao; Kida, Hiroyuki; Yamakawa, Toshitaka; Suzuki, Michiyasu

2017-01-01

Experiments with drug-induced epilepsy in rat brains and epileptic human brain region reveal that focal cooling can suppress epileptic discharges without affecting the brain’s normal neurological function. Findings suggest a viable treatment for intractable epilepsy cases via an implantable cooling device. However, precise mechanisms by which cooling suppresses epileptic discharges are still not clearly understood. Cooling experiments in vitro presented evidence of reduction in neurotransmitter release from presynaptic terminals and loss of dendritic spines at post-synaptic terminals offering a possible synaptic mechanism. We show that termination of epileptic discharges is possible by introducing a homogeneous temperature factor in a neural mass model which attenuates the post-synaptic impulse responses of the neuronal populations. This result however may be expected since such attenuation leads to reduced post-synaptic potential and when the effect on inhibitory interneurons is less than on excitatory interneurons, frequency of firing of pyramidal cells is consequently reduced. While this is observed in cooling experiments in vitro, experiments in vivo exhibit persistent discharges during cooling but suppressed in magnitude. This leads us to conjecture that reduction in the frequency of discharges may be compensated through intrinsic excitability mechanisms. Such compensatory mechanism is modelled using a reciprocal temperature factor in the firing response function in the neural mass model. We demonstrate that the complete model can reproduce attenuation of both magnitude and frequency of epileptic discharges during cooling. The compensatory mechanism suggests that cooling lowers the average and the variance of the distribution of threshold potential of firing across the population. Bifurcation study with respect to the temperature parameters of the model reveals how heterogeneous response of epileptic discharges to cooling (termination or suppression only) is exhibited. Possibility of differential temperature effects on post-synaptic potential generation of different populations is also explored. PMID:28981509

Learning and memory disabilities in IUGR babies: Functional and molecular analysis in a rat model.

PubMed

Camprubí Camprubí, Marta; Balada Caballé, Rafel; Ortega Cano, Juan A; Ortega de la Torre, Maria de Los Angeles; Duran Fernández-Feijoo, Cristina; Girabent-Farrés, Montserrat; Figueras-Aloy, Josep; Krauel, Xavier; Alcántara, Soledad

2017-03-01

1Intrauterine growth restriction (IUGR) is the failure of the fetus to achieve its inherent growth potential, and it has frequently been associated with neurodevelopmental problems in childhood. Neurological disorders are mostly associated with IUGR babies with an abnormally high cephalization index (CI) and a brain sparing effect. However, a similar correlation has never been demonstrated in an animal model. The aim of this study was to determine the correlations between CI, functional deficits in learning and memory and alterations in synaptic proteins in a rat model of IUGR. 2Utero-placental insufficiency was induced by meso-ovarian vessel cauterization (CMO) in pregnant rats at embryonic day 17 (E17). Learning performance in an aquatic learning test was evaluated 25 days after birth and during 10 days. Some synaptic proteins were analyzed (PSD95, Synaptophysin) by Western blot and immunohistochemistry. 3Placental insufficiency in CMO pups was associated with spatial memory deficits, which are correlated with a CI above the normal range. CMO pups presented altered levels of synaptic proteins PSD95 and synaptophysin in the hippocampus. 4The results of this study suggest that learning disabilities may be associated with altered development of excitatory neurotransmission and synaptic plasticity. Although interspecific differences in fetal response to placental insufficiency should be taken into account, the translation of these data to humans suggest that both IUGR babies and babies with a normal birth weight but with intrauterine Doppler alterations and abnormal CI should be closely followed to detect neurodevelopmental alterations during the postnatal period.

Seizures as imbalanced up states: excitatory and inhibitory conductances during seizure-like events

PubMed Central

Cressman, John R.; Schiff, Steven J.

2013-01-01

Precisely timed and dynamically balanced excitatory (E) and inhibitory (I) conductances underlie the basis of neural network activity. Normal E/I balance is often shifted in epilepsy, resulting in neuronal network hyperexcitability and recurrent seizures. However, dynamics of the actual excitatory and inhibitory synaptic conductances (ge and gi, respectively) during seizures remain unknown. To study the dynamics of E and I network balance, we calculated ge and gi during the initiation, body, and termination of seizure-like events (SLEs) in the rat hippocampus in vitro. Repetitive emergent SLEs in 4-aminopyridine (100 μM) and reduced extracellular magnesium (0.6 mM) were recorded in the identified CA1 pyramidal cells (PC) and oriens-lacunosum moleculare (O-LM) interneurons. Calculated ge/gi ratio dynamics showed that the initiation stage of the SLEs was dominated by inhibition in the PCs and was more balanced in the O-LM cells. During the body of the SLEs, the balance shifted toward excitation, with ge and gi peaking in both cell types at nearly the same time. In the termination phase, PCs were again dominated by inhibition, whereas O-LM cells experienced persistent excitatory synaptic barrage. In this way, increased excitability of interneurons may play roles in both seizure initiation (Žiburkus J, Cressman JR, Barreto E, Schiff SJ. J Neurophysiol 95: 3948–3954, 2006) and in their termination. Overall, SLE stages can be characterized in PC and O-LM cells by dynamically distinct changes in the balance of ge and gi, where a temporal sequence of imbalance shifts with the changing firing patterns of the cellular subtypes comprising the hyperexcitable microcircuits. PMID:23221405

Neonatal Nicotine Exposure Increases Excitatory Synaptic Transmission and Attenuates Nicotine-stimulated GABA release in the Adult Rat Hippocampus

PubMed Central

Damborsky, Joanne C.; Griffith, William H.; Winzer-Serhan, Ursula H.

2014-01-01

Developmental exposure to nicotine has been linked to long-lasting changes in synaptic transmission which may contribute to behavioral abnormalities seen in offspring of women who smoke during pregnancy. Here, we examined the long-lasting effects of developmental nicotine exposure on glutamatergic and GABAergic neurotransmission, and on acute nicotine-induced glutamate and GABA release in the adult hippocampus, a structure important in cognitive and emotional behaviors. We utilized a chronic neonatal nicotine treatment model to administer nicotine (6 mg/kg/day) to rat pups from postnatal day (P) 1–7, a period that falls developmentally into the third human trimester. Using whole-cell voltage clamp recordings from CA1 pyramidal neurons in hippocampal slices, we measured excitatory and inhibitory postsynaptic currents in neonatally control- and nicotine-treated young adult males. Neonatal nicotine exposure significantly increased AMPA receptor-mediated spontaneous and evoked excitatory signaling, with no change in glutamate release probability in adults. Conversely, there was no increase in spontaneous GABAergic neurotransmission in nicotine-males. Chronic neonatal nicotine treatment had no effect on acute nicotine-stimulated glutamate release in adults, but acute nicotine-stimulated GABA release was significantly attenuated. Thus, neonatal nicotine exposure results in a persistent net increase in excitation and a concurrent loss of nicotinic acetylcholine receptor (nAChR)-mediated regulation of presynaptic GABA but not glutamate release, which would exacerbate excitation following endogenous or exogenous nAChR activation. Our data underscore an important role for nAChRs in hippocampal excitatory synapse development, and suggest selective long-term changes at specific presynaptic nAChRs which together could explain some of the behavioral abnormalities associated with maternal smoking. PMID:24950455

Serotonin increases synaptic activity in olfactory bulb glomeruli

PubMed Central

Brill, Julia; Shao, Zuoyi; Puche, Adam C.; Wachowiak, Matt

2016-01-01

Serotoninergic fibers densely innervate olfactory bulb glomeruli, the first sites of synaptic integration in the olfactory system. Acting through 5HT2A receptors, serotonin (5HT) directly excites external tufted cells (ETCs), key excitatory glomerular neurons, and depolarizes some mitral cells (MCs), the olfactory bulb's main output neurons. We further investigated 5HT action on MCs and determined its effects on the two major classes of glomerular interneurons: GABAergic/dopaminergic short axon cells (SACs) and GABAergic periglomerular cells (PGCs). In SACs, 5HT evoked a depolarizing current mediated by 5HT2C receptors but did not significantly impact spike rate. 5HT had no measurable direct effect in PGCs. Serotonin increased spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and sIPSCs) in PGCs and SACs. Increased sEPSCs were mediated by 5HT2A receptors, suggesting that they are primarily due to enhanced excitatory drive from ETCs. Increased sIPSCs resulted from elevated excitatory drive onto GABAergic interneurons and augmented GABA release from SACs. Serotonin-mediated GABA release from SACs was action potential independent and significantly increased miniature IPSC frequency in glomerular neurons. When focally applied to a glomerulus, 5HT increased MC spontaneous firing greater than twofold but did not increase olfactory nerve-evoked responses. Taken together, 5HT modulates glomerular network activity in several ways: 1) it increases ETC-mediated feed-forward excitation onto MCs, SACs, and PGCs; 2) it increases inhibition of glomerular interneurons; 3) it directly triggers action potential-independent GABA release from SACs; and 4) these network actions increase spontaneous MC firing without enhancing responses to suprathreshold sensory input. This may enhance MC sensitivity while maintaining dynamic range. PMID:26655822

Serotonin increases synaptic activity in olfactory bulb glomeruli.

PubMed

Brill, Julia; Shao, Zuoyi; Puche, Adam C; Wachowiak, Matt; Shipley, Michael T

2016-03-01

Serotoninergic fibers densely innervate olfactory bulb glomeruli, the first sites of synaptic integration in the olfactory system. Acting through 5HT2A receptors, serotonin (5HT) directly excites external tufted cells (ETCs), key excitatory glomerular neurons, and depolarizes some mitral cells (MCs), the olfactory bulb's main output neurons. We further investigated 5HT action on MCs and determined its effects on the two major classes of glomerular interneurons: GABAergic/dopaminergic short axon cells (SACs) and GABAergic periglomerular cells (PGCs). In SACs, 5HT evoked a depolarizing current mediated by 5HT2C receptors but did not significantly impact spike rate. 5HT had no measurable direct effect in PGCs. Serotonin increased spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and sIPSCs) in PGCs and SACs. Increased sEPSCs were mediated by 5HT2A receptors, suggesting that they are primarily due to enhanced excitatory drive from ETCs. Increased sIPSCs resulted from elevated excitatory drive onto GABAergic interneurons and augmented GABA release from SACs. Serotonin-mediated GABA release from SACs was action potential independent and significantly increased miniature IPSC frequency in glomerular neurons. When focally applied to a glomerulus, 5HT increased MC spontaneous firing greater than twofold but did not increase olfactory nerve-evoked responses. Taken together, 5HT modulates glomerular network activity in several ways: 1) it increases ETC-mediated feed-forward excitation onto MCs, SACs, and PGCs; 2) it increases inhibition of glomerular interneurons; 3) it directly triggers action potential-independent GABA release from SACs; and 4) these network actions increase spontaneous MC firing without enhancing responses to suprathreshold sensory input. This may enhance MC sensitivity while maintaining dynamic range. Copyright © 2016 the American Physiological Society.

Ligands for Ionotropic Glutamate Receptors

PubMed Central

Swanson, Geoffrey T.; Sakai, Ryuichi

2010-01-01

Marine-derived small molecules and peptides have played a central role in elaborating pharmacological specificities and neuronal functions of mammalian ionotropic glutamate receptors (iGluRs), the primary mediators of excitatory synaptic transmission in the central nervous system (CNS). As well, the pathological sequelae elicited by one class of compounds (the kainoids) constitute a widely-used animal model for human mesial temporal lobe epilepsy (mTLE). New and existing molecules could prove useful as lead compounds for the development of therapeutics for neuropathologies that have aberrant glutamatergic signaling as a central component. In this chapter we discuss natural source origins and pharmacological activities of those marine compounds that target ionotropic glutamate receptors. PMID:19184587

Ligands for Ionotropic Glutamate Receptors

NASA Astrophysics Data System (ADS)

Swanson, Geoffrey T.; Sakai, Ryuichi

Marine-derived small molecules and peptides have played a central role in elaborating pharmacological specificities and neuronal functions of mammalian ionotropic glutamate receptors (iGluRs), the primary mediators of excitatory syn-aptic transmission in the central nervous system (CNS). As well, the pathological sequelae elicited by one class of compounds (the kainoids) constitute a widely-used animal model for human mesial temporal lobe epilepsy (mTLE). New and existing molecules could prove useful as lead compounds for the development of therapeutics for neuropathologies that have aberrant glutamatergic signaling as a central component. In this chapter we discuss natural source origins and pharmacological activities of those marine compounds that target ionotropic glutamate receptors.

Amplitude Normalization of Dendritic EPSPs at the Soma of Binaural Coincidence Detector Neurons of the Medial Superior Olive.

PubMed

Winters, Bradley D; Jin, Shan-Xue; Ledford, Kenneth R; Golding, Nace L

2017-03-22

The principal neurons of the medial superior olive (MSO) encode cues for horizontal sound localization through comparisons of the relative timing of EPSPs. To understand how the timing and amplitude of EPSPs are maintained during propagation in the dendrites, we made dendritic and somatic whole-cell recordings from MSO principal neurons in brain slices from Mongolian gerbils. In somatic recordings, EPSP amplitudes were largely uniform following minimal stimulation of excitatory synapses at visualized locations along the dendrites. Similar results were obtained when excitatory synaptic transmission was eliminated in a low calcium solution and then restored at specific dendritic sites by pairing input stimulation and focal application of a higher calcium solution. We performed dual dendritic and somatic whole-cell recordings to measure spontaneous EPSPs using a dual-channel template-matching algorithm to separate out those events initiated at or distal to the dendritic recording location. Local dendritic spontaneous EPSP amplitudes increased sharply in the dendrite with distance from the soma (length constant, 53.6 μm), but their attenuation during propagation resulted in a uniform amplitude of ∼0.2 mV at the soma. The amplitude gradient of dendritic EPSPs was also apparent in responses to injections of identical simulated excitatory synaptic currents in the dendrites. Compartmental models support the view that these results extensively reflect the influence of dendritic cable properties. With relatively few excitatory axons innervating MSO neurons, the normalization of dendritic EPSPs at the soma would increase the importance of input timing versus location during the processing of interaural time difference cues in vivo SIGNIFICANCE STATEMENT The neurons of the medial superior olive analyze cues for sound localization by detecting the coincidence of binaural excitatory synaptic inputs distributed along the dendrites. Previous studies have shown that dendritic voltages undergo severe attenuation as they propagate to the soma, potentially reducing the influence of distal inputs. However, using dendritic and somatic patch recordings, we found that dendritic EPSP amplitude increased with distance from the soma, compensating for dendritic attenuation and normalizing EPSP amplitude at the soma. Much of this normalization reflected the influence of dendritic morphology. As different combinations of presynaptic axons may be active during consecutive cycles of sound stimuli, somatic EPSP normalization renders spike initiation more sensitive to synapse timing than dendritic location. Copyright © 2017 the authors 0270-6474/17/373138-12$15.00/0.

Identification of endophilins 1 and 3 as selective binding partners for VGLUT1 and their co-localization in neocortical glutamatergic synapses: implications for vesicular glutamate transporter trafficking and excitatory vesicle formation.

PubMed

De Gois, Stephanie; Jeanclos, Elisabeth; Morris, Marie; Grewal, Sukhjeevan; Varoqui, Helene; Erickson, Jeffrey D

2006-01-01

1. Selective protein-protein interactions between neurotransmitter transporters and their synaptic targets play important roles in regulating chemical neurotransmission. We screened a yeast two-hybrid library with bait containing the C-terminal amino acids of VGLUT1 and obtained clones that encode endophilin 1 and endophilin 3, proteins considered to play an integral role in glutamatergic vesicle formation. 2. Using a modified yeast plasmid vector to enable more cost-effective screens, we analyzed the selectivity and specificity of this interaction. Endophilins 1 and 3 selectively recognize only VGLUT1 as the C-terminus of VGLUT2 and VGLUT3 do not interact with either endophilin isoform. We mutagenized four conserved stretches of primary sequence in VGLUT1 that includes two polyproline motifs (Pro1, PPAPPP, and Pro2, PPRPPPP), found only in VGLUT1, and two conserved stretches (SEEK, SYGAT), found also in VGLUT2 and VGLUT3. The absence of the VGLUT conserved regions does not affect VGLUT1-endophilin association. Of the two polyproline stretches, only one (Pro2) is required for binding specificity to both endophilin 1 and endophilin 3. 3. We also show that endophilin 1 and endophilin 3 co-localize with VGLUT1 in synaptic terminals of differentiated rat neocortical neurons in primary culture. These results indicate that VGLUT1 and both endophilins are enriched in a class of excitatory synaptic terminals in cortical neurons and there, may interact to play an important role affecting the vesicular sequestration and synaptic release of glutamate.

Interaction between the glutamate transporter GLT1b and the synaptic PDZ domain protein PICK1

PubMed Central

Bassan, Merav; Liu, Hongguang; Madsen, Kenneth L.; Armsen, Wencke; Zhou, Jiayi; DeSilva, Tara; Chen, Weizhi; Paradise, Allison; Brasch, Michael A.; Staudinger, Jeff; Gether, Ulrik; Irwin, Nina; Rosenberg, Paul A.

2015-01-01

Synaptic plasticity is implemented by the interaction of glutamate receptors with PDZ domain proteins. Glutamate transporters provide the only known mechanism of clearance of glutamate from excitatory synapses, and GLT1 is the major glutamate transporter. We show here that GLT1 interacts with the PDZ domain protein PICK1, which plays a critical role in regulating the expression of glutamate receptors at excitatory synapses. A yeast two-hybrid screen of a neuronal library using the carboxyl tail of GLT1b yielded clones expressing PICK1. The GLT1b C-terminal peptide bound to PICK1 with high affinity (Ki = 6.5 ± 0.4 μm) in an in vitro fluorescence polarization assay. We also tested peptides based on other variants of GLT1 and other glutamate transporters. GLT1b co-immunoprecipitated with PICK1 from rat brain lysates and COS7 cell lysates derived from cells transfected with plasmids expressing PICK1 and GLT1b. In addition, expression of GLT1b in COS7 cells changed the distribution of PICK1, bringing it to the surface. GLT1b and PICK1 co-localized with each other and with synaptic markers in hippocampal neurons in culture. Phorbol ester, an activator of protein kinase C (PKC), a known PICK1 interactor, had no effect on glutamate transport in rat forebrain neurons in culture. However, we found that exposure of neurons to a myristolated decoy peptide with sequence identical to the C-terminal sequence of GLT1b designed to block the PICK1–GLT1b interaction rendered glutamate transport into neurons responsive to phorbol ester. These results suggest that the PICK1–GLT1b interaction regulates the modulation of GLT1 function by PKC. PMID:18184314

Increased expression of the Drosophila vesicular glutamate transporter leads to excess glutamate release and a compensatory decrease in quantal content.

PubMed

Daniels, Richard W; Collins, Catherine A; Gelfand, Maria V; Dant, Jaime; Brooks, Elizabeth S; Krantz, David E; DiAntonio, Aaron

2004-11-17

Quantal size is a fundamental parameter controlling the strength of synaptic transmission. The transmitter content of synaptic vesicles is one mechanism that can affect the physiological response to the release of a single vesicle. At glutamatergic synapses, vesicular glutamate transporters (VGLUTs) are responsible for filling synaptic vesicles with glutamate. To investigate how VGLUT expression can regulate synaptic strength in vivo, we have identified the Drosophila vesicular glutamate transporter, which we name DVGLUT. DVGLUT mRNA is expressed in glutamatergic motoneurons and a large number of interneurons in the Drosophila CNS. DVGLUT protein resides on synaptic vesicles and localizes to the presynaptic terminals of all known glutamatergic neuromuscular junctions as well as to synapses throughout the CNS neuropil. Increasing the expression of DVGLUT in motoneurons leads to an increase in quantal size that is accompanied by an increase in synaptic vesicle volume. At synapses confronted with increased glutamate release from each vesicle, there is a compensatory decrease in the number of synaptic vesicles released that maintains normal levels of synaptic excitation. These results demonstrate that (1) expression of DVGLUT determines the size and glutamate content of synaptic vesicles and (2) homeostatic mechanisms exist to attenuate the excitatory effects of excess glutamate release.

Zinc-mediated transactivation of TrkB potentiates the hippocampal mossy fiber-CA3 pyramid synapse.

PubMed

Huang, Yang Z; Pan, Enhui; Xiong, Zhi-Qi; McNamara, James O

2008-02-28

The receptor tyrosine kinase, TrkB, is critical to diverse functions of the mammalian nervous system in health and disease. Evidence of TrkB activation during epileptogenesis in vivo despite genetic deletion of its prototypic neurotrophin ligands led us to hypothesize that a non-neurotrophin, the divalent cation zinc, can transactivate TrkB. We found that zinc activates TrkB through increasing Src family kinase activity by an activity-regulated mechanism independent of neurotrophins. One subcellular locale at which zinc activates TrkB is the postsynaptic density of excitatory synapses. Exogenous zinc potentiates the efficacy of the hippocampal mossy fiber (mf)-CA3 pyramid synapse by a TrkB-requiring mechanism. Long-term potentiation of this synapse is impaired by deletion of TrkB, inhibition of TrkB kinase activity, and by CaEDTA, a selective chelator of zinc. The activity-dependent activation of synaptic TrkB in a neurotrophin-independent manner provides a mechanism by which this receptor can regulate synaptic plasticity.

Ambra1 Shapes Hippocampal Inhibition/Excitation Balance: Role in Neurodevelopmental Disorders.

PubMed

Nobili, Annalisa; Krashia, Paraskevi; Cordella, Alberto; La Barbera, Livia; Dell'Acqua, Maria Concetta; Caruso, Angela; Pignataro, Annabella; Marino, Ramona; Sciarra, Francesca; Biamonte, Filippo; Scattoni, Maria Luisa; Ammassari-Teule, Martine; Cecconi, Francesco; Berretta, Nicola; Keller, Flavio; Mercuri, Nicola Biagio; D'Amelio, Marcello

2018-02-27

Imbalances between excitatory and inhibitory synaptic transmission cause brain network dysfunction and are central to the pathogenesis of neurodevelopmental disorders. Parvalbumin interneurons are highly implicated in this imbalance. Here, we probed the social behavior and hippocampal function of mice carrying a haploinsufficiency for Ambra1, a pro-autophagic gene crucial for brain development. We show that heterozygous Ambra1 mice (Ambra +/- ) are characterized by loss of hippocampal parvalbumin interneurons, decreases in the inhibition/excitation ratio, and altered social behaviors that are solely restricted to the female gender. Loss of parvalbumin interneurons in Ambra1 +/- females is further linked to reductions of the inhibitory drive onto principal neurons and alterations in network oscillatory activity, CA1 synaptic plasticity, and pyramidal neuron spine density. Parvalbumin interneuron loss is underlined by increased apoptosis during the embryonic development of progenitor neurons in the medial ganglionic eminence. Together, these findings identify an Ambra1-dependent mechanism that drives inhibition/excitation imbalance in the hippocampus, contributing to abnormal brain activity reminiscent of neurodevelopmental disorders.

Retinal co-mediator acetylcholine evokes muscarinic inhibition of recurrent excitation in frog tectum column.

PubMed

Baginskas, Armantas; Kuras, Antanas

2016-08-26

Acetylcholine receptors contribute to the control of neuronal and neuronal network activity from insects to humans. We have investigated the action of acetylcholine receptors in the optic tectum of Rana temporaria (common frog). Our previous studies have demonstrated that acetylcholine activates presynaptic nicotinic receptors, when released into the frog optic tectum as a co-mediator during firing of a single retinal ganglion cell, and causes: a) potentiation of retinotectal synaptic transmission, and b) facilitation of transition of the tectum column to a higher level of activity. In the present study we have shown that endogenous acetylcholine also activates muscarinic receptors, leading to a delayed inhibition of recurrent excitatory synaptic transmission in the tectum column. The delay of muscarinic inhibition was evaluated to be of ∼80ms, with an extent of inhibition of ∼2 times. The inhibition of the recurrent excitation determines transition of the tectum column back to its resting state, giving a functional sense for the inhibition. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Asynchronous Cholinergic Drive Correlates with Excitation-Inhibition Imbalance via a Neuronal Ca2+ Sensor Protein.

PubMed

Zhou, Keming; Cherra, Salvatore J; Goncharov, Alexandr; Jin, Yishi

2017-05-09

Excitation-inhibition imbalance in neural networks is widely linked to neurological and neuropsychiatric disorders. However, how genetic factors alter neuronal activity, leading to excitation-inhibition imbalance, remains unclear. Here, using the C. elegans locomotor circuit, we examine how altering neuronal activity for varying time periods affects synaptic release pattern and animal behavior. We show that while short-duration activation of excitatory cholinergic neurons elicits a reversible enhancement of presynaptic strength, persistent activation results to asynchronous and reduced cholinergic drive, inducing imbalance between endogenous excitation and inhibition. We find that the neuronal calcium sensor protein NCS-2 is required for asynchronous cholinergic release in an activity-dependent manner and dampens excitability of inhibitory neurons non-cell autonomously. The function of NCS-2 requires its Ca 2+ binding and membrane association domains. These results reveal a synaptic mechanism implicating asynchronous release in regulation of excitation-inhibition balance. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Hippocampal dendritic spines modifications induced by perinatal asphyxia.

PubMed

Saraceno, G E; Castilla, R; Barreto, G E; Gonzalez, J; Kölliker-Frers, R A; Capani, F

2012-01-01

Perinatal asphyxia (PA) affects the synaptic function and morphological organization. In previous works, we have shown neuronal and synaptic changes in rat neostriatum subjected to hypoxia leading to long-term ubi-protein accumulation. Since F-actin is highly concentrated in dendritic spines, modifications in its organization could be related with alterations induced by hypoxia in the central nervous system (CNS). In the present study, we investigate the effects of PA on the actin cytoskeleton of hippocampal postsynaptic densities (PSD) in 4-month-old rats. PSD showed an increment in their thickness and in the level of ubiquitination. Correlative fluorescence-electron microscopy photooxidation showed a decrease in the number of F-actin-stained spines in hippocampal excitatory synapses subjected to PA. Although western blot analysis also showed a slight decrease in β-actin in PSD in PA animals, the difference was not significant. Taken together, this data suggests that long-term actin cytoskeleton might have role in PSD alterations which would be a spread phenomenon induced by PA.

Hippocampal Dendritic Spines Modifications Induced by Perinatal Asphyxia

PubMed Central

Saraceno, G. E.; Castilla, R.; Barreto, G. E.; Gonzalez, J.; Kölliker-Frers, R. A.; Capani, F.

2012-01-01

Perinatal asphyxia (PA) affects the synaptic function and morphological organization. In previous works, we have shown neuronal and synaptic changes in rat neostriatum subjected to hypoxia leading to long-term ubi-protein accumulation. Since F-actin is highly concentrated in dendritic spines, modifications in its organization could be related with alterations induced by hypoxia in the central nervous system (CNS). In the present study, we investigate the effects of PA on the actin cytoskeleton of hippocampal postsynaptic densities (PSD) in 4-month-old rats. PSD showed an increment in their thickness and in the level of ubiquitination. Correlative fluorescence-electron microscopy photooxidation showed a decrease in the number of F-actin-stained spines in hippocampal excitatory synapses subjected to PA. Although Western Blot analysis also showed a slight decrease in β-actin in PSD in PA animals, the difference was not significant. Taken together, this data suggests that long-term actin cytoskeleton might have role in PSD alterations which would be a spread phenomenon induced by PA. PMID:22645692

The Polarity Protein Partitioning-defective 1 (PAR-1) Regulates Dendritic Spine Morphogenesis through Phosphorylating Postsynaptic Density Protein 95 (PSD-95)*

PubMed Central

Wu, Qian; DiBona, Victoria L.; Bernard, Laura P.; Zhang, Huaye

2012-01-01

The polarity protein PAR-1 plays an essential role in many cellular contexts, including embryogenesis, asymmetric cell division, directional migration, and epithelial morphogenesis. Despite its known importance in different cellular processes, the role of PAR-1 in neuronal morphogenesis is less well understood. In particular, its role in the morphogenesis of dendritic spines, which are sites of excitatory synaptic inputs, has been unclear. Here, we show that PAR-1 is required for normal spine morphogenesis in hippocampal neurons. We further show that PAR-1 functions through phosphorylating the synaptic scaffolding protein PSD-95 in this process. Phosphorylation at a conserved serine residue in the KXGS motif in PSD-95 regulates spine morphogenesis, and a phosphomimetic mutant of this site can rescue the defects of kinase-dead PAR-1. Together, our findings uncover a role of PAR-1 in spine morphogenesis in hippocampal neurons through phosphorylating PSD-95. PMID:22807451

Involvement of Mossy Cells in Sharp Wave-Ripple Activity In Vitro.

PubMed

Swaminathan, Aarti; Wichert, Ines; Schmitz, Dietmar; Maier, Nikolaus

2018-05-29

The role of mossy cells (MCs) of the hippocampal dentate area has long remained mysterious. Recent research has begun to unveil their significance in spatial computation of the hippocampus. Here, we used an in vitro model of sharp wave-ripple complexes (SWRs), which contribute to hippocampal memory formation, to investigate MC involvement in this fundamental population activity. We find that a significant fraction of MCs (∼47%) is recruited into the active neuronal network during SWRs in the CA3 area. Moreover, MCs receive pronounced, ripple-coherent, excitatory and inhibitory synaptic input. Finally, we find evidence for SWR-related synaptic activity in granule cells that is mediated by MCs. Given the widespread connectivity of MCs within and between hippocampi, our data suggest a role for MCs as a hub functionally coupling the CA3 and the DG during ripple-associated computations. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Balanced Synaptic Input Shapes the Correlation between Neural Spike Trains

PubMed Central

Litwin-Kumar, Ashok; Oswald, Anne-Marie M.; Urban, Nathaniel N.; Doiron, Brent

2011-01-01

Stimulus properties, attention, and behavioral context influence correlations between the spike times produced by a pair of neurons. However, the biophysical mechanisms that modulate these correlations are poorly understood. With a combined theoretical and experimental approach, we show that the rate of balanced excitatory and inhibitory synaptic input modulates the magnitude and timescale of pairwise spike train correlation. High rate synaptic inputs promote spike time synchrony rather than long timescale spike rate correlations, while low rate synaptic inputs produce opposite results. This correlation shaping is due to a combination of enhanced high frequency input transfer and reduced firing rate gain in the high input rate state compared to the low state. Our study extends neural modulation from single neuron responses to population activity, a necessary step in understanding how the dynamics and processing of neural activity change across distinct brain states. PMID:22215995

Critical period plasticity is disrupted in the barrel cortex of Fmr1 knockout mice

PubMed Central

Harlow, Emily G.; Till, Sally M.; Russell, Theron A.; Wijetunge, Lasani S.; Kind, Peter; Contractor, Anis

2010-01-01

Summary Alterations in sensory processing constitute prominent symptoms of Fragile X syndrome; however, little is known about how disrupted synaptic and circuit development in sensory cortex contributes to these deficits. To investigate how the loss of fragile X mental retardation protein (FMRP) impacts the development of cortical synapses, we examined excitatory thalamocortical synapses in somatosensory cortex during the perinatal critical period in Fmr1 knockout mice. FMRP ablation resulted in dysregulation of glutamatergic signaling maturation. The fraction of silent synapses persisting to later developmental times was increased, there was a temporal delay in the window for synaptic plasticity, while other forms of developmental plasticity were not altered in Fmr1 knockout mice. Our results indicate that FMRP is required for the normal developmental progression of synaptic maturation, and loss of this important RNA binding protein impacts the timing of the critical period for layer IV synaptic plasticity. PMID:20159451

Protons Regulate Vesicular Glutamate Transporters through an Allosteric Mechanism.

PubMed

Eriksen, Jacob; Chang, Roger; McGregor, Matt; Silm, Katlin; Suzuki, Toshiharu; Edwards, Robert H

2016-05-18

The quantal nature of synaptic transmission requires a mechanism to transport neurotransmitter into synaptic vesicles without promoting non-vesicular efflux across the plasma membrane. Indeed, the vesicular transport of most classical transmitters involves a mechanism of H(+) exchange, which restricts flux to acidic membranes such as synaptic vesicles. However, vesicular transport of the principal excitatory transmitter glutamate depends primarily on membrane potential, which would drive non-vesicular efflux, and the role of protons is unclear. Adapting electrophysiology to record currents associated with the vesicular glutamate transporters (VGLUTs), we characterize a chloride conductance that is gated by lumenal protons and chloride and supports glutamate uptake. Rather than coupling stoichiometrically to glutamate flux, lumenal protons and chloride allosterically activate vesicular glutamate transport. Gating by protons serves to inhibit what would otherwise be substantial non-vesicular glutamate efflux at the plasma membrane, thereby restricting VGLUT activity to synaptic vesicles. Copyright © 2016 Elsevier Inc. All rights reserved.

Energy Efficient Sparse Connectivity from Imbalanced Synaptic Plasticity Rules

PubMed Central

Sacramento, João; Wichert, Andreas; van Rossum, Mark C. W.

2015-01-01

It is believed that energy efficiency is an important constraint in brain evolution. As synaptic transmission dominates energy consumption, energy can be saved by ensuring that only a few synapses are active. It is therefore likely that the formation of sparse codes and sparse connectivity are fundamental objectives of synaptic plasticity. In this work we study how sparse connectivity can result from a synaptic learning rule of excitatory synapses. Information is maximised when potentiation and depression are balanced according to the mean presynaptic activity level and the resulting fraction of zero-weight synapses is around 50%. However, an imbalance towards depression increases the fraction of zero-weight synapses without significantly affecting performance. We show that imbalanced plasticity corresponds to imposing a regularising constraint on the L 1-norm of the synaptic weight vector, a procedure that is well-known to induce sparseness. Imbalanced plasticity is biophysically plausible and leads to more efficient synaptic configurations than a previously suggested approach that prunes synapses after learning. Our framework gives a novel interpretation to the high fraction of silent synapses found in brain regions like the cerebellum. PMID:26046817

Anchoring and Synaptic stability of PSD-95 is driven by ephrin-B3

PubMed Central

Hruska, Martin; Henderson, Nathan T.; Xia, Nan L.; Le Marchand, Sylvain J.; Dalva, Matthew B.

2015-01-01

Summary Organization of signaling complexes at excitatory synapses by Membrane Associated Guanylate Kinase (MAGUK) proteins regulates synapse development, plasticity, senescence, and disease. Post-translational modification of MAGUK family proteins can drive their membrane localization, yet it is unclear how these intracellular proteins are targeted to sites of synaptic contact. Here we show using super-resolution imaging, biochemical approaches, and in vivo models that the trans-synaptic organizing protein, ephrin-B3, controls the synaptic localization and stability of PSD-95 and links these events to changes in neuronal activity via negative regulation of a novel MAPK-dependent phosphorylation site on ephrin-B3 (S332). Unphosphorylated ephrin-B3 is enriched at synapses, interacts directly with and stabilizes PSD-95 at synapses. Activity induced phosphorylation of S332 disperses ephrin-B3 from synapses, prevents the interaction with, and enhances the turnover of PSD-95. Thus, ephrin-B3 specifies the synaptic localization of PSD-95 and likely links the synaptic stability of PSD-95 to changes in neuronal activity. PMID:26479588

Anchoring and synaptic stability of PSD-95 is driven by ephrin-B3.

PubMed

Hruska, Martin; Henderson, Nathan T; Xia, Nan L; Le Marchand, Sylvain J; Dalva, Matthew B

2015-11-01

Organization of signaling complexes at excitatory synapses by membrane-associated guanylate kinase (MAGUK) proteins regulates synapse development, plasticity, senescence and disease. Post-translational modification of MAGUK family proteins can drive their membrane localization, yet it is unclear how these intracellular proteins are targeted to sites of synaptic contact. Here we show using super-resolution imaging, biochemical approaches and in vivo models that the trans-synaptic organizing protein ephrin-B3 controls the synaptic localization and stability of PSD-95 and links these events to changes in neuronal activity via negative regulation of a newly identified mitogen-associated protein kinase (MAPK)-dependent phosphorylation site on ephrin-B3, Ser332. Unphosphorylated ephrin-B3 was enriched at synapses, and interacted directly with and stabilized PSD-95 at synapses. Activity-induced phosphorylation of Ser332 dispersed ephrin-B3 from synapses, prevented the interaction with PSD-95 and enhanced the turnover of PSD-95. Thus, ephrin-B3 specifies the synaptic localization of PSD-95 and likely links the synaptic stability of PSD-95 to changes in neuronal activity.

The actions of volatile anaesthetics on synaptic transmission in the dentate gyrus.

PubMed Central

Richards, C D; White, A E

1975-01-01

1. The action of four volatile anaesthetics on the evoked synaptic potentials of in vitro preparations of the hippocampus were examined. 2. All four anaesthetics (ether, halothane, methoxyflurane and trichloroethylene) depressed the synaptic transmission between the perforant path and the granule cells at concentrations lower than those required to maintain anaesthesia in intact animals. 3. The population excitatory post-synaptic potential (e.p.s.p.) and massed discharge of the cortical cells (population spike) were depressed at concentrations of the anaesthetics lower than those required to depress the compound action potential of the perforant path nerve fibres. None of the anaesthetics studied increased the threshold depolarization required for granule cell discharge. Furthermore, frequency potentiation of the evoked cortical e.p.s.p.s was not impaired by any of the anaesthetics studied. 4. It is concluded that all four anaesthetics depress synaptic transmission in the dentate gyrus either by reducing the amount of transmitter released from each nerve terminal in response to an afferent volley, or by decreasing the sensitivity of the post-synaptic membrane to released transmitted or by both effects together. PMID:1202196

Morphological evidence for novel enteric neuronal circuitry in guinea pig distal colon.

PubMed

Smolilo, D J; Costa, M; Hibberd, T J; Wattchow, D A; Spencer, Nick J

2018-07-01

The gastrointestinal (GI) tract is unique compared to all other internal organs; it is the only organ with its own nervous system and its own population of intrinsic sensory neurons, known as intrinsic primary afferent neurons (IPANs). How these IPANs form neuronal circuits with other functional classes of neurons in the enteric nervous system (ENS) is incompletely understood. We used a combination of light microscopy, immunohistochemistry and confocal microscopy to examine the topographical distribution of specific classes of neurons in the myenteric plexus of guinea-pig colon, including putative IPANs, with other classes of enteric neurons. These findings were based on immunoreactivity to the neuronal markers, calbindin, calretinin and nitric oxide synthase. We then correlated the varicose outputs formed by putative IPANs with subclasses of excitatory interneurons and motor neurons. We revealed that calbindin-immunoreactive varicosities form specialized structures resembling 'baskets' within the majority of myenteric ganglia, which were arranged in clusters around calretinin-immunoreactive neurons. These calbindin baskets directly arose from projections of putative IPANs and represent morphological evidence of preferential input from sensory neurons directly to a select group of calretinin neurons. Our findings uncovered that these neurons are likely to be ascending excitatory interneurons and excitatory motor neurons. Our study reveals for the first time in the colon, a novel enteric neural circuit, whereby calbindin-immunoreactive putative sensory neurons form specialized varicose structures that likely direct synaptic outputs to excitatory interneurons and motor neurons. This circuit likely forms the basis of polarized neuronal pathways underlying motility. © 2018 Wiley Periodicals, Inc.

Functional Characterization of a Vesicular Glutamate Transporter in an Interneuron That Makes Excitatory and Inhibitory Synaptic Connections in a Molluscan Neural Circuit

PubMed Central

Alexeeva, Vera; Chen, Song-an; Yu, Ke; Due, Michael R.; Tan, Li-nuo; Chen, Ting-ting; Liu, Dan-dan; Cropper, Elizabeth C.; Vilim, Ferdinand S.; Weiss, Klaudiusz R.

2015-01-01

Understanding circuit function requires the characterization of component neurons and their neurotransmitters. Previous work on radula protraction in the Aplysia feeding circuit demonstrated that critical neurons initiate feeding via cholinergic excitation. In contrast, it is less clear how retraction is mediated at the interneuronal level. In particular, glutamate involvement was suggested, but was not directly confirmed. Here we study a suspected glutamatergic retraction interneuron, B64. We used the representational difference analysis (RDA) method to successfully clone an Aplysia vesicular glutamate transporter (ApVGLUT) from B64 and from a glutamatergic motor neuron B38. Previously, RDA was used to characterize novel neuropeptides. Here we demonstrate its utility for characterizing other types of molecules. Bioinformatics suggests that ApVGLUT is more closely related to mammalian VGLUTs than to Drosophila and Caenorhabditis elegans VGLUTs. We expressed ApVGLUT in a cell line, and demonstrated that it indeed transports glutamate in an ATP and proton gradient-dependent manner. We mapped the ApVGLUT distribution in the CNS using in situ hybridization and immunocytochemistry. Further, we demonstrated that B64 is ApVGLUT positive, supporting the idea that it is glutamatergic. Although glutamate is primarily an excitatory transmitter in the mammalian CNS, B64 elicits inhibitory PSPs in protraction neurons to terminate protraction and excitatory PSPs in retraction neurons to maintain retraction. Pharmacological data indicated that both types of PSPs are mediated by glutamate. Thus, glutamate mediates the dual function of B64 in Aplysia. More generally, our systematic approaches based on RDA may facilitate analyses of transmitter actions in small circuits with identifiable neurons. PMID:26085636

Blockade of adenosine A2A receptors recovers early deficits of memory and plasticity in the triple transgenic mouse model of Alzheimer's disease.

PubMed

Silva, António C; Lemos, Cristina; Gonçalves, Francisco Q; Pliássova, Anna V; Machado, Nuno J; Silva, Henrique B; Canas, Paula M; Cunha, Rodrigo A; Lopes, João Pedro; Agostinho, Paula

2018-05-31

Alzheimer's disease (AD) begins with a deficit of synaptic function and adenosine A 2A receptors (A 2A R) are mostly located in synapses controlling synaptic plasticity. The over-activation of adenosine A 2A receptors (A 2A R) causes memory deficits and the blockade of A 2A R prevents memory damage in AD models. We now enquired if this prophylactic role of A 2A R might be extended to a therapeutic potential. We used the triple transgenic model of AD (3xTg-AD) and defined that the onset of memory dysfunction occurred at 4 months of age in the absence of locomotor or emotional alterations. At the onset of memory deficits, 3xTg mice displayed a decreased density of markers of excitatory synapses (10.6 ± 3.8% decrease of vGluT1) without neuronal or glial overt damage and an increase of synaptic A 2A R in the hippocampus (130 ± 22%). After the onset of memory deficits in 3xTg-AD mice, a three weeks treatment with the selective A 2A R antagonist normalized the up-regulation of hippocampal A 2A R and restored hippocampal-dependent reference memory, as well as the decrease of hippocampal synaptic plasticity (60.0 ± 3.7% decrease of long-term potentiation amplitude) and the decrease of global (syntaxin-I) and glutamatergic synaptic markers (vGluT1). These findings show a therapeutic-like ability of A 2A R antagonists to recover synaptic and memory dysfunction in early AD. Copyright © 2018 Elsevier Inc. All rights reserved.

Theta frequency background tunes transmission but not summation of spiking responses.

PubMed

Parameshwaran, Dhanya; Bhalla, Upinder S

2013-01-01

Hippocampal neurons are known to fire as a function of frequency and phase of spontaneous network rhythms, associated with the animal's behaviour. This dependence is believed to give rise to precise rate and temporal codes. However, it is not well understood how these periodic membrane potential fluctuations affect the integration of synaptic inputs. Here we used sinusoidal current injection to the soma of CA1 pyramidal neurons in the rat brain slice to simulate background oscillations in the physiologically relevant theta and gamma frequency range. We used a detailed compartmental model to show that somatic current injection gave comparable results to more physiological synaptically driven theta rhythms incorporating excitatory input in the dendrites, and inhibitory input near the soma. We systematically varied the phase of synaptic inputs with respect to this background, and recorded changes in response and summation properties of CA1 neurons using whole-cell patch recordings. The response of the cell was dependent on both the phase of synaptic inputs and frequency of the background input. The probability of the cell spiking for a given synaptic input was up to 40% greater during the depolarized phases between 30-135 degrees of theta frequency current injection. Summation gain on the other hand, was not affected either by the background frequency or the phasic afferent inputs. This flat summation gain, coupled with the enhanced spiking probability during depolarized phases of the theta cycle, resulted in enhanced transmission of summed inputs during the same phase window of 30-135 degrees. Overall, our study suggests that although oscillations provide windows of opportunity to selectively boost transmission and EPSP size, summation of synaptic inputs remains unaffected during membrane oscillations.

Adenosine A2A Receptors in the Amygdala Control Synaptic Plasticity and Contextual Fear Memory.

PubMed

Simões, Ana Patrícia; Machado, Nuno J; Gonçalves, Nélio; Kaster, Manuella P; Simões, Ana T; Nunes, Ana; Pereira de Almeida, Luís; Goosens, Ki Ann; Rial, Daniel; Cunha, Rodrigo A

2016-11-01

The consumption of caffeine modulates working and reference memory through the antagonism of adenosine A 2A receptors (A 2A Rs) controlling synaptic plasticity processes in hippocampal excitatory synapses. Fear memory essentially involves plastic changes in amygdala circuits. However, it is unknown if A 2A Rs in the amygdala regulate synaptic plasticity and fear memory. We report that A 2A Rs in the amygdala are enriched in synapses and located to glutamatergic synapses, where they selectively control synaptic plasticity rather than synaptic transmission at a major afferent pathway to the amygdala. Notably, the downregulation of A 2A Rs selectively in the basolateral complex of the amygdala, using a lentivirus with a silencing shRNA (small hairpin RNA targeting A 2A R (shA 2A R)), impaired fear acquisition as well as Pavlovian fear retrieval. This is probably associated with the upregulation and gain of function of A 2A Rs in the amygdala after fear acquisition. The importance of A 2A Rs to control fear memory was further confirmed by the ability of SCH58261 (0.1 mg/kg; A 2A R antagonist), caffeine (5 mg/kg), but not DPCPX (0.5 mg/kg; A 1 R antagonist), treatment for 7 days before fear conditioning onwards, to attenuate the retrieval of context fear after 24-48 h and after 7-8 days. These results demonstrate that amygdala A 2A Rs control fear memory and the underlying process of synaptic plasticity in this brain region. This provides a neurophysiological basis for the association between A 2A R polymorphisms and phobia or panic attacks in humans and prompts a therapeutic interest in A 2A Rs to manage fear-related pathologies.

Brivaracetam augments short-term depression and slows vesicle recycling.

PubMed

Yang, Xiaofeng; Bognar, Joseph; He, Tianyu; Mohammed, Mouhari; Niespodziany, Isabelle; Wolff, Christian; Esguerra, Manuel; Rothman, Steven M; Dubinsky, Janet M

2015-12-01

Brivaracetam (BRV) decreases seizure activity in a number of epilepsy models and binds to the synaptic vesicle glycoprotein 2A (SV2A) with a higher affinity than the antiepileptic drug levetiracetam (LEV). Experiments were performed to determine if BRV acted similarly to LEV to induce or augment short-term depression (STD) under high-frequency neuronal stimulation and slow synaptic vesicle recycling. Electrophysiologic field excitatory postsynaptic potential (fEPSP) recordings were made from CA1 synapses in rat hippocampal slices loaded with BRV or LEV during intrinsic activity or with BRV actively loaded during hypertonic stimulation. STD was examined in response to 5 or 40 Hz stimulus trains. Presynaptic release of FM1-43 was visualized using two-photon microscopy to assess drug effects upon synaptic vesicle mobilization. When hippocampal slices were incubated in 0.1-30 μm BRV or 30 μm-1 mm LEV for 3 h, the relative CA1 field EPSPs decreased over the course of a high-frequency train of stimuli more than for control slices. This STD was frequency- and concentration-dependent, with BRV being 100-fold more potent than LEV. The extent of STD depended on the length of the incubation time for both drugs. Pretreatment with LEV occluded the effects of BRV. Repeated hypertonic sucrose treatments and train stimulation successfully unloaded BRV from recycling vesicles and reversed BRVs effects on STD, as previously reported for LEV. At their maximal concentrations, BRV slowed FM1-43 release to a greater extent than in slices loaded with LEV during prolonged stimulation. BRV, similar to LEV, entered into recycling synaptic vesicles and produced a frequency-dependent decrement of synaptic transmission at 100-fold lower concentrations than LEV. In addition, BRV slowed synaptic vesicle mobilization more effectively than LEV, suggesting that these drugs may modify multiple functions of the synaptic vesicle protein SV2A to curb synaptic transmission and limit epileptic activity. Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.

Mice lacking the transcriptional regulator Bhlhe40 have enhanced neuronal excitability and impaired synaptic plasticity in the hippocampus.

PubMed

Hamilton, Kelly A; Wang, Yue; Raefsky, Sophia M; Berkowitz, Sean; Spangler, Ryan; Suire, Caitlin N; Camandola, Simonetta; Lipsky, Robert H; Mattson, Mark P

2018-01-01

Bhlhe40 is a transcription factor that is highly expressed in the hippocampus; however, its role in neuronal function is not well understood. Here, we used Bhlhe40 null mice on a congenic C57Bl6/J background (Bhlhe40 KO) to investigate the impact of Bhlhe40 on neuronal excitability and synaptic plasticity in the hippocampus. Bhlhe40 KO CA1 neurons had increased miniature excitatory post-synaptic current amplitude and decreased inhibitory post-synaptic current amplitude, indicating CA1 neuronal hyperexcitability. Increased CA1 neuronal excitability was not associated with increased seizure severity as Bhlhe40 KO relative to +/+ (WT) control mice injected with the convulsant kainic acid. However, significant reductions in long term potentiation and long term depression at CA1 synapses were observed in Bhlhe40 KO mice, indicating impaired hippocampal synaptic plasticity. Behavioral testing for spatial learning and memory on the Morris Water Maze (MWM) revealed that while Bhlhe40 KO mice performed similarly to WT controls initially, when the hidden platform was moved to the opposite quadrant Bhlhe40 KO mice showed impairments in relearning, consistent with decreased hippocampal synaptic plasticity. To investigate possible mechanisms for increased neuronal excitability and decreased synaptic plasticity, a whole genome mRNA expression profile of Bhlhe40 KO hippocampus was performed followed by a chromatin immunoprecipitation sequencing (ChIP-Seq) screen of the validated candidate genes for Bhlhe40 protein-DNA interactions consistent with transcriptional regulation. Of the validated genes identified from mRNA expression analysis, insulin degrading enzyme (Ide) had the most significantly altered expression in hippocampus and was significantly downregulated on the RNA and protein levels; although Bhlhe40 did not occupy the Ide gene by ChIP-Seq. Together, these findings support a role for Bhlhe40 in regulating neuronal excitability and synaptic plasticity in the hippocampus and that indirect regulation of Ide transcription may be involved in these phenotypes.

Endocannabinoid-Dependent Long-Term Potentiation of Synaptic Transmission at Rat Barrel Cortex.

PubMed

Maglio, Laura Eva; Noriega-Prieto, José Antonio; Maraver, Maria Jesús; Fernández de Sevilla, David

2018-05-01

Brain-derived neurotrophic factor (BDNF) plays a critical role in modulating plasticity in sensory cortices. Indeed, a BDNF-dependent long-term potentiation (LTP) at distal basal excitatory synapses of Layer 5 pyramidal neurons (L5PNs) has been demonstrated in disinhibited rat barrel cortex slices. Although it is well established that this LTP requires the pairing of excitatory postsynaptic potentials (PSPs) with Ca2+ spikes, its induction when synaptic inhibition is working remains unexplored. Here we show that low-frequency stimulation at basal dendrites of L5PNs is able to trigger a PSP followed by an action potential (AP) and a slow depolarization (termed PSP-Ca2+ response) in thalamocortical slices without blocking synaptic inhibition. We demonstrate that AP barrage-mediated release of endocannabinoids (eCBs) from the recorded L5PNs induces PSP-Ca2+ response facilitation and BDNF-dependent LTP. Indeed, this LTP requires the type 1 cannabinoid receptors activation, is prevented by postsynaptic intracellular 1,2-bis(2-aminophenoxy) ethane-N,N,N,N'-tetraacetic acid (BAPTA) or the anandamide membrane transporter inhibitor AM404, and only occurs in L5PNs neurons showing depolarization-induced suppression of inhibition. Additionally, electrical stimulation at the posteromedial thalamic nucleus induced similar response and LTP. These results reveal a novel form of eCB-dependent LTP at L5PNs that could be relevant in the processing of sensory information in the barrel cortex.

Qualitative and quantitative estimation of comprehensive synaptic connectivity in short- and long-term cultured rat hippocampal neurons with new analytical methods inspired by Scatchard and Hill plots

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tanamoto, Ryo; Shindo, Yutaka; Niwano, Mariko

2016-03-18

To investigate comprehensive synaptic connectivity, we examined Ca{sup 2+} responses with quantitative electric current stimulation by indium-tin-oxide (ITO) glass electrode with transparent and high electro-conductivity. The number of neurons with Ca{sup 2+} responses was low during the application of stepwise increase of electric current in short-term cultured neurons (less than 17 days in-vitro (DIV)). The neurons cultured over 17 DIV showed two-type responses: S-shaped (sigmoid) and monotonous saturated responses, and Scatchard plots well illustrated the difference of these two responses. Furthermore, sigmoid like neural network responses over 17 DIV were altered to the monotonous saturated ones by the application ofmore » the mixture of AP5 and CNQX, specific blockers of NMDA and AMPA receptors, respectively. This alternation was also characterized by the change of Hill coefficients. These findings indicate that the neural network with sigmoid-like responses has strong synergetic or cooperative synaptic connectivity via excitatory glutamate synapses. - Highlights: • We succeed to evaluate the maturation of neural network by Scathard and Hill Plots. • Long-term cultured neurons showed two-type responses: sigmoid and monotonous. • The sigmoid-like increase indicates the cooperatevity of neural networks. • Excitatory glutamate synapses cause the cooperatevity of neural networks.« less

Unsupervised learning in neural networks with short range synapses

NASA Astrophysics Data System (ADS)

Brunnet, L. G.; Agnes, E. J.; Mizusaki, B. E. P.; Erichsen, R., Jr.

2013-01-01

Different areas of the brain are involved in specific aspects of the information being processed both in learning and in memory formation. For example, the hippocampus is important in the consolidation of information from short-term memory to long-term memory, while emotional memory seems to be dealt by the amygdala. On the microscopic scale the underlying structures in these areas differ in the kind of neurons involved, in their connectivity, or in their clustering degree but, at this level, learning and memory are attributed to neuronal synapses mediated by longterm potentiation and long-term depression. In this work we explore the properties of a short range synaptic connection network, a nearest neighbor lattice composed mostly by excitatory neurons and a fraction of inhibitory ones. The mechanism of synaptic modification responsible for the emergence of memory is Spike-Timing-Dependent Plasticity (STDP), a Hebbian-like rule, where potentiation/depression is acquired when causal/non-causal spikes happen in a synapse involving two neurons. The system is intended to store and recognize memories associated to spatial external inputs presented as simple geometrical forms. The synaptic modifications are continuously applied to excitatory connections, including a homeostasis rule and STDP. In this work we explore the different scenarios under which a network with short range connections can accomplish the task of storing and recognizing simple connected patterns.

Bovine neuronal vesicular glutamate transporter activity is inhibited by ergovaline and other ergopeptines

USDA-ARS?s Scientific Manuscript database

L-Glutamate (Glu) is the major excitatory neurotransmitter responsible for neurotransmission in the vertebrate central nervous system, including the gastrointestinal tract (GIT) of cattle. Vesicular Glu transporters VGLUT1 and VGLUT2 concentrate (50 mM) Glu (Km = 1 to 4 mM) into synaptic vesicles (S...

Regulation of hippocampus-dependent memory by the zinc finger protein Zbtb20 in mature CA1 neurons.

PubMed

Ren, Anjing; Zhang, Huan; Xie, Zhifang; Ma, Xianhua; Ji, Wenli; He, David Z Z; Yuan, Wenjun; Ding, Yu-Qiang; Zhang, Xiao-Hui; Zhang, Weiping J

2012-10-01

The mammalian hippocampus harbours neural circuitry that is crucial for associative learning and memory. The mechanisms that underlie the development and regulation of this complex circuitry are not fully understood. Our previous study established an essential role for the zinc finger protein Zbtb20 in the specification of CA1 field identity in the developing hippocampus. Here, we show that conditionally deleting Zbtb20 specifically in mature CA1 pyramidal neurons impaired hippocampus-dependent memory formation, without affecting hippocampal architecture or the survival, identity and basal excitatory synaptic activity of CA1 pyramidal neurons. We demonstrate that mature CA1-specific Zbtb20 knockout mice exhibited reductions in long-term potentiation (LTP) and NMDA receptor (NMDAR)-mediated excitatory post-synaptic currents. Furthermore, we show that activity-induced phosphorylation of ERK and CREB is impaired in the hippocampal CA1 of Zbtb20 mutant mice. Collectively, these results indicate that Zbtb20 in mature CA1 plays an important role in LTP and memory by regulating NMDAR activity, and activation of ERK and CREB.