Somatostatin-Expressing Inhibitory Interneurons in Cortical Circuits

PubMed Central

Yavorska, Iryna; Wehr, Michael

2016-01-01

Cortical inhibitory neurons exhibit remarkable diversity in their morphology, connectivity, and synaptic properties. Here, we review the function of somatostatin-expressing (SOM) inhibitory interneurons, focusing largely on sensory cortex. SOM neurons also comprise a number of subpopulations that can be distinguished by their morphology, input and output connectivity, laminar location, firing properties, and expression of molecular markers. Several of these classes of SOM neurons show unique dynamics and characteristics, such as facilitating synapses, specific axonal projections, intralaminar input, and top-down modulation, which suggest possible computational roles. SOM cells can be differentially modulated by behavioral state depending on their class, sensory system, and behavioral paradigm. The functional effects of such modulation have been studied with optogenetic manipulation of SOM cells, which produces effects on learning and memory, task performance, and the integration of cortical activity. Different classes of SOM cells participate in distinct disinhibitory circuits with different inhibitory partners and in different cortical layers. Through these disinhibitory circuits, SOM cells help encode the behavioral relevance of sensory stimuli by regulating the activity of cortical neurons based on subcortical and intracortical modulatory input. Associative learning leads to long-term changes in the strength of connectivity of SOM cells with other neurons, often influencing the strength of inhibitory input they receive. Thus despite their heterogeneity and variability across cortical areas, current evidence shows that SOM neurons perform unique neural computations, forming not only distinct molecular but also functional subclasses of cortical inhibitory interneurons. PMID:27746722

Distinct cortical and sub-cortical neurogenic domains for GABAergic interneuron precursor transcription factors NKX2.1, OLIG2 and COUP-TFII in early fetal human telencephalon.

PubMed

Alzu'bi, Ayman; Lindsay, Susan; Kerwin, Janet; Looi, Shi Jie; Khalil, Fareha; Clowry, Gavin J

2017-07-01

The extent of similarities and differences between cortical GABAergic interneuron generation in rodent and primate telencephalon remains contentious. We examined expression of three interneuron precursor transcription factors, alongside other markers, using immunohistochemistry on 8-12 post-conceptional weeks (PCW) human telencephalon sections. NKX2.1, OLIG2, and COUP-TFII expression occupied distinct (although overlapping) neurogenic domains which extended into the cortex and revealed three CGE compartments: lateral, medial, and ventral. NKX2.1 expression was very largely confined to the MGE, medial CGE, and ventral septum confirming that, at this developmental stage, interneuron generation from NKX2.1+ precursors closely resembles the process observed in rodents. OLIG2 immunoreactivity was observed in GABAergic cells of the proliferative zones of the MGE and septum, but not necessarily co-expressed with NKX2.1, and OLIG2 expression was also extensively seen in the LGE, CGE, and cortex. At 8 PCW, OLIG2+ cells were only present in the medial and anterior cortical wall suggesting a migratory pathway for interneuron precursors via the septum into the medial cortex. By 12 PCW, OLIG2+ cells were present throughout the cortex and many were actively dividing but without co-expressing cortical progenitor markers. Dividing COUP-TFII+ progenitor cells were localized to ventral CGE as previously described but were also numerous in adjacent ventral cortex; in both the cases, COUP-TFII was co-expressed with PAX6 in proliferative zones and TBR1 or calretinin in post-mitotic cortical neurons. Thus COUP-TFII+ progenitors gave rise to pyramidal cells, but also interneurons which not only migrated posteriorly into the cortex from ventral CGE but also anteriorly via the LGE.

Cortical GABAergic Interneurons in Cross-Modal Plasticity following Early Blindness

PubMed Central

Desgent, Sébastien; Ptito, Maurice

2012-01-01

Early loss of a given sensory input in mammals causes anatomical and functional modifications in the brain via a process called cross-modal plasticity. In the past four decades, several animal models have illuminated our understanding of the biological substrates involved in cross-modal plasticity. Progressively, studies are now starting to emphasise on cell-specific mechanisms that may be responsible for this intermodal sensory plasticity. Inhibitory interneurons expressing γ-aminobutyric acid (GABA) play an important role in maintaining the appropriate dynamic range of cortical excitation, in critical periods of developmental plasticity, in receptive field refinement, and in treatment of sensory information reaching the cerebral cortex. The diverse interneuron population is very sensitive to sensory experience during development. GABAergic neurons are therefore well suited to act as a gate for mediating cross-modal plasticity. This paper attempts to highlight the links between early sensory deprivation, cortical GABAergic interneuron alterations, and cross-modal plasticity, discuss its implications, and further provide insights for future research in the field. PMID:22720175

Neurogliaform cortical interneurons derive from cells in the preoptic area

PubMed Central

Cadilhac, Christelle; Prados, Julien; Holtmaat, Anthony

2018-01-01

Delineating the basic cellular components of cortical inhibitory circuits remains a fundamental issue in order to understand their specific contributions to microcircuit function. It is still unclear how current classifications of cortical interneuron subtypes relate to biological processes such as their developmental specification. Here we identified the developmental trajectory of neurogliaform cells (NGCs), the main effectors of a powerful inhibitory motif recruited by long-range connections. Using in vivo genetic lineage-tracing in mice, we report that NGCs originate from a specific pool of 5-HT3AR-expressing Hmx3+ cells located in the preoptic area (POA). Hmx3-derived 5-HT3AR+ cortical interneurons (INs) expressed the transcription factors PROX1, NR2F2, the marker reelin but not VIP and exhibited the molecular, morphological and electrophysiological profile of NGCs. Overall, these results indicate that NGCs are a distinct class of INs with a unique developmental trajectory and open the possibility to study their specific functional contribution to cortical inhibitory microcircuit motifs. PMID:29557780

Probing phase- and frequency-dependent characteristics of cortical interneurons using combined transcranial alternating current stimulation and transcranial magnetic stimulation.

PubMed

Hussain, Sara J; Thirugnanasambandam, Nivethida

2017-06-01

Paired-pulse transcranial magnetic stimulation (TMS) and peripheral stimulation combined with TMS can be used to study cortical interneuronal circuitry. By combining these procedures with concurrent transcranial alternating current stimulation (tACS), Guerra and colleagues recently showed that different cortical interneuronal populations are differentially modulated by the phase and frequency of tACS-imposed oscillations (Guerra A, Pogosyan A, Nowak M, Tan H, Ferreri F, Di Lazzaro V, Brown P. Cerebral Cortex 26: 3977-2990, 2016). This work suggests that different cortical interneuronal populations can be characterized by their phase and frequency dependency. Here we discuss how combining TMS and tACS can reveal the frequency at which cortical interneuronal populations oscillate, the neuronal origins of behaviorally relevant cortical oscillations, and how entraining cortical oscillations could potentially treat brain disorders. Copyright © 2017 the American Physiological Society.

New insights into the classification and nomenclature of cortical GABAergic interneurons.

PubMed

DeFelipe, Javier; López-Cruz, Pedro L; Benavides-Piccione, Ruth; Bielza, Concha; Larrañaga, Pedro; Anderson, Stewart; Burkhalter, Andreas; Cauli, Bruno; Fairén, Alfonso; Feldmeyer, Dirk; Fishell, Gord; Fitzpatrick, David; Freund, Tamás F; González-Burgos, Guillermo; Hestrin, Shaul; Hill, Sean; Hof, Patrick R; Huang, Josh; Jones, Edward G; Kawaguchi, Yasuo; Kisvárday, Zoltán; Kubota, Yoshiyuki; Lewis, David A; Marín, Oscar; Markram, Henry; McBain, Chris J; Meyer, Hanno S; Monyer, Hannah; Nelson, Sacha B; Rockland, Kathleen; Rossier, Jean; Rubenstein, John L R; Rudy, Bernardo; Scanziani, Massimo; Shepherd, Gordon M; Sherwood, Chet C; Staiger, Jochen F; Tamás, Gábor; Thomson, Alex; Wang, Yun; Yuste, Rafael; Ascoli, Giorgio A

2013-03-01

A systematic classification and accepted nomenclature of neuron types is much needed but is currently lacking. This article describes a possible taxonomical solution for classifying GABAergic interneurons of the cerebral cortex based on a novel, web-based interactive system that allows experts to classify neurons with pre-determined criteria. Using Bayesian analysis and clustering algorithms on the resulting data, we investigated the suitability of several anatomical terms and neuron names for cortical GABAergic interneurons. Moreover, we show that supervised classification models could automatically categorize interneurons in agreement with experts' assignments. These results demonstrate a practical and objective approach to the naming, characterization and classification of neurons based on community consensus.

Coherent ongoing subthreshold state of a cortical neural network regulated by slow- and fast-spiking interneurons.

PubMed

Hoshino, Osamu

2006-12-01

Although details of cortical interneurons in anatomy and physiology have been well understood, little is known about how they contribute to ongoing spontaneous neuronal activity that could have a great impact on subsequent neuronal information processing. Simulating a cortical neural network model of an early sensory area, we investigated whether and how two distinct types of inhibitory interneurons, or fast-spiking interneurons with narrow axonal arbors and slow-spiking interneurons with wide axonal arbors, have a spatiotemporal influence on the ongoing activity of principal cells and subsequent cognitive information processing. In the model, dynamic cell assemblies, or population activation of principal cells, expressed information about specific sensory features. Within cell assemblies, fast-spiking interneurons give a feedback inhibitory effect on principal cells. Between cell assemblies, slow-spiking interneurons give a lateral inhibitory effect on principal cells. Here, we show that these interneurons keep the network at a subthreshold level for action potential generation under the ongoing state, by which the reaction time of principal cells to sensory stimulation could be accelerated. We suggest that the best timing of inhibition mediated by fast-spiking interneurons and slow-spiking interneurons allows the network to remain near threshold for rapid responses to input.

New insights into the classification and nomenclature of cortical GABAergic interneurons

PubMed Central

DeFelipe, Javier; López-Cruz, Pedro L.; Benavides-Piccione, Ruth; Bielza, Concha; Larrañaga, Pedro; Anderson, Stewart; Burkhalter, Andreas; Cauli, Bruno; Fairén, Alfonso; Feldmeyer, Dirk; Fishell, Gord; Fitzpatrick, David; Freund, Tamás F.; González-Burgos, Guillermo; Hestrin, Shaul; Hill, Sean; Hof, Patrick R.; Huang, Josh; Jones, Edward G.; Kawaguchi, Yasuo; Kisvárday, Zoltán; Kubota, Yoshiyuki; Lewis, David A.; Marín, Oscar; Markram, Henry; McBain, Chris J.; Meyer, Hanno S.; Monyer, Hannah; Nelson, Sacha B.; Rockland, Kathleen; Rossier, Jean; Rubenstein, John L. R.; Rudy, Bernardo; Scanziani, Massimo; Shepherd, Gordon M.; Sherwood, Chet C.; Staiger, Jochen F.; Tamás, Gábor; Thomson, Alex; Wang, Yun; Yuste, Rafael; Ascoli, Giorgio A.

2013-01-01

A systematic classification and accepted nomenclature of neuron types is much needed but is currently lacking. This article describes a possible taxonomical solution for classifying GABAergic interneurons of the cerebral cortex based on a novel, web-based interactive system that allows experts to classify neurons with pre-determined criteria. Using Bayesian analysis and clustering algorithms on the resulting data, we investigated the suitability of several anatomical terms and neuron names for cortical GABAergic interneurons. Moreover, we show that supervised classification models could automatically categorize interneurons in agreement with experts’ assignments. These results demonstrate a practical and objective approach to the naming, characterization and classification of neurons based on community consensus. PMID:23385869

Dendritic and Axonal Wiring Optimization of Cortical GABAergic Interneurons.

PubMed

Anton-Sanchez, Laura; Bielza, Concha; Benavides-Piccione, Ruth; DeFelipe, Javier; Larrañaga, Pedro

2016-10-01

The way in which a neuronal tree expands plays an important role in its functional and computational characteristics. We aimed to study the existence of an optimal neuronal design for different types of cortical GABAergic neurons. To do this, we hypothesized that both the axonal and dendritic trees of individual neurons optimize brain connectivity in terms of wiring length. We took the branching points of real three-dimensional neuronal reconstructions of the axonal and dendritic trees of different types of cortical interneurons and searched for the minimal wiring arborization structure that respects the branching points. We compared the minimal wiring arborization with real axonal and dendritic trees. We tested this optimization problem using a new approach based on graph theory and evolutionary computation techniques. We concluded that neuronal wiring is near-optimal in most of the tested neurons, although the wiring length of dendritic trees is generally nearer to the optimum. Therefore, wiring economy is related to the way in which neuronal arborizations grow irrespective of the marked differences in the morphology of the examined interneurons.

Dlx1&2-Dependent Expression of Zfhx1b (Sip1, Zeb2) Regulates the Fate Switch Between Cortical and Striatal Interneurons

PubMed Central

McKinsey, Gabriel L.; Lindtner, Susan; Trzcinski, Brett; Visel, Axel; Pennacchio, Len A.; Huylebroeck, Danny; Higashi, Yujiro; Rubenstein, John L. R.

2013-01-01

Summary Mammalian pallial (cortical and hippocampal) and striatal interneurons are both generated in the embryonic subpallium, including the medial ganglionic eminence (MGE). Herein we demonstrate that the Zfhx1b (Sip1, Zeb2) zinc finger homeobox gene is required in the MGE, directly downstream of Dlx1&2, to generate cortical interneurons that express Cxcr7, MafB and cMaf. In its absence, Nkx2-1 expression is not repressed, and cells that ordinarily would become cortical interneurons appear to transform towards a subtype of GABAeric striatal interneurons. These results show that Zfhx1b is required to generate cortical interneurons, and suggest a mechanism for the epilepsy observed in humans with Zfhx1b mutations (Mowat-Wilson syndrome). PMID:23312518

Somatostatin-Positive Gamma-Aminobutyric Acid Interneuron Deficits in Depression: Cortical Microcircuit and Therapeutic Perspectives.

PubMed

Fee, Corey; Banasr, Mounira; Sibille, Etienne

2017-10-15

The functional integration of external and internal signals forms the basis of information processing and is essential for higher cognitive functions. This occurs in finely tuned cortical microcircuits whose functions are balanced at the cellular level by excitatory glutamatergic pyramidal neurons and inhibitory gamma-aminobutyric acidergic (GABAergic) interneurons. The balance of excitation and inhibition, from cellular processes to neural network activity, is characteristically disrupted in multiple neuropsychiatric disorders, including major depressive disorder (MDD), bipolar disorder, anxiety disorders, and schizophrenia. Specifically, nearly 3 decades of research demonstrate a role for reduced inhibitory GABA level and function across disorders. In MDD, recent evidence from human postmortem and animal studies suggests a selective vulnerability of GABAergic interneurons that coexpress the neuropeptide somatostatin (SST). Advances in cell type-specific molecular genetics have now helped to elucidate several important roles for SST interneurons in cortical processing (regulation of pyramidal cell excitatory input) and behavioral control (mood and cognition). Here, we review evidence for altered inhibitory function arising from GABAergic deficits across disorders and specifically in MDD. We then focus on properties of the cortical microcircuit, where SST-positive GABAergic interneuron deficits may disrupt functioning in several ways. Finally, we discuss the putative origins of SST cell deficits, as informed by recent research, and implications for therapeutic approaches. We conclude that deficits in SST interneurons represent a contributing cellular pathology and therefore a promising target for normalizing altered inhibitory function in MDD and other disorders with reduced SST cell and GABA functions. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Tangential migration of glutamatergic neurons and cortical patterning during development: Lessons from Cajal-Retzius cells.

PubMed

Barber, Melissa; Pierani, Alessandra

2016-08-01

Tangential migration is a mode of cell movement, which in the developing cerebral cortex, is defined by displacement parallel to the ventricular surface and orthogonal to the radial glial fibers. This mode of long-range migration is a strategy by which distinct neuronal classes generated from spatially and molecularly distinct origins can integrate to form appropriate neural circuits within the cortical plate. While it was previously believed that only GABAergic cortical interneurons migrate tangentially from their origins in the subpallial ganglionic eminences to integrate in the cortical plate, it is now known that transient populations of glutamatergic neurons also adopt this mode of migration. These include Cajal-Retzius cells (CRs), subplate neurons (SPs), and cortical plate transient neurons (CPTs), which have crucial roles in orchestrating the radial and tangential development of the embryonic cerebral cortex in a noncell-autonomous manner. While CRs have been extensively studied, it is only in the last decade that the molecular mechanisms governing their tangential migration have begun to be elucidated. To date, the mechanisms of SPs and CPTs tangential migration remain unknown. We therefore review the known signaling pathways, which regulate parameters of CRs migration including their motility, contact-redistribution and adhesion to the pial surface, and discuss this in the context of how CR migration may regulate their signaling activity in a spatial and temporal manner. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 847-881, 2016. © 2015 Wiley Periodicals, Inc.

SDF1 Reduces Interneuron Leading Process Branching through Dual Regulation of Actin and Microtubules

PubMed Central

Lysko, Daniel E.; Putt, Mary

2014-01-01

Normal cerebral cortical function requires a highly ordered balance between projection neurons and interneurons. During development these two neuronal populations migrate from distinct progenitor zones to form the cerebral cortex, with interneurons originating in the more distant ganglionic eminences. Moreover, deficits in interneurons have been linked to a variety of neurodevelopmental disorders underscoring the importance of understanding interneuron development and function. We, and others, have identified SDF1 signaling as one important modulator of interneuron migration speed and leading process branching behavior in mice, although how SDF1 signaling impacts these behaviors remains unknown. We previously found SDF1 inhibited leading process branching while increasing the rate of migration. We have now mechanistically linked SDF1 modulation of leading process branching behavior to a dual regulation of both actin and microtubule organization. We find SDF1 consolidates actin at the leading process tip by de-repressing calpain protease and increasing proteolysis of branched-actin-supporting cortactin. Additionally, SDF1 stabilizes the microtubule array in the leading process through activation of the microtubule-associated protein doublecortin (DCX). DCX stabilizes the microtubule array by bundling microtubules within the leading process, reducing branching. These data provide mechanistic insight into the regulation of interneuron leading process dynamics during neuronal migration in mice and provides insight into how cortactin and DCX, a known human neuronal migration disorder gene, participate in this process. PMID:24695713

GSK-3 signaling in developing cortical neurons is essential for radial migration and dendritic orientation.

PubMed

Morgan-Smith, Meghan; Wu, Yaohong; Zhu, Xiaoqin; Pringle, Julia; Snider, William D

2014-07-29

GSK-3 is an essential mediator of several signaling pathways that regulate cortical development. We therefore created conditional mouse mutants lacking both GSK-3α and GSK-3β in newly born cortical excitatory neurons. Gsk3-deleted neurons expressing upper layer markers exhibited striking migration failure in all areas of the cortex. Radial migration in hippocampus was similarly affected. In contrast, tangential migration was not grossly impaired after Gsk3 deletion in interneuron precursors. Gsk3-deleted neurons extended axons and developed dendritic arbors. However, the apical dendrite was frequently branched while basal dendrites exhibited abnormal orientation. GSK-3 regulation of migration in neurons was independent of Wnt/β-catenin signaling. Importantly, phosphorylation of the migration mediator, DCX, at ser327, and phosphorylation of the semaphorin signaling mediator, CRMP-2, at Thr514 were markedly decreased. Our data demonstrate that GSK-3 signaling is essential for radial migration and dendritic orientation and suggest that GSK-3 mediates these effects by phosphorylating key microtubule regulatory proteins.DOI: http://dx.doi.org/10.7554/eLife.02663.001. Copyright © 2014, Morgan-Smith et al.

Arid1b haploinsufficiency disrupts cortical interneuron development and mouse behavior.

PubMed

Jung, Eui-Man; Moffat, Jeffrey Jay; Liu, Jinxu; Dravid, Shashank Manohar; Gurumurthy, Channabasavaiah Basavaraju; Kim, Woo-Yang

2017-12-01

Haploinsufficiency of the AT-rich interactive domain 1B (ARID1B) gene causes autism spectrum disorder and intellectual disability; however, the neurobiological basis for this is unknown. Here we generated Arid1b-knockout mice and examined heterozygotes to model human patients. Arid1b-heterozygous mice showed a decreased number of cortical GABAergic interneurons and reduced proliferation of interneuron progenitors in the ganglionic eminence. Arid1b haploinsufficiency also led to an imbalance between excitatory and inhibitory synapses in the cerebral cortex. Furthermore, we found that Arid1b haploinsufficiency suppressed histone H3 lysine 9 acetylation (H3K9ac) overall and particularly reduced H3K9ac of the Pvalb promoter, resulting in decreased transcription. Arid1b-heterozygous mice exhibited abnormal cognitive and social behaviors, which were rescued by treatment with a positive allosteric GABA A receptor modulator. Our results demonstrate a critical role for Arid1b in interneuron development and behavior and provide insight into the pathogenesis of autism spectrum disorder and intellectual disability.

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

Role of Somatostatin-Positive Cortical Interneurons in the Generation of Sleep Slow Waves.

PubMed

Funk, Chadd M; Peelman, Kayla; Bellesi, Michele; Marshall, William; Cirelli, Chiara; Tononi, Giulio

2017-09-20

During non-rapid eye-movement (NREM) sleep, cortical and thalamic neurons oscillate every second or so between ON periods, characterized by membrane depolarization and wake-like tonic firing, and OFF periods, characterized by membrane hyperpolarization and neuronal silence. Cortical slow waves, the hallmark of NREM sleep, reflect near-synchronous OFF periods in cortical neurons. However, the mechanisms triggering such OFF periods are unclear, as there is little evidence for somatic inhibition. We studied cortical inhibitory interneurons that express somatostatin (SOM), because ∼70% of them are Martinotti cells that target diffusely layer I and can block excitatory transmission presynaptically, at glutamatergic terminals, and postsynaptically, at apical dendrites, without inhibiting the soma. In freely moving male mice, we show that SOM+ cells can fire immediately before slow waves and their optogenetic stimulation during ON periods of NREM sleep triggers long OFF periods. Next, we show that chemogenetic activation of SOM+ cells increases slow-wave activity (SWA), slope of individual slow waves, and NREM sleep duration; whereas their chemogenetic inhibition decreases SWA and slow-wave incidence without changing time spent in NREM sleep. By contrast, activation of parvalbumin+ (PV+) cells, the most numerous population of cortical inhibitory neurons, greatly decreases SWA and cortical firing, triggers short OFF periods in NREM sleep, and increases NREM sleep duration. Thus SOM+ cells, but not PV+ cells, are involved in the generation of sleep slow waves. Whether Martinotti cells are solely responsible for this effect, or are complemented by other classes of inhibitory neurons, remains to be investigated. SIGNIFICANCE STATEMENT Cortical slow waves are a defining feature of non-rapid eye-movement (NREM) sleep and are thought to be important for many of its restorative benefits. Yet, the mechanism by which cortical neurons abruptly and synchronously cease firing, the

Characterization of focal cortical dysplasia with balloon cells by layer-specific markers: Evidence for differential vulnerability of interneurons.

PubMed

Nakagawa, Julia M; Donkels, Catharina; Fauser, Susanne; Schulze-Bonhage, Andreas; Prinz, Marco; Zentner, Josef; Haas, Carola A

2017-04-01

Focal cortical dysplasia (FCD) is a major cause of pharmacoresistant focal epilepsy. Little is known about the pathomechanisms underlying the characteristic cytoarchitectural abnormalities associated with FCD. In the present study, a broad panel of markers identifying layer-specific neuron subpopulations was applied to characterize dyslamination and structural alterations in FCD with balloon cells (FCD 2b). Pan-neuronal neuronal nuclei (NeuN) and layer-specific protein expression (Reelin, Calbindin, Calretinin, SMI32 (nonphosphorylated neurofilament H), Parvalbumin, transducin-like enhancer protein 4 (TLE4), and Vimentin) was studied by immunohistochemistry on paraffin sections of FCD2b cases (n = 22) and was compared to two control groups with (n = 7) or without epilepsy (n = 4 postmortem cases). Total and layer-specific neuron densities were systematically quantified by cell counting considering age at surgery and brain region. We show that in FCD2b total neuron densities across all six cortical layers were not significantly different from controls. In addition, we present evidence that a basic laminar arrangement of layer-specific neuron subtypes was preserved despite the severe disturbance of cortical structure. SMI32-positive pyramidal neurons showed no significant difference in total numbers, but a reduction in layers III and V. The densities of supragranular Calbindin- and Calretinin-positive interneurons in layers II and III were not different from controls, whereas Parvalbumin-expressing interneurons, primarily located in layer IV, were significantly reduced in numbers when compared to control cases without epilepsy. In layer VI, the density of TLE4-positive projection neurons was significantly increased. Altogether, these data show that changes in cellular composition mainly affect deep cortical layers in FCD2b. The application of a broad panel of markers defining layer-specific neuronal subpopulations revealed that in FCD2b neuronal diversity and a basic

Ketamine alters cortical integration of GABAergic interneurons and induces long-term sex-dependent impairments in transgenic Gad67-GFP mice.

PubMed

Aligny, C; Roux, C; Dourmap, N; Ramdani, Y; Do-Rego, J-C; Jégou, S; Leroux, P; Leroux-Nicollet, I; Marret, S; Gonzalez, B J

2014-07-03

Ketamine, a non-competitive N-methyl-D-aspartate (NMDA) antagonist, widely used as an anesthetic in neonatal pediatrics, is also an illicit drug named Super K or KitKat consumed by teens and young adults. In the immature brain, despite several studies indicating that NMDA antagonists are neuroprotective against excitotoxic injuries, there is more and more evidence indicating that these molecules exert a deleterious effect by suppressing a trophic function of glutamate. In the present study, we show using Gad67-GFP mice that prenatal exposure to ketamine during a time-window in which GABAergic precursors are migrating results in (i) strong apoptotic death in the ganglionic eminences and along the migratory routes of GABAergic interneurons; (ii) long-term deficits in interneuron density, dendrite numbers and spine morphology; (iii) a sex-dependent deregulation of γ-aminobutyric acid (GABA) levels and GABA transporter expression; (iv) sex-dependent changes in the response to glutamate-induced calcium mobilization; and (v) the long-term sex-dependent behavioral impairment of locomotor activity. In conclusion, using a preclinical approach, the present study shows that ketamine exposure during cortical maturation durably affects the integration of GABAergic interneurons by reducing their survival and differentiation. The resulting molecular, morphological and functional modifications are associated with sex-specific behavioral deficits in adults. In light of the present data, it appears that in humans, ketamine could be deleterious for the development of the brain of preterm neonates and fetuses of addicted pregnant women.

Temporal lobe cortical pathology and inhibitory GABA interneuron cell loss are associated with seizures in multiple sclerosis

PubMed Central

Nicholas, Richard; Magliozzi, Roberta; Campbell, Graham; Mahad, Don; Reynolds, Richard

2016-01-01

Background: Seizures are recognised in multiple sclerosis (MS), but their true incidence and the mechanism by which they are associated with MS is unclear. Objective: The objective of this paper is to determine the lifetime frequency of seizures in the United Kingdom MS Tissue Bank (UKMSTB) population and any pathological features associated with seizures. Methods: We evaluated 255 individuals from the UKMSTB. A subset underwent analysis of cortical thickness, grey matter lesion (GML) (type and number) and cortical neuronal numbers (total and GABAergic). Results: A total of 37/255 patients had seizures (14.5% lifetime incidence); in 47% they were associated with concurrent infection. In those with seizures, death and wheelchair use occurred earlier and in 59% seizures developed after 15 years of disease. Seizures were associated with Type 1 GMLs and reduced cortical thickness in the middle temporal gyrus. Localised selective GABAergic interneuron loss in layers IV and VI was related to GMLs but was not explained by the presence of inflammation or by mitochondrial dysfunction within Type I GMLs. Conclusion: We confirm that seizure frequency rises in MS. Type I GMLs in the temporal lobe underlie a loss of inhibitory interneurons in cortical layers IV and VI and these changes could together with concurrent infection enhance susceptibility to seizures. PMID:25921040

Temporal lobe cortical pathology and inhibitory GABA interneuron cell loss are associated with seizures in multiple sclerosis.

PubMed

Nicholas, Richard; Magliozzi, Roberta; Campbell, Graham; Mahad, Don; Reynolds, Richard

2016-01-01

Seizures are recognised in multiple sclerosis (MS), but their true incidence and the mechanism by which they are associated with MS is unclear. The objective of this paper is to determine the lifetime frequency of seizures in the United Kingdom MS Tissue Bank (UKMSTB) population and any pathological features associated with seizures. We evaluated 255 individuals from the UKMSTB. A subset underwent analysis of cortical thickness, grey matter lesion (GML) (type and number) and cortical neuronal numbers (total and GABAergic). A total of 37/255 patients had seizures (14.5% lifetime incidence); in 47% they were associated with concurrent infection. In those with seizures, death and wheelchair use occurred earlier and in 59% seizures developed after 15 years of disease. Seizures were associated with Type 1 GMLs and reduced cortical thickness in the middle temporal gyrus. Localised selective GABAergic interneuron loss in layers IV and VI was related to GMLs but was not explained by the presence of inflammation or by mitochondrial dysfunction within Type I GMLs. We confirm that seizure frequency rises in MS. Type I GMLs in the temporal lobe underlie a loss of inhibitory interneurons in cortical layers IV and VI and these changes could together with concurrent infection enhance susceptibility to seizures. © The Author(s), 2015.

Cortical interneuron dysfunction in epilepsy associated with autism spectrum disorders.

PubMed

Jacob, John

2016-02-01

Autism and epilepsy are two associated disorders that are highly prevalent, share common developmental origins, and demonstrate substantial heritability. In this review, cross-disciplinary data in a rapidly evolving field that bridges neurology and psychiatry are synthesized to identify shared biologic mechanisms. The relationship between these debilitating, lifelong conditions is examined at the clinical, genetic, and neurophysiologic levels in humans and in animal models. Scopus and PubMed searches were used to identify relevant literature. Clinical observations have prompted speculation about the interdependence of autism and epilepsy, but causal relationships have proved difficult to determine. Despite their heritability, the genetic basis of autism spectrum disorder (ASD) and epilepsy has remained largely elusive until the advent of next-generation sequencing. This approach has revealed that mutations that are either causal or confer an increased disease risk are found in numerous different genes, any one of which accounts for only a small percentage of cases. Conversely, even cases with identical clinical phenotypes can be genetically heterogeneous. Candidate gene identification has facilitated the development of mouse genetic models, which in parallel with human studies have implicated shared brain regions and circuits that mediate disease expression. Diverse genetic causes of ASD and epilepsy converge on cortical interneuron circuits as one important mediator of both disorders. Cortical interneurons are among the most diverse cell types in the brain and their unique chemical and electrical coupling exert a powerful inhibitory influence on excitatory neurons via the release of the neurotransmitter, γ-aminobutyric acid (GABA). These multifaceted approaches have validated theories derived from the field of developmental neurobiology, which propose that the neurologic and neuropsychiatric manifestations are caused by an altered ratio of excitation to

Aging increases microglial proliferation, delays cell migration, and decreases cortical neurogenesis after focal cerebral ischemia.

PubMed

Moraga, Ana; Pradillo, Jesús M; García-Culebras, Alicia; Palma-Tortosa, Sara; Ballesteros, Ivan; Hernández-Jiménez, Macarena; Moro, María A; Lizasoain, Ignacio

2015-05-10

Aging is not just a risk factor of stroke, but it has also been associated with poor recovery. It is known that stroke-induced neurogenesis is reduced but maintained in the aged brain. However, there is no consensus on how neurogenesis is affected after stroke in aged animals. Our objective is to determine the role of aging on the process of neurogenesis after stroke. We have studied neurogenesis by analyzing proliferation, migration, and formation of new neurons, as well as inflammatory parameters, in a model of cerebral ischemia induced by permanent occlusion of the middle cerebral artery in young- (2 to 3 months) and middle-aged mice (13 to 14 months). Aging increased both microglial proliferation, as shown by a higher number of BrdU(+) cells and BrdU/Iba1(+) cells in the ischemic boundary and neutrophil infiltration. Interestingly, aging increased the number of M1 monocytes and N1 neutrophils, consistent with pro-inflammatory phenotypes when compared with the alternative M2 and N2 phenotypes. Aging also inhibited (subventricular zone) SVZ cell proliferation by decreasing both the number of astrocyte-like type-B (prominin-1(+)/epidermal growth factor receptor (EGFR)(+)/nestin(+)/glial fibrillary acidic protein (GFAP)(+) cells) and type-C cells (prominin-1(+)/EGFR(+)/nestin(-)/Mash1(+) cells), and not affecting apoptosis, 1 day after stroke. Aging also inhibited migration of neuroblasts (DCX(+) cells), as indicated by an accumulation of neuroblasts at migratory zones 14 days after injury; consistently, aged mice presented a smaller number of differentiated interneurons (NeuN(+)/BrdU(+) and GAD67(+) cells) in the peri-infarct cortical area 14 days after stroke. Our data confirm that stroke-induced neurogenesis is maintained but reduced in aged animals. Importantly, we now demonstrate that aging not only inhibits proliferation of specific SVZ cell subtypes but also blocks migration of neuroblasts to the damaged area and decreases the number of new interneurons in

Bayesian network classifiers for categorizing cortical GABAergic interneurons.

PubMed

Mihaljević, Bojan; Benavides-Piccione, Ruth; Bielza, Concha; DeFelipe, Javier; Larrañaga, Pedro

2015-04-01

An accepted classification of GABAergic interneurons of the cerebral cortex is a major goal in neuroscience. A recently proposed taxonomy based on patterns of axonal arborization promises to be a pragmatic method for achieving this goal. It involves characterizing interneurons according to five axonal arborization features, called F1-F5, and classifying them into a set of predefined types, most of which are established in the literature. Unfortunately, there is little consensus among expert neuroscientists regarding the morphological definitions of some of the proposed types. While supervised classifiers were able to categorize the interneurons in accordance with experts' assignments, their accuracy was limited because they were trained with disputed labels. Thus, here we automatically classify interneuron subsets with different label reliability thresholds (i.e., such that every cell's label is backed by at least a certain (threshold) number of experts). We quantify the cells with parameters of axonal and dendritic morphologies and, in order to predict the type, also with axonal features F1-F4 provided by the experts. Using Bayesian network classifiers, we accurately characterize and classify the interneurons and identify useful predictor variables. In particular, we discriminate among reliable examples of common basket, horse-tail, large basket, and Martinotti cells with up to 89.52% accuracy, and single out the number of branches at 180 μm from the soma, the convex hull 2D area, and the axonal features F1-F4 as especially useful predictors for distinguishing among these types. These results open up new possibilities for an objective and pragmatic classification of interneurons.

Chemokine receptors and cortical interneuron dysfunction in schizophrenia.

PubMed

Volk, David W; Chitrapu, Anjani; Edelson, Jessica R; Lewis, David A

2015-09-01

Alterations in inhibitory (GABA) neurons, including deficiencies in the GABA synthesizing enzyme GAD67, in the prefrontal cortex in schizophrenia are pronounced in the subpopulations of neurons that contain the calcium-binding protein parvalbumin or the neuropeptide somatostatin. The presence of similar illness-related deficits in the transcription factor Lhx6, which regulates prenatal development of parvalbumin and somatostatin neurons, suggests that cortical GABA neuron dysfunction may be related to disturbances in utero. Since the chemokine receptors CXCR4 and CXCR7 guide the migration of cortical parvalbumin and somatostatin neurons from their birthplace in the medial ganglionic eminence to their final destination in the neocortex, we sought to determine whether altered CXCR4 and/or CXCR7 mRNA levels were associated with disturbances in GABA-related markers in schizophrenia. Quantitative PCR was used to quantify CXCR4 and CXCR7 mRNA levels in the prefrontal cortex of 62 schizophrenia and 62 healthy comparison subjects that were previously characterized for markers of parvalbumin and somatostatin neurons and in antipsychotic-exposed monkeys. We found elevated mRNA levels for CXCR7 (+29%; p<.0001) and CXCR4 (+14%, p=.052) in schizophrenia subjects but not in antipsychotic-exposed monkeys. CXCR7 mRNA levels were inversely correlated with mRNA levels for GAD67, parvalbumin, somatostatin, and Lhx6 in schizophrenia but not in healthy subjects. These findings suggest that higher mRNA levels for CXCR7, and possibly CXCR4, may represent a compensatory mechanism to sustain the migration and correct positioning of cortical parvalbumin and somatostatin neurons in the face of other insults that disrupt the prenatal development of cortical GABA neurons in schizophrenia. Copyright © 2014 Elsevier B.V. All rights reserved.

Ex Utero Electroporation and Organotypic Slice Cultures of Embryonic Mouse Brains for Live-Imaging of Migrating GABAergic Interneurons.

PubMed

Eid, Lara; Lachance, Mathieu; Hickson, Gilles; Rossignol, Elsa

2018-04-20

GABAergic interneurons (INs) are critical components of neuronal networks that drive cognition and behavior. INs destined to populate the cortex migrate tangentially from their place of origin in the ventral telencephalon (including from the medial and caudal ganglionic eminences (MGE, CGE)) to the dorsal cortical plate in response to a variety of intrinsic and extrinsic cues. Different methodologies have been developed over the years to genetically manipulate specific pathways and investigate how they regulate the dynamic cytoskeletal changes required for proper IN migration. In utero electroporation has been extensively used to study the effect of gene repression or overexpression in specific IN subtypes while assessing the impact on morphology and final position. However, while this approach is readily used to modify radially migrating pyramidal cells, it is more technically challenging when targeting INs. In utero electroporation generates a low yield given the decreased survival rates of pups when electroporation is conducted before e14.5, as is customary when studying MGE-derived INs. In an alternative approach, MGE explants provide easy access to the MGE and facilitate the imaging of genetically modified INs. However, in these explants, INs migrate into an artificial matrix, devoid of endogenous guidance cues and thalamic inputs. This prompted us to optimize a method where INs can migrate in a more naturalistic environment, while circumventing the technical challenges of in utero approaches. In this paper, we describe the combination of ex utero electroporation of embryonic mouse brains followed by organotypic slice cultures to readily track, image and reconstruct genetically modified INs migrating along their natural paths in response to endogenous cues. This approach allows for both the quantification of the dynamic aspects of IN migration with time-lapse confocal imaging, as well as the detailed analysis of various morphological parameters using neuronal

Postnatal development of GABAergic interneurons in the neocortical subplate of mice.

PubMed

Qu, G-J; Ma, J; Yu, Y-C; Fu, Y

2016-05-13

The subplate (SP) plays important roles in developmental and functional events in the neocortex, such as thalamocortical and corticofugal projection, cortical oscillation generation and corticocortical connectivity. Although accumulated evidence indicates that SP interneurons are crucial for SP function, the molecular composition of SP interneurons as well as their developmental profile and distribution remain largely unclear. In this study, we systematically investigated dynamic development of SP thickness and chemical marker expression in SP interneurons in distinct cortical regions during the first postnatal month. We found that, although the relative area of the SP in the cerebral cortex significantly declined with postnatal development, the absolute thickness did not change markedly. We also found that somatostatin (SOM), the ionotropic serotonin receptor 3A (5HT3AR), and parvalbumin (PV) reliably identify three distinct non-overlapping subpopulations of SP interneurons. The SOM group, which represents ~30% of total SP interneurons, expresses neuronal nitric oxide synthase (nNOS) and calbindin (CB) and colocalizes entirely with neuropeptide Y (NPY). The 5HT3AR group, which accounts for ~60% of the total interneuronal population, expresses calretinin (CR) and GABA-A receptor subunit delta (GABAARδ). The PV group accounts for ~10% of total SP interneurons and coexpressed GABAARδ. Moreover, distinct interneuron subtypes show characteristic temporal and spatial distribution in the SP. nNOS(+) interneurons in the SP increase from the anterior motor cortex to posterior visual cortex, while CR(+) and CB(+) interneurons the opposite. Interestedly, the majority of GABAARδ(+) neurons in SP are non-GABAergic neurons in contrast to other cortical layers. These findings clarify and extend our understanding of SP interneurons in the developing cerebral cortex and will underpin further study of SP function. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights

Transcriptional and electrophysiological maturation of neocortical fastspiking GABAergic interneurons

PubMed Central

Okaty, Benjamin W; Miller, Mark N; Sugino, Ken; Hempel, Chris M; Nelson, Sacha B

2009-01-01

Fast-spiking (FS) interneurons are important elements of neocortical circuitry that constitute the primary source of synaptic inhibition in adult cortex and impart temporal organization on ongoing cortical activity. The highly specialized intrinsic membrane and firing properties that allow cortical FS interneurons to perform these functions are due to equally specialized gene expression, which is ultimately coordinated by cell-type-specific transcriptional regulation. While embryonic transcriptional events govern the initial steps of cell-type specification in most cortical interneurons, including FS cells, the electrophysiological properties that distinguish adult cortical cell types emerge relatively late in postnatal development, and the transcriptional events that drive this maturational process are not known. To address this, we used mouse whole-genome microarrays and whole-cell patch clamp to characterize the transcriptional and electrophysiological maturation of cortical FS interneurons between postnatal day 7 (P7) and P40. We found that the intrinsic and synaptic physiology of FS cells undergoes profound regulation over the first four postnatal weeks, and that these changes are correlated with largely monotonic but bidirectional transcriptional regulation of thousands of genes belonging to multiple functional classes. Using our microarray screen as a guide, we discovered that upregulation of 2-pore K+ leak channels between P10 and P25 contributes to one of the major differences between the intrinsic membrane properties of immature and adult FS cells, and found a number of other candidate genes that likely confer cell-type specificity on mature FS cells. PMID:19474331

Ascl1 promotes tangential migration and confines migratory routes by induction of Ephb2 in the telencephalon

PubMed Central

Liu, Yuan-Hsuan; Tsai, Jin-Wu; Chen, Jia-Long; Yang, Wan-Shan; Chang, Pei-Ching; Cheng, Pei-Lin; Turner, David L.; Yanagawa, Yuchio; Wang, Tsu-Wei; Yu, Jenn-Yah

2017-01-01

During development, cortical interneurons generated from the ventral telencephalon migrate tangentially into the dorsal telencephalon. Although Achaete-scute family bHLH transcription factor 1 (Ascl1) plays important roles in the developing telencephalon, whether Ascl1 regulates tangential migration remains unclear. Here, we found that Ascl1 promoted tangential migration along the ventricular zone/subventricular zone (VZ/SVZ) and intermediate zone (IZ) of the dorsal telencephalon. Distal-less homeobox 2 (Dlx2) acted downstream of Ascl1 in promoting tangential migration along the VZ/SVZ but not IZ. We further identified Eph receptor B2 (Ephb2) as a direct target of Ascl1. Knockdown of EphB2 disrupted the separation of the VZ/SVZ and IZ migratory routes. Ephrin-A5, a ligand of EphB2, was sufficient to repel both Ascl1-expressing cells in vitro and tangentially migrating cortical interneurons in vivo. Together, our results demonstrate that Ascl1 induces expression of Dlx2 and Ephb2 to maintain distinct tangential migratory routes in the dorsal telencephalon. PMID:28276447

Molecular and Electrophysiological Characterization of GABAergic Interneurons Expressing the Transcription Factor COUP-TFII in the Adult Human Temporal Cortex

PubMed Central

Varga, Csaba; Tamas, Gabor; Barzo, Pal; Olah, Szabolcs; Somogyi, Peter

2015-01-01

Transcription factors contribute to the differentiation of cortical neurons, orchestrate specific interneuronal circuits, and define synaptic relationships. We have investigated neurons expressing chicken ovalbumin upstream promoter transcription factor II (COUP-TFII), which plays a role in the migration of GABAergic neurons. Whole-cell, patch-clamp recording in vitro combined with colocalization of molecular cell markers in the adult cortex differentiates distinct interneurons. The majority of strongly COUP-TFII-expressing neurons were in layers I–III. Most calretinin (CR) and/or cholecystokinin- (CCK) and/or reelin-positive interneurons were also COUP-TFII-positive. CR-, CCK-, or reelin-positive neurons formed 80%, 20%, or 17% of COUP-TFII-positive interneurons, respectively. About half of COUP-TFII-/CCK-positive interneurons were CR-positive, a quarter of them reelin-positive, but none expressed both. Interneurons positive for COUP-TFII fired irregular, accommodating and adapting trains of action potentials (APs) and innervated mostly small dendritic shafts and rarely spines or somata. Paired recording showed that a calretinin-/COUP-TFII-positive interneuron elicited inhibitory postsynaptic potentials (IPSPs) in a reciprocally connected pyramidal cell. Calbindin, somatostatin, or parvalbumin-immunoreactive interneurons and most pyramidal cells express no immunohistochemically detectable COUP-TFII. In layers V and VI, some pyramidal cells expressed a low level of COUP-TFII in the nucleus. In conclusion, COUP-TFII is expressed in a diverse subset of GABAergic interneurons predominantly innervating small dendritic shafts originating from both interneurons and pyramidal cells. PMID:25787832

Endothelial cell-derived GABA signaling modulates neuronal migration and postnatal behavior

PubMed Central

Li, Suyan; Kumar T, Peeyush; Joshee, Sampada; Kirschstein, Timo; Subburaju, Sivan; Khalili, Jahan S; Kloepper, Jonas; Du, Chuang; Elkhal, Abdallah; Szabó, Gábor; Jain, Rakesh K; Köhling, Rüdiger; Vasudevan, Anju

2018-01-01

The cerebral cortex is essential for integration and processing of information that is required for most behaviors. The exquisitely precise laminar organization of the cerebral cortex arises during embryonic development when neurons migrate successively from ventricular zones to coalesce into specific cortical layers. While radial glia act as guide rails for projection neuron migration, pre-formed vascular networks provide support and guidance cues for GABAergic interneuron migration. This study provides novel conceptual and mechanistic insights into this paradigm of vascular-neuronal interactions, revealing new mechanisms of GABA and its receptor-mediated signaling via embryonic forebrain endothelial cells. With the use of two new endothelial cell specific conditional mouse models of the GABA pathway (Gabrb3ΔTie2-Cre and VgatΔTie2-Cre), we show that partial or complete loss of GABA release from endothelial cells during embryogenesis results in vascular defects and impairs long-distance migration and positioning of cortical interneurons. The downstream effects of perturbed endothelial cell-derived GABA signaling are critical, leading to lasting changes to cortical circuits and persistent behavioral deficits. Furthermore, we illustrate new mechanisms of activation of GABA signaling in forebrain endothelial cells that promotes their migration, angiogenesis and acquisition of blood-brain barrier properties. Our findings uncover and elucidate a novel endothelial GABA signaling pathway in the CNS that is distinct from the classical neuronal GABA signaling pathway and shed new light on the etiology and pathophysiology of neuropsychiatric diseases, such as autism spectrum disorders, epilepsy, anxiety, depression and schizophrenia. PMID:29086765

The Current Status of Somatostatin-Interneurons in Inhibitory Control of Brain Function and Plasticity

PubMed Central

2016-01-01

The mammalian neocortex contains many distinct inhibitory neuronal populations to balance excitatory neurotransmission. A correct excitation/inhibition equilibrium is crucial for normal brain development, functioning, and controlling lifelong cortical plasticity. Knowledge about how the inhibitory network contributes to brain plasticity however remains incomplete. Somatostatin- (SST-) interneurons constitute a large neocortical subpopulation of interneurons, next to parvalbumin- (PV-) and vasoactive intestinal peptide- (VIP-) interneurons. Unlike the extensively studied PV-interneurons, acknowledged as key components in guiding ocular dominance plasticity, the contribution of SST-interneurons is less understood. Nevertheless, SST-interneurons are ideally situated within cortical networks to integrate unimodal or cross-modal sensory information processing and therefore likely to be important mediators of experience-dependent plasticity. The lack of knowledge on SST-interneurons partially relates to the wide variety of distinct subpopulations present in the sensory neocortex. This review informs on those SST-subpopulations hitherto described based on anatomical, molecular, or electrophysiological characteristics and whose functional roles can be attributed based on specific cortical wiring patterns. A possible role for these subpopulations in experience-dependent plasticity will be discussed, emphasizing on learning-induced plasticity and on unimodal and cross-modal plasticity upon sensory loss. This knowledge will ultimately contribute to guide brain plasticity into well-defined directions to restore sensory function and promote lifelong learning. PMID:27403348

Dual role for DOCK7 in tangential migration of interneuron precursors in the postnatal forebrain.

PubMed

Nakamuta, Shinichi; Yang, Yu-Ting; Wang, Chia-Lin; Gallo, Nicholas B; Yu, Jia-Ray; Tai, Yilin; Van Aelst, Linda

2017-12-04

Throughout life, stem cells in the ventricular-subventricular zone generate neuroblasts that migrate via the rostral migratory stream (RMS) to the olfactory bulb, where they differentiate into local interneurons. Although progress has been made toward identifying extracellular factors that guide the migration of these cells, little is known about the intracellular mechanisms that govern the dynamic reshaping of the neuroblasts' morphology required for their migration along the RMS. In this study, we identify DOCK7, a member of the DOCK180-family, as a molecule essential for tangential neuroblast migration in the postnatal mouse forebrain. DOCK7 regulates the migration of these cells by controlling both leading process (LP) extension and somal translocation via distinct pathways. It controls LP stability/growth via a Rac-dependent pathway, likely by modulating microtubule networks while also regulating F-actin remodeling at the cell rear to promote somal translocation via a previously unrecognized myosin phosphatase-RhoA-interacting protein-dependent pathway. The coordinated action of both pathways is required to ensure efficient neuroblast migration along the RMS. © 2017 Nakamuta et al.

Dual role for DOCK7 in tangential migration of interneuron precursors in the postnatal forebrain

PubMed Central

Yang, Yu-Ting; Yu, Jia-Ray; Tai, Yilin

2017-01-01

Throughout life, stem cells in the ventricular–subventricular zone generate neuroblasts that migrate via the rostral migratory stream (RMS) to the olfactory bulb, where they differentiate into local interneurons. Although progress has been made toward identifying extracellular factors that guide the migration of these cells, little is known about the intracellular mechanisms that govern the dynamic reshaping of the neuroblasts’ morphology required for their migration along the RMS. In this study, we identify DOCK7, a member of the DOCK180-family, as a molecule essential for tangential neuroblast migration in the postnatal mouse forebrain. DOCK7 regulates the migration of these cells by controlling both leading process (LP) extension and somal translocation via distinct pathways. It controls LP stability/growth via a Rac-dependent pathway, likely by modulating microtubule networks while also regulating F-actin remodeling at the cell rear to promote somal translocation via a previously unrecognized myosin phosphatase–RhoA–interacting protein-dependent pathway. The coordinated action of both pathways is required to ensure efficient neuroblast migration along the RMS. PMID:29089377

Mechanisms of Firing Patterns in Fast-Spiking Cortical Interneurons

PubMed Central

Golomb, David; Donner, Karnit; Shacham, Liron; Shlosberg, Dan; Amitai, Yael; Hansel, David

2007-01-01

Cortical fast-spiking (FS) interneurons display highly variable electrophysiological properties. Their spike responses to step currents occur almost immediately following the step onset or after a substantial delay, during which subthreshold oscillations are frequently observed. Their firing patterns include high-frequency tonic firing and rhythmic or irregular bursting (stuttering). What is the origin of this variability? In the present paper, we hypothesize that it emerges naturally if one assumes a continuous distribution of properties in a small set of active channels. To test this hypothesis, we construct a minimal, single-compartment conductance-based model of FS cells that includes transient Na+, delayed-rectifier K+, and slowly inactivating d-type K+ conductances. The model is analyzed using nonlinear dynamical system theory. For small Na+ window current, the neuron exhibits high-frequency tonic firing. At current threshold, the spike response is almost instantaneous for small d-current conductance, g d, and it is delayed for larger g d. As g d further increases, the neuron stutters. Noise substantially reduces the delay duration and induces subthreshold oscillations. In contrast, when the Na+ window current is large, the neuron always fires tonically. Near threshold, the firing rates are low, and the delay to firing is only weakly sensitive to noise; subthreshold oscillations are not observed. We propose that the variability in the response of cortical FS neurons is a consequence of heterogeneities in their g d and in the strength of their Na+ window current. We predict the existence of two types of firing patterns in FS neurons, differing in the sensitivity of the delay duration to noise, in the minimal firing rate of the tonic discharge, and in the existence of subthreshold oscillations. We report experimental results from intracellular recordings supporting this prediction. PMID:17696606

Mechanisms of firing patterns in fast-spiking cortical interneurons.

PubMed

Golomb, David; Donner, Karnit; Shacham, Liron; Shlosberg, Dan; Amitai, Yael; Hansel, David

2007-08-01

Cortical fast-spiking (FS) interneurons display highly variable electrophysiological properties. Their spike responses to step currents occur almost immediately following the step onset or after a substantial delay, during which subthreshold oscillations are frequently observed. Their firing patterns include high-frequency tonic firing and rhythmic or irregular bursting (stuttering). What is the origin of this variability? In the present paper, we hypothesize that it emerges naturally if one assumes a continuous distribution of properties in a small set of active channels. To test this hypothesis, we construct a minimal, single-compartment conductance-based model of FS cells that includes transient Na(+), delayed-rectifier K(+), and slowly inactivating d-type K(+) conductances. The model is analyzed using nonlinear dynamical system theory. For small Na(+) window current, the neuron exhibits high-frequency tonic firing. At current threshold, the spike response is almost instantaneous for small d-current conductance, gd, and it is delayed for larger gd. As gd further increases, the neuron stutters. Noise substantially reduces the delay duration and induces subthreshold oscillations. In contrast, when the Na(+) window current is large, the neuron always fires tonically. Near threshold, the firing rates are low, and the delay to firing is only weakly sensitive to noise; subthreshold oscillations are not observed. We propose that the variability in the response of cortical FS neurons is a consequence of heterogeneities in their gd and in the strength of their Na(+) window current. We predict the existence of two types of firing patterns in FS neurons, differing in the sensitivity of the delay duration to noise, in the minimal firing rate of the tonic discharge, and in the existence of subthreshold oscillations. We report experimental results from intracellular recordings supporting this prediction.

Visualization of migration of human cortical neurons generated from induced pluripotent stem cells.

PubMed

Bamba, Yohei; Kanemura, Yonehiro; Okano, Hideyuki; Yamasaki, Mami

2017-09-01

Neuronal migration is considered a key process in human brain development. However, direct observation of migrating human cortical neurons in the fetal brain is accompanied by ethical concerns and is a major obstacle in investigating human cortical neuronal migration. We established a novel system that enables direct visualization of migrating cortical neurons generated from human induced pluripotent stem cells (hiPSCs). We observed the migration of cortical neurons generated from hiPSCs derived from a control and from a patient with lissencephaly. Our system needs no viable brain tissue, which is usually used in slice culture. Migratory behavior of human cortical neuron can be observed more easily and more vividly by its fluorescence and glial scaffold than that by earlier methods. Our in vitro experimental system provides a new platform for investigating development of the human central nervous system and brain malformation. Copyright © 2017 Elsevier B.V. All rights reserved.

GABA Signaling Promotes Synapse Elimination and Axon Pruning in Developing Cortical Inhibitory Interneurons

PubMed Central

Wu, Xiaoyun; Fu, Yu; Knott, Graham; Lu, Jiangteng; Di Cristo, Graziella

2012-01-01

Accumulating evidence indicates that GABA acts beyond inhibitory synaptic transmission and regulates the development of inhibitory synapses in the vertebrate brain, but the underlying cellular mechanism is not well understood. We have combined live imaging of cortical GABAergic axons across time scales from minutes to days with single-cell genetic manipulation of GABA release to examine its role in distinct steps of inhibitory synapse formation in the mouse neocortex. We have shown previously, by genetic knockdown of GABA synthesis in developing interneurons, that GABA signaling promotes the maturation of inhibitory synapses and axons. Here we found that a complete blockade of GABA release in basket interneurons resulted in an opposite effect, a cell-autonomous increase in axon and bouton density with apparently normal synapse structures. These results not only demonstrate that GABA is unnecessary for synapse formation per se but also uncover a novel facet of GABA in regulating synapse elimination and axon pruning. Live imaging revealed that developing GABAergic axons form a large number of transient boutons, but only a subset was stabilized. Release blockade led to significantly increased bouton stability and filopodia density, increased axon branch extension, and decreased branch retraction. Our results suggest that a major component of GABA function in synapse development is transmission-mediated elimination of subsets of nascent contacts. Therefore, GABA may regulate activity-dependent inhibitory synapse formation by coordinately eliminating certain nascent contacts while promoting the maturation of other nascent synapses. PMID:22219294

Soluble guanylate cyclase generation of cGMP regulates migration of MGE neurons.

PubMed

Mandal, Shyamali; Stanco, Amelia; Buys, Emmanuel S; Enikolopov, Grigori; Rubenstein, John L R

2013-10-23

Here we have provided evidence that nitric oxide-cyclic GMP (NO-cGMP) signaling regulates neurite length and migration of immature neurons derived from the medial ganglionic eminence (MGE). Dlx1/2(-/-) and Lhx6(-/-) mouse mutants, which exhibit MGE interneuron migration defects, have reduced expression of the gene encoding the α subunit of a soluble guanylate cyclase (Gucy1A3). Furthermore, Dlx1/2(-/-) mouse mutants have reduced expression of NO synthase 1 (NOS1). Gucy1A3(-/-) mice have a transient reduction in cortical interneuron number. Pharmacological inhibition of soluble guanylate cyclase and NOS activity rapidly induces neurite retraction of MGE cells in vitro and in slice culture and robustly inhibits cell migration from the MGE and caudal ganglionic eminence. We provide evidence that these cellular phenotypes are mediated by activation of the Rho signaling pathway and inhibition of myosin light chain phosphatase activity.

Extensive respiratory chain defects in inhibitory interneurones in patients with mitochondrial disease

PubMed Central

Lax, Nichola Z.; Grady, John; Laude, Alex; Chan, Felix; Hepplewhite, Philippa D.; Gorman, Grainne; Whittaker, Roger G.; Ng, Yi; Cunningham, Mark O.

2015-01-01

Aims Mitochondrial disorders are among the most frequently inherited cause of neurological disease and arise due to mutations in mitochondrial or nuclear DNA. Currently, we do not understand the specific involvement of certain brain regions or selective neuronal vulnerability in mitochondrial disease. Recent studies suggest γ‐aminobutyric acid (GABA)‐ergic interneurones are particularly susceptible to respiratory chain dysfunction. In this neuropathological study, we assess the impact of mitochondrial DNA defects on inhibitory interneurones in patients with mitochondrial disease. Methods Histochemical, immunohistochemical and immunofluorescent assays were performed on post‐mortem brain tissue from 10 patients and 10 age‐matched control individuals. We applied a quantitative immunofluorescent method to interrogate complex I and IV protein expression in mitochondria within GABAergic interneurone populations in the frontal, temporal and occipital cortices. We also evaluated the density of inhibitory interneurones in serial sections to determine if cell loss was occurring. Results We observed significant, global reductions in complex I expression within GABAergic interneurones in frontal, temporal and occipital cortices in the majority of patients. While complex IV expression is more variable, there is reduced expression in patients harbouring m.8344A>G point mutations and POLG mutations. In addition to the severe respiratory chain deficiencies observed in remaining interneurones, quantification of GABAergic cell density showed a dramatic reduction in cell density suggesting interneurone loss. Conclusions We propose that the combined loss of interneurones and severe respiratory deficiency in remaining interneurones contributes to impaired neuronal network oscillations and could underlie development of neurological deficits, such as cognitive impairment and epilepsy, in mitochondrial disease. PMID:25786813

Differential inputs to striatal cholinergic and parvalbumin interneurons imply functional distinctions

PubMed Central

Klug, Jason R; Engelhardt, Max D; Cadman, Cara N; Li, Hao; Smith, Jared B; Ayala, Sarah; Williams, Elora W; Hoffman, Hilary

2018-01-01

Striatal cholinergic (ChAT) and parvalbumin (PV) interneurons exert powerful influences on striatal function in health and disease, yet little is known about the organization of their inputs. Here using rabies tracing, electrophysiology and genetic tools, we compare the whole-brain inputs to these two types of striatal interneurons and dissect their functional connectivity in mice. ChAT interneurons receive a substantial cortical input from associative regions of cortex, such as the orbitofrontal cortex. Amongst subcortical inputs, a previously unknown inhibitory thalamic reticular nucleus input to striatal PV interneurons is identified. Additionally, the external segment of the globus pallidus targets striatal ChAT interneurons, which is sufficient to inhibit tonic ChAT interneuron firing. Finally, we describe a novel excitatory pathway from the pedunculopontine nucleus that innervates ChAT interneurons. These results establish the brain-wide direct inputs of two major types of striatal interneurons and allude to distinct roles in regulating striatal activity and controlling behavior. PMID:29714166

Olig1 function is required to repress Dlx1/2 and interneuron production in mammalian brain

PubMed Central

Silbereis, John C.; Nobuta, Hiroko; Tsai, Hui-Hsin; Heine, Vivi M.; McKinsey, Gabriel L.; Meijer, Dimphna H.; Howard, MacKenzie A.; Petryniak, Magda A.; Potter, Gregory B.; Alberta, John A.; Baraban, Scott C.; Stiles, Charles D.; Rubenstein, John L.R.; Rowitch, David H.

2014-01-01

Summary Abnormal GABAergic interneuron density, and imbalance of excitatory versus inhibitory tone, is thought to result in epilepsy, neurodevelopmental disorders and psychiatric disease. Recent studies indicate that interneuron cortical density is determined primarily by the size of the precursor pool in the embryonic telencephalon. However, factors essential to regulate interneuron allocation from telencephalic multipotent precursors are poorly understood. Here we report that Olig1 represses production of GABAergic interneurons throughout the mouse brain. Olig1 deletion in mutant mice results in ectopic expression and upregulation of Dlx1/2 genes in the ventral medial ganglionic eminences and adjacent regions of the septum resulting in a ~30% increase in adult cortical interneuron numbers. We show that Olig1 directly represses the Dlx1/2 I12b intergenic enhancer and that Dlx1/2 functions genetically downstream of Olig1. These findings establish Olig1 as an essential repressor of Dlx1/2 and interneuron production in developing mammalian brain. PMID:24507192

Parvalbumin-expressing interneurons can act solo while somatostatin-expressing interneurons act in chorus in most cases on cortical pyramidal cells.

PubMed

Safari, Mir-Shahram; Mirnajafi-Zadeh, Javad; Hioki, Hiroyuki; Tsumoto, Tadaharu

2017-10-06

Neural circuits in the cerebral cortex consist primarily of excitatory pyramidal (Pyr) cells and inhibitory interneurons. Interneurons are divided into several subtypes, in which the two major groups are those expressing parvalbumin (PV) or somatostatin (SOM). These subtypes of interneurons are reported to play distinct roles in tuning and/or gain of visual response of pyramidal cells in the visual cortex. It remains unclear whether there is any quantitative and functional difference between the PV → Pyr and SOM → Pyr connections. We compared unitary inhibitory postsynaptic currents (uIPSCs) evoked by electrophysiological activation of single presynaptic interneurons with population IPSCs evoked by photo-activation of a mass of interneurons in vivo and in vitro in transgenic mice in which PV or SOM neurons expressed channelrhodopsin-2, and found that at least about 14 PV neurons made strong connections with a postsynaptic Pyr cell while a much larger number of SOM neurons made weak connections. Activation or suppression of single PV neurons modified visual responses of postsynaptic Pyr cells in 6 of 7 pairs whereas that of single SOM neurons showed no significant modification in 8 of 11 pairs, suggesting that PV neurons can act solo whereas most of SOM neurons may act in chorus on Pyr cells.

Extensive respiratory chain defects in inhibitory interneurones in patients with mitochondrial disease.

PubMed

Lax, Nichola Z; Grady, John; Laude, Alex; Chan, Felix; Hepplewhite, Philippa D; Gorman, Grainne; Whittaker, Roger G; Ng, Yi; Cunningham, Mark O; Turnbull, Doug M

2016-02-01

Mitochondrial disorders are among the most frequently inherited cause of neurological disease and arise due to mutations in mitochondrial or nuclear DNA. Currently, we do not understand the specific involvement of certain brain regions or selective neuronal vulnerability in mitochondrial disease. Recent studies suggest γ-aminobutyric acid (GABA)-ergic interneurones are particularly susceptible to respiratory chain dysfunction. In this neuropathological study, we assess the impact of mitochondrial DNA defects on inhibitory interneurones in patients with mitochondrial disease. Histochemical, immunohistochemical and immunofluorescent assays were performed on post-mortem brain tissue from 10 patients and 10 age-matched control individuals. We applied a quantitative immunofluorescent method to interrogate complex I and IV protein expression in mitochondria within GABAergic interneurone populations in the frontal, temporal and occipital cortices. We also evaluated the density of inhibitory interneurones in serial sections to determine if cell loss was occurring. We observed significant, global reductions in complex I expression within GABAergic interneurones in frontal, temporal and occipital cortices in the majority of patients. While complex IV expression is more variable, there is reduced expression in patients harbouring m.8344A>G point mutations and POLG mutations. In addition to the severe respiratory chain deficiencies observed in remaining interneurones, quantification of GABAergic cell density showed a dramatic reduction in cell density suggesting interneurone loss. We propose that the combined loss of interneurones and severe respiratory deficiency in remaining interneurones contributes to impaired neuronal network oscillations and could underlie development of neurological deficits, such as cognitive impairment and epilepsy, in mitochondrial disease. © 2015 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of

Voronoi-based spatial analysis reveals selective interneuron changes in the cortex of FALS mice.

PubMed

Minciacchi, Diego; Kassa, Roman M; Del Tongo, Claudia; Mariotti, Raffaella; Bentivoglio, Marina

2009-01-01

The neurodegenerative disease amyotrophic lateral sclerosis affects lower motoneurons and corticospinal cells. Mice expressing human mutant superoxide dismutase (SOD)1 provide widely investigated models of the familial form of disease, but information on cortical changes in these mice is still limited. We here analyzed the spatial organization of interneurons characterized by parvalbumin immunoreactivity in the motor, somatosensory, and visual cortical areas of SOD1(G93A) mice. Cell number and sociological spatial behavior were assessed by digital charts of cell location in cortical samples, cell counts, and generation of two-dimensional Voronoi diagrams. In end-stage SOD1-mutant mice, an increase of parvalbumin-containing cortical interneurons was found in the motor and somatosensory areas (about 35% and 20%, respectively) with respect to wild-type littermates. Changes in cell spatial distribution, as documented by Voronoi-derived coefficients of variation, indicated increased tendency of parvalbumin cells to aggregate into clusters in the same areas of the SOD1-mutant cortex. Counts and coefficients of variation of parvalbumin cells in the visual cortex gave instead similar results in SOD1-mutant and wild-type mice. Analyses of motor and somatosensory areas in presymptomatic SOD1-mutant mice provided findings very similar to those obtained at end-stage, indicating early changes of interneurons in these cortical areas during the pathology. Altogether the data reveal in the SOD1-mutant mouse cortex an altered architectonic pattern of interneurons, which selectively affects areas involved in motor control. The findings, which can be interpreted as pathogenic factors or early disease-related adaptations, point to changes in the cortical regulation and modulation of the motor circuit during motoneuron disease.

Olig1 function is required to repress dlx1/2 and interneuron production in Mammalian brain.

PubMed

Silbereis, John C; Nobuta, Hiroko; Tsai, Hui-Hsin; Heine, Vivi M; McKinsey, Gabriel L; Meijer, Dimphna H; Howard, Mackenzie A; Petryniak, Magda A; Potter, Gregory B; Alberta, John A; Baraban, Scott C; Stiles, Charles D; Rubenstein, John L R; Rowitch, David H

2014-02-05

Abnormal GABAergic interneuron density, and imbalance of excitatory versus inhibitory tone, is thought to result in epilepsy, neurodevelopmental disorders, and psychiatric disease. Recent studies indicate that interneuron cortical density is determined primarily by the size of the precursor pool in the embryonic telencephalon. However, factors essential for regulating interneuron allocation from telencephalic multipotent precursors are poorly understood. Here we report that Olig1 represses production of GABAergic interneurons throughout the mouse brain. Olig1 deletion in mutant mice results in ectopic expression and upregulation of Dlx1/2 genes in the ventral medial ganglionic eminences and adjacent regions of the septum, resulting in an ∼30% increase in adult cortical interneuron numbers. We show that Olig1 directly represses the Dlx1/2 I12b intergenic enhancer and that Dlx1/2 functions genetically downstream of Olig1. These findings establish Olig1 as an essential repressor of Dlx1/2 and interneuron production in developing mammalian brain. Copyright © 2014 Elsevier Inc. All rights reserved.

Cortical Development Requires Mesodermal Expression of Tbx1, a Gene Haploinsufficient in 22q11.2 Deletion Syndrome.

PubMed

Flore, Gemma; Cioffi, Sara; Bilio, Marchesa; Illingworth, Elizabeth

2017-03-01

In mammals, proper temporal control of neurogenesis and neural migration during embryonic development ensures correct formation of the cerebral cortex. Changes in the distribution of cortical projection neurons and interneurons are associated with behavioral disorders and psychiatric diseases, including schizophrenia and autism, suggesting that disrupted cortical connectivity contributes to the brain pathology. TBX1 is the major candidate gene for 22q11.2 deletion syndrome (22q11.2DS), a chromosomal deletion disorder characterized by a greatly increased risk for schizophrenia. We have previously shown that Tbx1 heterozygous mice have reduced prepulse inhibition, a behavioral abnormality that is associated with 22q11.2DS and nonsyndromic schizophrenia. Here, we show that loss of Tbx1 disrupts corticogenesis in mice by promoting premature neuronal differentiation in the medio-lateral embryonic cortex, which gives rise to the somatosensory cortex (S1). In addition, we found altered polarity in both radially migrating excitatory neurons and tangentially migrating inhibitory interneurons. Together, these abnormalities lead to altered lamination in the S1 at the terminal stages of corticogenesis in Tbx1 null mice and similar anomalies in Tbx1 heterozygous adult mice. Finally, we show that mesoderm-specific inactivation of Tbx1 is sufficient to recapitulate the brain phenotype indicating that Tbx1 exerts a cell nonautonomous role in cortical development from the mesoderm. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Alterations in hippocampal and cortical densities of functionally different interneurons in rat models of absence epilepsy.

PubMed

Papp, Péter; Kovács, Zsolt; Szocsics, Péter; Juhász, Gábor; Maglóczky, Zsófia

2018-05-31

Recent data from absence epileptic patients and animal models provide evidence for significant impairments of attention, memory, and psychosocial functioning. Here, we outline aspects of the electrophysiological and structural background of these dysfunctions by investigating changes in hippocampal and cortical GABAergic inhibitory interneurons in two genetically absence epileptic rat strains: the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and the Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. Using simultaneously recorded field potentials from the primary somatosensory cortex (S1 cortex, seizure focus) and the hippocampal hilus, we demonstrated that typical frequencies of spike-wave discharges (SWDs; 7-8 Hz, GAERS; 7-9 Hz, WAG/Rij) and their harmonics appeared and their EEG spectral power markedly increased on recordings not only from the S1 cortex, but also from the hilus in both GAERS and WAG/Rij rats during SWDs. Moreover, we observed an increased synchronization between S1 cortex and hilus at 7-8 Hz (GAERS) and 7-9 Hz (WAG/Rij) and at their harmonics when SWDs occurred in the S1 cortex in both rat strains. In addition, using immunohistochemistry we demonstrated changes in the densities of perisomatic (parvalbumin-immunopositive, PV+) and interneuron-selective (calretinin-immunopositive, CR+) GABAergic inhibitory interneuron somata. Specifically, GAERS and WAG/Rij rats displayed lower densities of PV-immunopositivity in the hippocampal hilus compared to non-epileptic control (NEC) and normal Wistar rats. GAERS and WAG/Rij rats also show a marked reduction in the density of CR + interneurons in the same region in comparison with NEC rats. Data from the S1 cortex reveals bidirectional differences in PV + density, with GAERS displaying a significant increase, whereas WAG/Rij a reduction compared to control rat strains. Our results suggest an enhanced synchronization and functional connections between the hippocampus and S1 cortex as well

Cortical parvalbumin GABAergic deficits with α7 nicotinic acetylcholine receptor deletion: Implications for schizophrenia

PubMed Central

Lin, Hong; Hsu, Fu-Chun; Baumann, Bailey H.; Coulter, Douglas A.; Anderson, Stewart A.; Lynch, David R.

2014-01-01

Dysfunction of cortical parvalbumin (PV)-containing GABAergic interneurons has been implicated in cognitive deficits of schizophrenia. In humans microdeletion of the CHRNA7 (α7 nicotinic acetylcholine receptor, nAChR) gene is associated with cortical dysfunction in a broad spectrum of neurodevelopmental and neuropsychiatric disorders including schizophrenia while in mice similar deletion causes analogous abnormalities including impaired attention, working-memory and learning. However, the pathophysiological roles of α7 nAChRs in cortical PV GABAergic development remain largely uncharacterized. In both in vivo and in vitro models, we identify here that deletion of the α7 nAChR gene in mice impairs cortical PV GABAergic development and recapitulates many of the characteristic neurochemical deficits in PV-positive GABAergic interneurons found in schizophrenia. α7 nAChR null mice had decreased cortical levels of GABAergic markers including PV, Glutamic Acid Decarboxylase 65/67 (GAD65/67) and the α1 subunit of GABAA receptors, particularly reductions of PV and GAD67 levels in cortical PV-positive interneurons during late postnatal life and adulthood. Cortical GABAergic synaptic deficits were identified in the prefrontal cortex of α7 nAChR null mice and α7 nAChR null cortical cultures. Similar disruptions in development of PV-positive GABAergic interneurons and perisomatic synapses were found in cortical cultures lacking α7 nAChRs. Moreover, NMDA receptor expression was reduced in GABAergic interneurons, implicating NMDA receptor hypofunction in GABAergic deficits in α7 nAChR null mice. Our findings thus demonstrate impaired cortical PV GABAergic development and multiple characteristic neurochemical deficits reminiscent of schizophrenia in cortical PV-positive interneurons in α7 nAChR gene deletion models. This implicates crucial roles of α7 nAChRs in cortical PV GABAergic development and dysfunction in schizophrenia and other neuropsychiatric disorders. PMID

Fast spiking interneuron control of seizure propagation in a cortical slice model of focal epilepsy

PubMed Central

Cammarota, Mario; Losi, Gabriele; Chiavegato, Angela; Zonta, Micaela; Carmignoto, Giorgio

2013-01-01

In different animal models of focal epilepsy, seizure-like ictal discharge propagation is transiently opposed by feedforward inhibition. The specific cellular source of this signal and the mechanism by which inhibition ultimately becomes ineffective are, however, undefined. We used a brain slice model to study how focal ictal discharges that were repetitively evoked from the same site, and at precise times, propagate across the cortex. We used Ca2+ imaging and simultaneous single/dual cell recordings from pyramidal neurons (PyNs) and different classes of interneurons in rodents, including G42 and GIN transgenic mice expressing the green fluorescence protein in parvalbumin (Pv)-fast spiking (FS) and somatostatin (Som) interneurons, respectively. We found that these two classes of interneurons fired intensively shortly after ictal discharge generation at the focus. The inhibitory barrages that were recorded in PyNs occurred in coincidence with Pv-FS, but not with Som interneuron burst discharges. Furthermore, the strength of inhibitory barrages increased or decreased in parallel with increased or decreased firing in Pv-FS interneurons but not in Som interneurons. A firing impairment of Pv-FS interneurons caused by a membrane depolarization was found to precede ictal discharge onset in neighbouring pyramidal neurons. This event may account for the collapse of local inhibition that allows spatially defined clusters of PyNs to be recruited into propagating ictal discharges. Our study demonstrates that Pv-FS interneurons are a major source of the inhibitory barrages that oppose ictal discharge propagation and raises the possibility that targeting Pv-FS interneurons represents a new therapeutic strategy to prevent the generalization of human focal seizures. PMID:23207591

Spatiotemporal alterations of cortical network activity by selective loss of NOS-expressing interneurons.

PubMed

Shlosberg, Dan; Buskila, Yossi; Abu-Ghanem, Yasmin; Amitai, Yael

2012-01-01

Deciphering the role of GABAergic neurons in large neuronal networks such as the neocortex forms a particularly complex task as they comprise a highly diverse population. The neuronal isoform of the enzyme nitric oxide synthase (nNOS) is expressed in the neocortex by specific subsets of GABAergic neurons. These neurons can be identified in live brain slices by the nitric oxide (NO) fluorescent indicator diaminofluorescein-2 diacetate (DAF-2DA). However, this indicator was found to be highly toxic to the stained neurons. We used this feature to induce acute phototoxic damage to NO-producing neurons in cortical slices, and measured subsequent alterations in parameters of cellular and network activity. Neocortical slices were briefly incubated in DAF-2DA and then illuminated through the 4× objective. Histochemistry for NADPH-diaphorase (NADPH-d), a marker for nNOS activity, revealed elimination of staining in the illuminated areas following treatment. Whole cell recordings from several neuronal types before, during, and after illumination confirmed the selective damage to non-fast-spiking (FS) interneurons. Treated slices displayed mild disinhibition. The reversal potential of compound synaptic events on pyramidal neurons became more positive, and their decay time constant was elongated, substantiating the removal of an inhibitory conductance. The horizontal decay of local field potentials (LFPs) was significantly reduced at distances of 300-400 μm from the stimulation, but not when inhibition was non-selectively weakened with the GABA(A) blocker picrotoxin. Finally, whereas the depression of LFPs along short trains of 40 Hz stimuli was linearly reduced with distance or initial amplitude in control slices, this ordered relationship was disrupted in DAF-treated slices. These results reveal that NO-producing interneurons in the neocortex convey lateral inhibition to neighboring columns, and shape the spatiotemporal dynamics of the network's activity.

Anatomical and Electrophysiological Clustering of Superficial Medial Entorhinal Cortex Interneurons

PubMed Central

2017-01-01

Abstract Local GABAergic interneurons regulate the activity of spatially-modulated principal cells in the medial entorhinal cortex (MEC), mediating stellate-to-stellate connectivity and possibly enabling grid formation via recurrent inhibitory circuitry. Despite the important role interneurons seem to play in the MEC cortical circuit, the combination of low cell counts and functional diversity has made systematic electrophysiological studies of these neurons difficult. For these reasons, there remains a paucity of knowledge on the electrophysiological profiles of superficial MEC interneuron populations. Taking advantage of glutamic acid decarboxylase 2 (GAD2)-IRES-tdTomato and PV-tdTomato transgenic mice, we targeted GABAergic interneurons for whole-cell patch-clamp recordings and characterized their passive membrane features, basic input/output properties and action potential (AP) shape. These electrophysiologically characterized cells were then anatomically reconstructed, with emphasis on axonal projections and pial depth. K-means clustering of interneuron anatomical and electrophysiological data optimally classified a population of 106 interneurons into four distinct clusters. The first cluster is comprised of layer 2- and 3-projecting, slow-firing interneurons. The second cluster is comprised largely of PV+ fast-firing interneurons that project mainly to layers 2 and 3. The third cluster contains layer 1- and 2-projecting interneurons, and the fourth cluster is made up of layer 1-projecting horizontal interneurons. These results, among others, will provide greater understanding of the electrophysiological characteristics of MEC interneurons, help guide future in vivo studies, and may aid in uncovering the mechanism of grid field formation. PMID:29085901

Expression of β1- and β2-adrenoceptors in different subtypes of interneurons in the medial prefrontal cortex of mice.

PubMed

Liu, Y; Liang, X; Ren, W-W; Li, B-M

2014-01-17

Noradrenaline acting via β-adrenoceptors (β-ARs) in the CNS plays an important role in learning/memory and cognitive functions. β-ARs have been shown to be expressed in cortical pyramidal and subcortical principal cells. However, little is known about β-AR expression in different subtypes of GABAergic neurons. Here, we report that both β1- and β2-ARs are expressed in a majority of GABAergic interneurons in the medial prefrontal cortex of mice, including parvalbumin (PV)-, calretinin (CR)-, calbindin D-28k (CB)-, somatostatin (SST)- and Reelin-immunoreactive (ir) interneurons. Relative to PV-, CB-, SST- and Reelin-ir interneurons, CR-ir interneurons are less likely to express β1- and β2-ARs. SST-ir interneurons are more likely to express β2-AR compared with the other subtypes of interneurons. The present results are of significance for understanding the role of β-ARs in prefrontal cortical functions. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

Many Specialists for Suppressing Cortical Excitation

PubMed Central

Burkhalter, Andreas

2008-01-01

Cortical computations are critically dependent on GABA-releasing neurons for dynamically balancing excitation with inhibition that is proportional to the overall level of activity. Although it is widely accepted that there are multiple types of interneurons, defining their identities based on qualitative descriptions of morphological, molecular and physiological features has failed to produce a universally accepted ‘parts list’, which is needed to understand the roles that interneurons play in cortical processing. A list of features has been published by the Petilla Interneurons Nomenclature Group, which represents an important step toward an unbiased classification of interneurons. To this end some essential features have recently been studied quantitatively and their association was examined using multidimensional cluster analyses. These studies revealed at least 3 distinct electrophysiological, 6 morphological and 15 molecular phenotypes. This is a conservative estimate of the number of interneuron types, which almost certainly will be revised as more quantitative studies will be performed and similarities will be defined objectively. It is clear that interneurons are organized with physiological attributes representing the most general, molecular characteristics the most detailed and morphological features occupying the middle ground. By themselves, none of these features are sufficient to define classes of interneurons. The challenge will be to determine which features belong together and how cell type-specific feature combinations are genetically specified. PMID:19225588

Inhibitory dendrite dynamics as a general feature of the adult cortical microcircuit.

PubMed

Chen, Jerry L; Flanders, Genevieve H; Lee, Wei-Chung Allen; Lin, Walter C; Nedivi, Elly

2011-08-31

The mammalian neocortex is functionally subdivided into architectonically distinct regions that process various types of information based on their source of afferent input. Yet, the modularity of neocortical organization in terms of cell type and intrinsic circuitry allows afferent drive to continuously reassign cortical map space. New aspects of cortical map plasticity include dynamic turnover of dendritic spines on pyramidal neurons and remodeling of interneuron dendritic arbors. While spine remodeling occurs in multiple cortical regions, it is not yet known whether interneuron dendrite remodeling is common across primary sensory and higher-level cortices. It is also unknown whether, like pyramidal dendrites, inhibitory dendrites respect functional domain boundaries. Given the importance of the inhibitory circuitry to adult cortical plasticity and the reorganization of cortical maps, we sought to address these questions by using two-photon microscopy to monitor interneuron dendritic arbors of thy1-GFP-S transgenic mice expressing GFP in neurons sparsely distributed across the superficial layers of the neocortex. We find that interneuron dendritic branch tip remodeling is a general feature of the adult cortical microcircuit, and that remodeling rates are similar across primary sensory regions of different modalities, but may differ in magnitude between primary sensory versus higher cortical areas. We also show that branch tip remodeling occurs in bursts and respects functional domain boundaries.

GABAA receptor-mediated currents in interneurons and pyramidal cells of rat visual cortex

PubMed Central

Xiang, Zixiu; Huguenard, John R; Prince, David A

1998-01-01

We compared γ-aminobutyric acid (GABA)-mediated responses of identified pyramidal cells and fast spiking interneurons in layer V of visual cortical slices from young rats (P11-14). The frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) was similar in pyramidal cells and interneurons (1.7 vs. 1.9 Hz). For events with 10-90 % rise times less than 0.9 ms, no significant differences were found in mean amplitude (61 vs. 65 pA), mean rise time (0.58 vs. 0.61 ms), or the first time constant of decay (τ1, 6.4 vs. 6.5 ms) between pyramidal cells and interneurons. The second decay time constant (τ2) was significantly longer in interneurons than in pyramidal cells (49 vs. 22 ms). The difference in sIPSC decay kinetics between two cell types also existed in adult rats (P36-42), suggesting the kinetic difference is not due to differential development of GABAA receptors in these cell types. The decay kinetics of monosynaptic evoked IPSCs were also longer in interneurons. As in the case of sIPSCs, the difference was accounted for by the second decay time constant. τ1 and τ2 were, respectively, 13 and 64 ms for interneurons and 12 and 47 ms for pyramidal cells. Cell-attached patch recordings revealed that the mean open time for single Cl− channels in response to 2 μM GABA was significantly longer in interneurons than pyramidal cells (5.0 vs. 2.8 ms). The chord conductance of these channels in interneurons (12 pS) was significantly smaller than in pyramidal cells (15 pS). Single channel currents reversed polarity when the pipette potential was approximately -10 mV for both cell types. These results show that there is a functional diversity of GABAA receptors in electrophysiologically and morphologically identified cortical pyramidal cells and interneurons. This diversity might derive from the different molecular composition of the receptors in these two cell types. PMID:9503333

Global optogenetic activation of inhibitory interneurons during epileptiform activity.

PubMed

Ledri, Marco; Madsen, Marita Grønning; Nikitidou, Litsa; Kirik, Deniz; Kokaia, Merab

2014-02-26

Optogenetic techniques provide powerful tools for bidirectional control of neuronal activity and investigating alterations occurring in excitability disorders, such as epilepsy. In particular, the possibility to specifically activate by light-determined interneuron populations expressing channelrhodopsin-2 provides an unprecedented opportunity of exploring their contribution to physiological and pathological network activity. There are several subclasses of interneurons in cortical areas with different functional connectivity to the principal neurons (e.g., targeting their perisomatic or dendritic compartments). Therefore, one could optogenetically activate specific or a mixed population of interneurons and dissect their selective or concerted inhibitory action on principal cells. We chose to explore a conceptually novel strategy involving simultaneous activation of mixed populations of interneurons by optogenetics and study their impact on ongoing epileptiform activity in mouse acute hippocampal slices. Here we demonstrate that such approach results in a brief initial action potential discharge in CA3 pyramidal neurons, followed by prolonged suppression of ongoing epileptiform activity during light exposure. Such sequence of events was caused by massive light-induced release of GABA from ChR2-expressing interneurons. The inhibition of epileptiform activity was less pronounced if only parvalbumin- or somatostatin-expressing interneurons were activated by light. Our data suggest that global optogenetic activation of mixed interneuron populations is a more effective approach for development of novel therapeutic strategies for epilepsy, but the initial action potential generation in principal neurons needs to be taken in consideration.

Synaptic Targets of Medial Septal Projections in the Hippocampus and Extrahippocampal Cortices of the Mouse

PubMed Central

Joshi, Abhilasha; Viney, Tim J.; Kis, Viktor

2015-01-01

Temporal coordination of neuronal assemblies among cortical areas is essential for behavioral performance. GABAergic projections from the medial septum and diagonal band complex exclusively innervate GABAergic interneurons in the rat hippocampus, contributing to the coordination of neuronal activity, including the generation of theta oscillations. Much less is known about the synaptic target neurons outside the hippocampus. To reveal the contribution of synaptic circuits involving the medial septum of mice, we have identified postsynaptic cortical neurons in wild-type and parvalbumin-Cre knock-in mice. Anterograde axonal tracing from the septum revealed extensive innervation of the hippocampus as well as the subiculum, presubiculum, parasubiculum, the medial and lateral entorhinal cortices, and the retrosplenial cortex. In all examined cortical regions, many septal GABAergic boutons were in close apposition to somata or dendrites immunopositive for interneuron cell-type molecular markers, such as parvalbumin, calbindin, calretinin, N-terminal EF-hand calcium-binding protein 1, cholecystokinin, reelin, or a combination of these molecules. Electron microscopic observations revealed septal boutons forming axosomatic or axodendritic type II synapses. In the CA1 region of hippocampus, septal GABAergic projections exclusively targeted interneurons. In the retrosplenial cortex, 93% of identified postsynaptic targets belonged to interneurons and the rest to pyramidal cells. These results suggest that the GABAergic innervation from the medial septum and diagonal band complex contributes to temporal coordination of neuronal activity via several types of cortical GABAergic interneurons in both hippocampal and extrahippocampal cortices. Oscillatory septal neuronal firing at delta, theta, and gamma frequencies may phase interneuron activity. SIGNIFICANCE STATEMENT Diverse types of GABAergic interneurons coordinate the firing of cortical principal cells required for memory

Nitric oxide synthase-I containing cortical interneurons co-express antioxidative enzymes and anti-apoptotic Bcl-2 following focal ischemia: evidence for direct and indirect mechanisms towards their resistance to neuropathology.

PubMed

Bidmon, H J; Emde, B; Kowalski, T; Schmitt, M; Mayer, B; Kato, K; Asayama, K; Witte, O W; Zilles, K

2001-09-01

Neuronal nitric oxide-I is constitutively expressed in approximately 2% of cortical interneurons and is co-localized with gamma-amino butric acid, somatostatin or neuropeptide Y. These interneurons additionally express high amounts of glutamate receptors which mediate the glutamate-induced hyperexcitation following cerebral injury, under these conditions nitric oxide production increases contributing to a potentiation of oxidative stress. However, perilesional nitric oxide synthase-I containing neurons are known to be resistant to ischemic and excitotoxic injury. In vitro studies show that nitrosonium and nitroxyl ions inactivate N-methyl-D-aspartate receptors, resulting in neuroprotection. The question remains of how these cells are protected against their own high intracellular nitric oxide production after activation. In this study, we investigated immunocytochemically nitric oxide synthase-I containing cortical neurons in rats after unilateral, cortical photothrombosis. In this model of focal ischemia, perilesional, constitutively nitric oxide synthase-I containing neurons survived and co-expressed antioxidative enzymes, such as manganese- and copper-zinc-dependent superoxide dismutases, heme oxygenase-2 and cytosolic glutathione peroxidase. This enhanced antioxidant expression was accompanied by a strong perinuclear presence of the antiapoptotic Bcl-2 protein. No colocalization was detectable with upregulated heme oxygenase-1 in glia and the superoxide and prostaglandin G(2)-producing cyclooxygenase-2 in neurons. These results suggest that nitric oxide synthase-I containing interneurons are protected against intracellular oxidative damage and apoptosis by Bcl-2 and several potent antioxidative enzymes. Since nitric oxide synthase-I positive neurons do not express superoxide-producing enzymes such as cyclooxygenase-1, xanthine oxidase and cyclooxygenase-2 in response to injury, this may additionally contribute to their resistance by reducing their internal

Olfactory and cortical projections to bulbar and hippocampal adult-born neurons

PubMed Central

De La Rosa-Prieto, Carlos; De Moya-Pinilla, Miguel; Saiz-Sanchez, Daniel; Ubeda-banon, Isabel; Arzate, Dulce M.; Flores-Cuadrado, Alicia; Liberia, Teresa; Crespo, Carlos; Martinez-Marcos, Alino

2015-01-01

New neurons are continually generated in the subependymal layer of the lateral ventricles and the subgranular zone of dentate gyrus during adulthood. In the subventricular zone, neuroblasts migrate a long distance to the olfactory bulb where they differentiate into granule or periglomerular interneurons. In the hippocampus, neuroblasts migrate a short distance from the subgranular zone to the granule cell layer of the dentate gyrus to become granule neurons. In addition to the short-distance inputs, bulbar interneurons receive long-distance centrifugal afferents from olfactory-recipient structures. Similarly, dentate granule cells receive differential inputs from the medial and lateral entorhinal cortices through the perforant pathway. Little is known concerning these new inputs on the adult-born cells. In this work, we have characterized afferent inputs to 21-day old newly-born neurons. Mice were intraperitoneally injected with bromodeoxyuridine. Two weeks later, rhodamine-labeled dextran-amine was injected into the anterior olfactory nucleus, olfactory tubercle, piriform cortex and lateral and medial entorhinal cortices. One week later, animals were perfused and immunofluorescences were carried out. The data show that projection neurons from the mentioned structures, establish putative synaptic contacts onto 21-day-old neurons in the olfactory bulb and dentate gyrus, in some cases even before they start to express specific subpopulation proteins. Long-distance afferents reach middle and outer one-third portions of the molecular layer of the dentate gyrus and granule and, interestingly, periglomerular layers of the olfactory bulb. In the olfactory bulb, these fibers appear to establish presumptive axo-somatic contacts onto newly-born granule and periglomerular cells. PMID:25698936

Perineuronal Net Protein Neurocan Inhibits NCAM/EphA3 Repellent Signaling in GABAergic Interneurons.

PubMed

Sullivan, Chelsea S; Gotthard, Ingo; Wyatt, Elliott V; Bongu, Srihita; Mohan, Vishwa; Weinberg, Richard J; Maness, Patricia F

2018-04-18

Perineuronal nets (PNNs) are implicated in closure of critical periods of synaptic plasticity in the brain, but the molecular mechanisms by which PNNs regulate synapse development are obscure. A receptor complex of NCAM and EphA3 mediates postnatal remodeling of inhibitory perisomatic synapses of GABAergic interneurons onto pyramidal cells in the mouse frontal cortex necessary for excitatory/inhibitory balance. Here it is shown that enzymatic removal of PNN glycosaminoglycan chains decreased the density of GABAergic perisomatic synapses in mouse organotypic cortical slice cultures. Neurocan, a key component of PNNs, was expressed in postnatal frontal cortex in apposition to perisomatic synapses of parvalbumin-positive interneurons. Polysialylated NCAM (PSA-NCAM), which is required for ephrin-dependent synapse remodeling, bound less efficiently to neurocan than mature, non-PSA-NCAM. Neurocan bound the non-polysialylated form of NCAM at the EphA3 binding site within the immunoglobulin-2 domain. Neurocan inhibited NCAM/EphA3 association, membrane clustering of NCAM/EphA3 in cortical interneuron axons, EphA3 kinase activation, and ephrin-A5-induced growth cone collapse. These studies delineate a novel mechanism wherein neurocan inhibits NCAM/EphA3 signaling and axonal repulsion, which may terminate postnatal remodeling of interneuron axons to stabilize perisomatic synapses in vivo.

Defined types of cortical interneurone structure space and spike timing in the hippocampus

PubMed Central

Somogyi, Peter; Klausberger, Thomas

2005-01-01

The cerebral cortex encodes, stores and combines information about the internal and external environment in rhythmic activity of multiple frequency ranges. Neurones of the cortex can be defined, recognized and compared on the comprehensive application of the following measures: (i) brain area- and cell domain-specific distribution of input and output synapses, (ii) expression of molecules involved in cell signalling, (iii) membrane and synaptic properties reflecting the expression of membrane proteins, (iv) temporal structure of firing in vivo, resulting from (i)–(iii). Spatial and temporal measures of neurones in the network reflect an indivisible unity of evolutionary design, i.e. neurones do not have separate structure or function. The blueprint of this design is most easily accessible in the CA1 area of the hippocampus, where a relatively uniform population of pyramidal cells and their inputs follow an instantly recognizable laminated pattern and act within stereotyped network activity patterns. Reviewing the cell types and their spatio-temporal interactions, we suggest that CA1 pyramidal cells are supported by at least 16 distinct types of GABAergic neurone. During a given behaviour-contingent network oscillation, interneurones of a given type exhibit similar firing patterns. During different network oscillations representing two distinct brain states, interneurones of the same class show different firing patterns modulating their postsynaptic target-domain in a brain-state-dependent manner. These results suggest roles for specific interneurone types in structuring the activity of pyramidal cells via their respective target domains, and accurately timing and synchronizing pyramidal cell discharge, rather than providing generalized inhibition. Finally, interneurones belonging to different classes may fire preferentially at distinct time points during a given oscillation. As different interneurones innervate distinct domains of the pyramidal cells, the

Perinatal phencyclidine administration decreases the density of cortical interneurons and increases the expression of neuregulin-1.

PubMed

Radonjić, Nevena V; Jakovcevski, Igor; Bumbaširević, Vladimir; Petronijević, Nataša D

2013-06-01

Perinatal phencyclidine (PCP) administration in rat blocks the N-methyl D-aspartate receptor (NMDAR) and causes symptoms reminiscent of schizophrenia in human. A growing body of evidence suggests that alterations in γ-aminobutyric acid (GABA) interneuron neurotransmission may be associated with schizophrenia. Neuregulin-1 (NRG-1) is a trophic factor important for neurodevelopment, synaptic plasticity, and wiring of GABA circuits. The aim of this study was to determine the long-term effects of perinatal PCP administration on the projection and local circuit neurons and NRG-1 expression in the cortex and hippocampus. Rats were treated on postnatal day 2 (P2), P6, P9, and P12 with either PCP (10 mg/kg) or saline. Morphological studies and determination of NRG-1 expression were performed at P70. We demonstrate reduced densities of principal neurons in the CA3 and dentate gyrus (DG) subregions of the hippocampus and a reduction of major interneuronal populations in all cortical and hippocampal regions studied in PCP-treated rats compared with controls. For the first time, we show the reduced density of reelin- and somatostatin-positive cells in the cortex and hippocampus of animals perinatally treated with PCP. Furthermore, an increase in the numbers of perisomatic inhibitory terminals around the principal cells was observed in the motor cortex and DG. We also show that perinatal PCP administration leads to an increased NRG-1 expression in the cortex and hippocampus. Taken together, our findings demonstrate that perinatal PCP administration increases NRG-1 expression and reduces the number of projecting and local circuit neurons, revealing complex consequences of NMDAR blockade.

Netrin1/DCC signaling promotes neuronal migration in the dorsal spinal cord.

PubMed

Junge, Harald J; Yung, Andrea R; Goodrich, Lisa V; Chen, Zhe

2016-10-26

Newborn neurons often migrate before undergoing final differentiation, extending neurites, and forming synaptic connections. Therefore, neuronal migration is crucial for establishing neural circuitry during development. In the developing spinal cord, neuroprogenitors first undergo radial migration within the ventricular zone. Differentiated neurons continue to migrate tangentially before reaching the final positions. The molecular pathways that regulate these migration processes remain largely unknown. Our previous study suggests that the DCC receptor is important for the migration of the dorsal spinal cord progenitors and interneurons. In this study, we determined the involvement of the Netrin1 ligand and the ROBO3 coreceptor in the migration. By pulse labeling neuroprogenitors with electroporation, we examined their radial migration in Netrin1 (Ntn1), Dcc, and Robo3 knockout mice. We found that all three mutants exhibit delayed migration. Furthermore, using immunohistochemistry of the BARHL2 interneuron marker, we found that the mediolateral and dorsoventral migration of differentiated dorsal interneurons is also delayed. Together, our results suggest that Netrin1/DCC signaling induce neuronal migration in the dorsal spinal cord. Netrin1, DCC, and ROBO3 have been extensively studied for their functions in regulating axon guidance in the spinal commissural interneurons. We reveal that during earlier development of dorsal interneurons including commissural neurons, these molecules play an important role in promoting cell migration.

Diverse roles for ionotropic glutamate receptors on inhibitory interneurons in developing and adult brain.

PubMed

Akgül, Gülcan; McBain, Chris J

2016-10-01

Glutamate receptor-mediated recruitment of GABAergic inhibitory interneurons is a critical determinant of network processing. Early studies observed that many, but not all, interneuron glutamatergic synapses contain AMPA receptors that are GluA2-subunit lacking and Ca(2+) permeable, making them distinct from AMPA receptors at most principal cell synapses. Subsequent studies demonstrated considerable alignment of synaptic AMPA and NMDA receptor subunit composition within specific subtypes of interneurons, suggesting that both receptor expression profiles are developmentally and functionally linked. Indeed glutamate receptor expression profiles are largely predicted by the embryonic origins of cortical interneurons within the medial and caudal ganglionic eminences of the developing telencephalon. Distinct complements of AMPA and NMDA receptors within different interneuron subpopulations contribute to the differential recruitment of functionally divergent interneuron subtypes by common afferent inputs for appropriate feed-forward and feedback inhibitory drive and network entrainment. In contrast, the lesser-studied kainate receptors, which are often present at both pre- and postsynaptic sites, appear to follow an independent developmental expression profile. Loss of specific ionotropic glutamate receptor (iGluR) subunits during interneuron development has dramatic consequences for both cellular and network function, often precipitating circuit inhibition-excitation imbalances and in some cases lethality. Here we briefly review recent findings highlighting the roles of iGluRs in interneuron development. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Different correlation patterns of cholinergic and GABAergic interneurons with striatal projection neurons

PubMed Central

Adler, Avital; Katabi, Shiran; Finkes, Inna; Prut, Yifat; Bergman, Hagai

2013-01-01

The striatum is populated by a single projection neuron group, the medium spiny neurons (MSNs), and several groups of interneurons. Two of the electrophysiologically well-characterized striatal interneuron groups are the tonically active neurons (TANs), which are presumably cholinergic interneurons, and the fast spiking interneurons (FSIs), presumably parvalbumin (PV) expressing GABAergic interneurons. To better understand striatal processing it is thus crucial to define the functional relationship between MSNs and these interneurons in the awake and behaving animal. We used multiple electrodes and standard physiological methods to simultaneously record MSN spiking activity and the activity of TANs or FSIs from monkeys engaged in a classical conditioning paradigm. All three cell populations were highly responsive to the behavioral task. However, they displayed different average response profiles and a different degree of response synchronization (signal correlation). TANs displayed the most transient and synchronized response, MSNs the most diverse and sustained response and FSIs were in between on both parameters. We did not find evidence for direct monosynaptic connectivity between the MSNs and either the TANs or the FSIs. However, while the cross correlation histograms of TAN to MSN pairs were flat, those of FSI to MSN displayed positive asymmetrical broad peaks. The FSI-MSN correlogram profile implies that the spikes of MSNs follow those of FSIs and both are driven by a common, most likely cortical, input. Thus, the two populations of striatal interneurons are probably driven by different afferents and play complementary functional roles in the physiology of the striatal microcircuit. PMID:24027501

Regulation of synapse development by Vgat deletion from ErbB4-positive interneurons.

PubMed

Lin, Thiri W; Tan, Zhibing; Barik, Arnab; Yin, Dong-Min; Brudvik, Egil; Wang, Hongsheng; Xiong, Wen-Cheng; Mei, Lin

2018-02-05

GABA signaling has been implicated in neural development; however, in vivo genetic evidence is missing because mutant mice lacking GABA activity die prematurely. Here, we studied synapse development by ablating vesicular GABA transporter Vgat in in ErbB4-positive (ErbB4+) interneurons. We show that inhibitory axo-somatic synapses onto pyramidal neurons vary from one cortical layer to another; however, inhibitory synapses on axon initial segments (AISs) were similar across layers. On the other hand, PV-positive (PV+)/ErbB4+ interneurons and PV-only interneurons receive a higher number of inhibitory synapses from PV+ErbB4+ interneurons, compared with ErbB4-only interneurons. Notably, Vgat deletion from ErbB4+ interneurons reduced axo-somatic or axo-axonic synapses from PV+ErbB4+ interneurons onto excitatory neurons. This effect was associated with corresponding changes in neurotransmission. However, the Vgat mutation seemed to have little effect on inhibitory synapses onto PV+ and/or ErbB4+ interneurons. Interestingly, perineuronal nets (PNNs), extracellular matrix structures implicated in maturation, survival, protection and plasticity of PV+ interneurons, were increased in the cortex of ErbB4-Vgat-/- mice. No apparent difference was observed between males and females. These results demonstrate that Vgat of ErbB4+ interneurons is essential for the development of inhibitory synapses onto excitatory neurons and suggest a role of GABA in circuit assembly. SIGNIFICANCE STATEMENT GABA has been implicated in neural development; however, in vivo genetic evidence is missing because mutant mice lacking GABA die prematurely. To this end, we ablated Vgat in ErbB4+ interneurons in an inducible manner. We provide evidence that the formation of inhibitory as well as excitatory synapses onto excitatory neurons requires Vgat in interneurons. In particular, inhibitory axo-somatic and axo-axonic synapses are more vulnerable. Our results suggest a role of GABA in circuit assembly

Auditory cortex interneuron development requires cadherins operating hair-cell mechanoelectrical transduction.

PubMed

Libé-Philippot, Baptiste; Michel, Vincent; Boutet de Monvel, Jacques; Le Gal, Sébastien; Dupont, Typhaine; Avan, Paul; Métin, Christine; Michalski, Nicolas; Petit, Christine

2017-07-25

Many genetic forms of congenital deafness affect the sound reception antenna of cochlear sensory cells, the hair bundle. The resulting sensory deprivation jeopardizes auditory cortex (AC) maturation. Early prosthetic intervention should revive this process. Nevertheless, this view assumes that no intrinsic AC deficits coexist with the cochlear ones, a possibility as yet unexplored. We show here that many GABAergic interneurons, from their generation in the medial ganglionic eminence up to their settlement in the AC, express two cadherin-related (cdhr) proteins, cdhr23 and cdhr15, that form the hair bundle tip links gating the mechanoelectrical transduction channels. Mutant mice lacking either protein showed a major decrease in the number of parvalbumin interneurons specifically in the AC, and displayed audiogenic reflex seizures. Cdhr15 - and Cdhr23 -expressing interneuron precursors in Cdhr23 -/- and Cdhr15 -/- mouse embryos, respectively, failed to enter the embryonic cortex and were scattered throughout the subpallium, consistent with the cell polarity abnormalities we observed in vitro. In the absence of adhesion G protein-coupled receptor V1 (adgrv1), another hair bundle link protein, the entry of Cdhr23 - and Cdhr15 -expressing interneuron precursors into the embryonic cortex was also impaired. Our results demonstrate that a population of newborn interneurons is endowed with specific cdhr proteins necessary for these cells to reach the developing AC. We suggest that an "early adhesion code" targets populations of interneuron precursors to restricted neocortical regions belonging to the same functional area. These findings open up new perspectives for auditory rehabilitation and cortical therapies in patients.

Distinct Physiological Effects of Dopamine D4 Receptors on Prefrontal Cortical Pyramidal Neurons and Fast-Spiking Interneurons

PubMed Central

Zhong, Ping; Yan, Zhen

2016-01-01

Dopamine D4 receptor (D4R), which is strongly linked to neuropsychiatric disorders, such as attention-deficit hyperactivity disorder and schizophrenia, is highly expressed in pyramidal neurons and GABAergic interneurons in prefrontal cortex (PFC). In this study, we examined the impact of D4R on the excitability of these 2 neuronal populations. We found that D4R activation decreased the frequency of spontaneous action potentials (sAPs) in PFC pyramidal neurons, whereas it induced a transient increase followed by a decrease of sAP frequency in PFC parvalbumin-positive (PV+) interneurons. D4R activation also induced distinct effects in both types of PFC neurons on spontaneous excitatory and inhibitory postsynaptic currents, which drive the generation of sAP. Moreover, dopamine substantially decreased sAP frequency in PFC pyramidal neurons, but markedly increased sAP frequency in PV+ interneurons, and both effects were partially mediated by D4R activation. In the phencyclidine model of schizophrenia, the decreasing effect of D4R on sAP frequency in both types of PFC neurons was attenuated, whereas the increasing effect of D4R on sAP in PV+ interneurons was intact. These results suggest that D4R activation elicits distinct effects on synaptically driven excitability in PFC projection neurons versus fast-spiking interneurons, which are differentially altered in neuropsychiatric disorder-related conditions. PMID:25146372

Spontaneous Contractility-Mediated Cortical Flow Generates Cell Migration in Three-Dimensional Environments

PubMed Central

Hawkins, Rhoda J.; Poincloux, Renaud; Bénichou, Olivier; Piel, Matthieu; Chavrier, Philippe; Voituriez, Raphaël

2011-01-01

We present a model of cell motility generated by actomyosin contraction of the cell cortex. We identify, analytically, dynamical instabilities of the cortex and show that they yield steady-state cortical flows, which, in turn, can induce cell migration in three-dimensional environments. This mechanism relies on the regulation of contractility by myosin, whose transport is explicitly taken into account in the model. Theoretical predictions are compared to experimental data of tumor cells migrating in three-dimensional matrigel and suggest that this mechanism could be a general mode of cell migration in three-dimensional environments. PMID:21889440

Impaired discrimination learning in interneuronal NMDAR-GluN2B mutant mice.

PubMed

Brigman, Jonathan L; Daut, Rachel A; Saksida, Lisa; Bussey, Timothy J; Nakazawa, Kazu; Holmes, Andrew

2015-06-17

Previous studies have established a role for N-methyl-D-aspartate receptor (NMDAR) containing the GluN2B subunit in efficient learning behavior on a variety of tasks. Recent findings have suggested that NMDAR on GABAergic interneurons may underlie the modulation of striatal function necessary to balance efficient action with cortical excitatory input. Here we investigated how loss of GluN2B-containing NMDAR on GABAergic interneurons altered corticostriatal-mediated associative learning. Mutant mice (floxed-GluN2B×Ppp1r2-Cre) were generated to produce loss of GluN2B on forebrain interneurons and phenotyped on a touchscreen-based pairwise visual learning paradigm. We found that the mutants showed normal performance during Pavlovian and instrumental pretraining, but were significantly impaired on a discrimination learning task. Detailed analysis of the microstructure of discrimination performance revealed reduced win→stay behavior in the mutants. These results further support the role of NMDAR, and GluN2B in particular, on modulation of striatal function necessary for efficient choice behavior and suggest that NMDAR on interneurons may play a critical role in associative learning.

Hedgehog Promotes Production of Inhibitory Interneurons in Vivo and in Vitro from Pluripotent Stem Cells

PubMed Central

Anderson, Nickesha C.; Chen, Christopher Y.; Grabel, Laura

2016-01-01

Loss or damage of cortical inhibitory interneurons characterizes a number of neurological disorders. There is therefore a great deal of interest in learning how to generate these neurons from a pluripotent stem cell source so they can be used for cell replacement therapies or for in vitro drug testing. To design a directed differentiation protocol, a number of groups have used the information gained in the last 15 years detailing the conditions that promote interneuron progenitor differentiation in the ventral telencephalon during embryogenesis. The use of Hedgehog peptides and agonists is featured prominently in these approaches. We review here the data documenting a role for Hedgehog in specifying interneurons in both the embryonic brain during development and in vitro during the directed differentiation of pluripotent stem cells. PMID:29615590

Resonant Interneurons Can Increase Robustness of Gamma Oscillations.

PubMed

Tikidji-Hamburyan, Ruben A; Martínez, Joan José; White, John A; Canavier, Carmen C

2015-11-25

Gamma oscillations are believed to play a critical role in in information processing, encoding, and retrieval. Inhibitory interneuronal network gamma (ING) oscillations may arise from a coupled oscillator mechanism in which individual neurons oscillate or from a population oscillator in which individual neurons fire sparsely and stochastically. All ING mechanisms, including the one proposed herein, rely on alternating waves of inhibition and windows of opportunity for spiking. The coupled oscillator model implemented with Wang-Buzsáki model neurons is not sufficiently robust to heterogeneity in excitatory drive, and therefore intrinsic frequency, to account for in vitro models of ING. Similarly, in a tightly synchronized regime, the stochastic population oscillator model is often characterized by sparse firing, whereas interneurons both in vivo and in vitro do not fire sparsely during gamma, but rather on average every other cycle. We substituted so-called resonator neural models, which exhibit class 2 excitability and postinhibitory rebound (PIR), for the integrators that are typically used. This results in much greater robustness to heterogeneity that actually increases as the average participation in spikes per cycle approximates physiological levels. Moreover, dynamic clamp experiments that show autapse-induced firing in entorhinal cortical interneurons support the idea that PIR can serve as a network gamma mechanism. Furthermore, parvalbumin-positive (PV(+)) cells were much more likely to display both PIR and autapse-induced firing than GAD2(+) cells, supporting the view that PV(+) fast-firing basket cells are more likely to exhibit class 2 excitability than other types of inhibitory interneurons. Gamma oscillations are believed to play a critical role in information processing, encoding, and retrieval. Networks of inhibitory interneurons are thought to be essential for these oscillations. We show that one class of interneurons with an abrupt onset of firing

Dendritic A-type potassium channel subunit expression in CA1 hippocampal interneurons.

PubMed

Menegola, M; Misonou, H; Vacher, H; Trimmer, J S

2008-06-26

Voltage-gated potassium (Kv) channels are important and diverse determinants of neuronal excitability and exhibit specific expression patterns throughout the brain. Among Kv channels, Kv4 channels are major determinants of somatodendritic A-type current and are essential in controlling the amplitude of backpropagating action potentials (BAPs) into neuronal dendrites. BAPs have been well studied in a variety of neurons, and have been recently described in hippocampal and cortical interneurons, a heterogeneous population of GABAergic inhibitory cells that regulate activity of principal cells and neuronal networks. We used well-characterized mouse monoclonal antibodies against the Kv4.3 and potassium channel interacting protein (KChIP) 1 subunits of A-type Kv channels, and antibodies against different interneuron markers in single- and double-label immunohistochemistry experiments to analyze the expression patterns of Kv4.3 and KChIP1 in hippocampal Ammon's horn (CA1) neurons. Immunohistochemistry was performed on 40 mum rat brain sections using nickel-enhanced diaminobenzidine staining or multiple-label immunofluorescence. Our results show that Kv4.3 and KChIP1 component subunits of A-type channels are co-localized in the soma and dendrites of a large number of GABAergic hippocampal interneurons. These subunits co-localize extensively but not completely with markers defining the four major interneuron subpopulations tested (parvalbumin, calbindin, calretinin, and somatostatin). These results suggest that CA1 hippocampal interneurons can be divided in two groups according to the expression of Kv4.3/KChIP1 channel subunits. Antibodies against Kv4.3 and KChIP1 represent an important new tool for identifying a subpopulation of hippocampal interneurons with a unique dendritic A-type channel complement and ability to control BAPs.

Delayed Maturation of Fast-Spiking Interneurons Is Rectified by Activation of the TrkB Receptor in the Mouse Model of Fragile X Syndrome.

PubMed

Nomura, Toshihiro; Musial, Timothy F; Marshall, John J; Zhu, Yiwen; Remmers, Christine L; Xu, Jian; Nicholson, Daniel A; Contractor, Anis

2017-11-22

Fragile X syndrome (FXS) is a neurodevelopmental disorder that is a leading cause of inherited intellectual disability, and the most common known cause of autism spectrum disorder. FXS is broadly characterized by sensory hypersensitivity and several developmental alterations in synaptic and circuit function have been uncovered in the sensory cortex of the mouse model of FXS ( Fmr1 KO). GABA-mediated neurotransmission and fast-spiking (FS) GABAergic interneurons are central to cortical circuit development in the neonate. Here we demonstrate that there is a delay in the maturation of the intrinsic properties of FS interneurons in the sensory cortex, and a deficit in the formation of excitatory synaptic inputs on to these neurons in neonatal Fmr1 KO mice. Both these delays in neuronal and synaptic maturation were rectified by chronic administration of a TrkB receptor agonist. These results demonstrate that the maturation of the GABAergic circuit in the sensory cortex is altered during a critical developmental period due in part to a perturbation in BDNF-TrkB signaling, and could contribute to the alterations in cortical development underlying the sensory pathophysiology of FXS. SIGNIFICANCE STATEMENT Fragile X (FXS) individuals have a range of sensory related phenotypes, and there is growing evidence of alterations in neuronal circuits in the sensory cortex of the mouse model of FXS ( Fmr1 KO). GABAergic interneurons are central to the correct formation of circuits during cortical critical periods. Here we demonstrate a delay in the maturation of the properties and synaptic connectivity of interneurons in Fmr1 KO mice during a critical period of cortical development. The delays both in cellular and synaptic maturation were rectified by administration of a TrkB receptor agonist, suggesting reduced BDNF-TrkB signaling as a contributing factor. These results provide evidence that the function of fast-spiking interneurons is disrupted due to a deficiency in neurotrophin

Delayed Maturation of Fast-Spiking Interneurons Is Rectified by Activation of the TrkB Receptor in the Mouse Model of Fragile X Syndrome

PubMed Central

Nomura, Toshihiro; Zhu, Yiwen; Remmers, Christine L.; Xu, Jian; Nicholson, Daniel A.

2017-01-01

Fragile X syndrome (FXS) is a neurodevelopmental disorder that is a leading cause of inherited intellectual disability, and the most common known cause of autism spectrum disorder. FXS is broadly characterized by sensory hypersensitivity and several developmental alterations in synaptic and circuit function have been uncovered in the sensory cortex of the mouse model of FXS (Fmr1 KO). GABA-mediated neurotransmission and fast-spiking (FS) GABAergic interneurons are central to cortical circuit development in the neonate. Here we demonstrate that there is a delay in the maturation of the intrinsic properties of FS interneurons in the sensory cortex, and a deficit in the formation of excitatory synaptic inputs on to these neurons in neonatal Fmr1 KO mice. Both these delays in neuronal and synaptic maturation were rectified by chronic administration of a TrkB receptor agonist. These results demonstrate that the maturation of the GABAergic circuit in the sensory cortex is altered during a critical developmental period due in part to a perturbation in BDNF-TrkB signaling, and could contribute to the alterations in cortical development underlying the sensory pathophysiology of FXS. SIGNIFICANCE STATEMENT Fragile X (FXS) individuals have a range of sensory related phenotypes, and there is growing evidence of alterations in neuronal circuits in the sensory cortex of the mouse model of FXS (Fmr1 KO). GABAergic interneurons are central to the correct formation of circuits during cortical critical periods. Here we demonstrate a delay in the maturation of the properties and synaptic connectivity of interneurons in Fmr1 KO mice during a critical period of cortical development. The delays both in cellular and synaptic maturation were rectified by administration of a TrkB receptor agonist, suggesting reduced BDNF-TrkB signaling as a contributing factor. These results provide evidence that the function of fast-spiking interneurons is disrupted due to a deficiency in neurotrophin

Coup-TF1 and Coup-TF2 control subtype and laminar identity of MGE-derived neocortical interneurons.

PubMed

Hu, Jia Sheng; Vogt, Daniel; Lindtner, Susan; Sandberg, Magnus; Silberberg, Shanni N; Rubenstein, John L R

2017-08-01

Distinct cortical interneuron (CIN) subtypes have unique circuit functions; dysfunction in specific subtypes is implicated in neuropsychiatric disorders. Somatostatin- and parvalbumin-expressing (SST + and PV + ) interneurons are the two major subtypes generated by medial ganglionic eminence (MGE) progenitors. Spatial and temporal mechanisms governing their cell-fate specification and differential integration into cortical layers are largely unknown. We provide evidence that Coup-TF1 and Coup-TF2 ( Nr2f1 and Nr2f2 ) transcription factor expression in an arc-shaped progenitor domain within the MGE promotes time-dependent survival of this neuroepithelium and the time-dependent specification of layer V SST + CINs. Coup-TF1 and Coup-TF2 autonomously repress PV + fate in MGE progenitors, in part through directly driving Sox6 expression. These results have identified, in mouse, a transcriptional pathway that controls SST-PV fate. © 2017. Published by The Company of Biologists Ltd.

Cell Type-Specific Circuit Mapping Reveals the Presynaptic Connectivity of Developing Cortical Circuits

PubMed Central

Cocas, Laura A.; Fernandez, Gloria; Barch, Mariya; Doll, Jason; Zamora Diaz, Ivan

2016-01-01

The mammalian cerebral cortex is a dense network composed of local, subcortical, and intercortical synaptic connections. As a result, mapping cell type-specific neuronal connectivity in the cerebral cortex in vivo has long been a challenge for neurobiologists. In particular, the development of excitatory and inhibitory interneuron presynaptic input has been hard to capture. We set out to analyze the development of this connectivity in the first postnatal month using a murine model. First, we surveyed the connectivity of one of the earliest populations of neurons in the brain, the Cajal-Retzius (CR) cells in the neocortex, which are known to be critical for cortical layer formation and are hypothesized to be important in the establishment of early cortical networks. We found that CR cells receive inputs from deeper-layer excitatory neurons and inhibitory interneurons in the first postnatal week. We also found that both excitatory pyramidal neurons and inhibitory interneurons received broad inputs in the first postnatal week, including inputs from CR cells. Expanding our analysis into the more mature brain, we assessed the inputs onto inhibitory interneurons and excitatory projection neurons, labeling neuronal progenitors with Cre drivers to study discrete populations of neurons in older cortex, and found that excitatory cortical and subcortical inputs are refined by the fourth week of development, whereas local inhibitory inputs increase during this postnatal period. Cell type-specific circuit mapping is specific, reliable, and effective, and can be used on molecularly defined subtypes to determine connectivity in the cortex. SIGNIFICANCE STATEMENT Mapping cortical connectivity in the developing mammalian brain has been an intractable problem, in part because it has not been possible to analyze connectivity with cell subtype precision. Our study systematically targets the presynaptic connections of discrete neuronal subtypes in both the mature and developing

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.

Preprodynorphin-expressing neurons constitute a large subgroup of somatostatin-expressing GABAergic interneurons in the mouse neocortex.

PubMed

Sohn, Jaerin; Hioki, Hiroyuki; Okamoto, Shinichiro; Kaneko, Takeshi

2014-05-01

Dynorphins, leumorphin, and neoendorphins are preprodynorphin (PPD)-derived peptides and ligands for κ-opioid receptors. Using an antibody to PPD C-terminal, we investigated the chemical and molecular characteristics of PPD-expressing neurons in mouse neocortex. PPD-immunopositive neuronal somata were distributed most frequently in layer 5 and less frequently in layers 2-4 and 6 throughout neocortical regions. Combined labeling of immunofluorescence and fluorescent mRNA signals revealed that almost all PPD-immunopositive neurons expressed glutamic acid decarboxylase but not vesicular glutamate transporter, indicating their γ-aminobutyric acid (GABA)ergic characteristics, and that PPD-immunopositive neurons accounted for 15% of GABAergic interneurons in the primary somatosensory area. As GABAergic interneurons were divided into several groups by specific markers, we further examined the chemical characteristics of PPD-expressing neurons by the double immunofluorescence labeling method. More than 95% of PPD-immunopositive neurons were also somatostatin (SOM)-immunopositive in the primary somatosensory, primary motor, orbitofrontal, and primary visual areas, but only 24% were SOM-immunopositive in the medial prefrontal cortex. In the primary somatosensory area, PPD-immunopositive neurons constituted 50%, 79%, 55%, and 17% of SOM-immunopositive neurons in layers 2-3, 4, 5, and 6, respectively. Although SOM-expressing neurons contained calretinin-, neuropeptide Y-, nitric oxide synthase-, and reelin-expressing neurons as subgroups, only reelin immunoreactivity was detected in many PPD-immunopositive neurons. These results indicate that PPD-expressing neurons constitute a large subgroup of SOM-expressing cortical interneurons, and the PPD/SOM-expressing GABAergic neurons might serve not only as inhibitory elements in the local cortical circuit, but also as modulators for cortical neurons expressing κ-opioid and/or SOM receptors. Copyright © 2013 Wiley Periodicals

Inhibitory interneurons of the human prefrontal cortex display conserved evolution of the phenotype and related genes.

PubMed

Sherwood, Chet C; Raghanti, Mary Ann; Stimpson, Cheryl D; Spocter, Muhammad A; Uddin, Monica; Boddy, Amy M; Wildman, Derek E; Bonar, Christopher J; Lewandowski, Albert H; Phillips, Kimberley A; Erwin, Joseph M; Hof, Patrick R

2010-04-07

Inhibitory interneurons participate in local processing circuits, playing a central role in executive cognitive functions of the prefrontal cortex. Although humans differ from other primates in a number of cognitive domains, it is not currently known whether the interneuron system has changed in the course of primate evolution leading to our species. In this study, we examined the distribution of different interneuron subtypes in the prefrontal cortex of anthropoid primates as revealed by immunohistochemistry against the calcium-binding proteins calbindin, calretinin and parvalbumin. In addition, we tested whether genes involved in the specification, differentiation and migration of interneurons show evidence of positive selection in the evolution of humans. Our findings demonstrate that cellular distributions of interneuron subtypes in human prefrontal cortex are similar to other anthropoid primates and can be explained by general scaling rules. Furthermore, genes underlying interneuron development are highly conserved at the amino acid level in primate evolution. Taken together, these results suggest that the prefrontal cortex in humans retains a similar inhibitory circuitry to that in closely related primates, even though it performs functional operations that are unique to our species. Thus, it is likely that other significant modifications to the connectivity and molecular biology of the prefrontal cortex were overlaid on this conserved interneuron architecture in the course of human evolution.

Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex

PubMed Central

2010-01-01

Neuroscience produces a vast amount of data from an enormous diversity of neurons. A neuronal classification system is essential to organize such data and the knowledge that is derived from them. Classification depends on the unequivocal identification of the features that distinguish one type of neuron from another. The problems inherent in this are particularly acute when studying cortical interneurons. To tackle this, we convened a representative group of researchers to agree on a set of terms to describe the anatomical, physiological and molecular features of GABAergic interneurons of the cerebral cortex. The resulting terminology might provide a stepping stone towards a future classification of these complex and heterogeneous cells. Consistent adoption will be important for the success of such an initiative, and we also encourage the active involvement of the broader scientific community in the dynamic evolution of this project. PMID:18568015

Prenatal stress delays inhibitory neuron progenitor migration in the developing neocortex

PubMed Central

Stevens, Hanna E.; Su, Tina; Yanagawa, Yuchio; Vaccarino, Flora M.

2012-01-01

Summary Prenatal stress has been widely demonstrated to have links with behavioral problems in clinical populations and animal models, however, few investigations have examined the immediate developmental events that are affected by prenatal stress. Here, we utilize GAD67GFP transgenic mice in which GABAergic progenitors express green fluorescent protein (GFP) to examine the impact of prenatal stress on the development of these precursors to inhibitory neurons. Pregnant female mice were exposed to restraint stress three times daily from embryonic day 12 (E12) onwards. Their offspring demonstrated changes in the distribution of GFP-positive (GFP+) GABAergic progenitors in the telencephalon as early as E13 and persisting until postnatal day 0. Changes in distribution reflected alterations in tangential migration and radial integration of GFP+ cells into the developing cortical plate. Fate mapping of GAD67GFP+progenitors with bromodeoxyuridine injected at E13 demonstrated a significant increase of these cells at P0 in anterior white matter. An overall decrease in GAD67GFP+ progenitors at P0 in medial frontal cortex could not be attributed to a reduction in cell proliferation. Significant changes in dlx2, nkx2.1 and their downstream target erbb4, transcription factors which regulate interneuron migration, were found within the prenatally-stressed developing forebrain, while no differences were seen in mash1, a determinant of interneuron fate, bdnf, a maturation factor for GABAergic cells or fgf2, an early growth/differentiation factor. These results demonstrate that early disruption in GABAergic progenitor migration caused by prenatal stress may be responsible for neuronal defects in disorders with GABAergic abnormalities like schizophrenia. PMID:22910687

Cortical Feedback Control of Olfactory Bulb Circuits

PubMed Central

Boyd, Alison M.; Sturgill, James F.; Poo, Cindy; Isaacson, Jeffry S.

2013-01-01

SUMMARY Olfactory cortex pyramidal cells integrate sensory input from olfactory bulb mitral and tufted (M/T) cells and project axons back to the bulb. However, the impact of cortical feedback projections on olfactory bulb circuits is unclear. Here, we selectively express channelrhodopsin-2 in olfactory cortex pyramidal cells and show that cortical feedback projections excite diverse populations of bulb interneurons. Activation of cortical fibers directly excites GABAergic granule cells, which in turn inhibit M/T cells. However, we show that cortical inputs preferentially target short axon cells that drive feedforward inhibition of granule cells. In vivo, activation of olfactory cortex that only weakly affects spontaneous M/T cell firing strongly gates odor-evoked M/T cell responses: cortical activity suppresses odor-evoked excitation and enhances odor-evoked inhibition. Together, these results indicate that although cortical projections have diverse actions on olfactory bulb microcircuits, the net effect of cortical feedback on M/T cells is an amplification of odor-evoked inhibition. PMID:23259951

INTRINSIC CURVATURE: A MARKER OF MILLIMETER-SCALE TANGENTIAL CORTICO-CORTICAL CONNECTIVITY?

PubMed Central

RONAN, LISA; PIENAAR, RUDOLPH; WILLIAMS, GUY; BULLMORE, ED; CROW, TIM J.; ROBERTS, NEIL; JONES, PETER B.; SUCKLING, JOHN; FLETCHER, PAUL C.

2012-01-01

In this paper, we draw a link between cortical intrinsic curvature and the distributions of tangential connection lengths. We suggest that differential rates of surface expansion not only lead to intrinsic curvature of the cortical sheet, but also to differential inter-neuronal spacing. We propose that there follows a consequential change in the profile of neuronal connections: specifically an enhancement of the tendency towards proportionately more short connections. Thus, the degree of cortical intrinsic curvature may have implications for short-range connectivity. PMID:21956929

Inhibitory interneuron circuits at cortical and spinal levels are associated with individual differences in corticomuscular coherence during isometric voluntary contraction

PubMed Central

Matsuya, Ryosuke; Ushiyama, Junichi; Ushiba, Junichi

2017-01-01

Corticomuscular coherence (CMC) is an oscillatory synchronization of 15–35 Hz (β-band) between electroencephalogram (EEG) of the sensorimotor cortex and electromyogram of contracting muscles. Although we reported that the magnitude of CMC varies among individuals, the physiological mechanisms underlying this variation are still unclear. Here, we aimed to investigate the associations between CMC and intracortical inhibition (ICI) in the primary motor cortex (M1)/recurrent inhibition (RI) in the spinal cord, which probably affect oscillatory neural activities. Firstly, we quantified ICI from changes in motor-evoked potentials induced by paired-pulse transcranial magnetic stimulation in M1 during tonic isometric voluntary contraction of the first dorsal interosseous. ICI showed a significant, negative correlation with the strength of EEG β-oscillation, but not with the magnitude of CMC across individuals. Next, we quantified RI from changes in H-reflexes induced by paired-pulse electrical nerve stimulation to the posterior tibial nerve during isometric contraction of the soleus muscle. We observed a significant, positive correlation between RI and peak CMC across individuals. These results suggest that the local inhibitory interneuron networks in cortical and spinal levels are associated with the oscillatory activity in corticospinal loop. PMID:28290507

Increasing proportions of tyrosine hydroxylase-immunoreactive interneurons colocalize with choline acetyltransferase or vasoactive intestinal peptide in the developing rat cerebral cortex

PubMed Central

Asmus, Stephen E.; Cocanougher, Benjamin T.; Allen, Donald L.; Boone, John B.; Brooks, Elizabeth A.; Hawkins, Sarah M.; Hench, Laura A.; Ijaz, Talha; Mayfield, Meredith N.

2011-01-01

Cortical interneurons are critical for information processing, and their dysfunction has been implicated in neurological disorders. One subset of this diverse cell population expresses tyrosine hydroxylase (TH) during postnatal rat development. Cortical TH-immunoreactive neurons appear at postnatal day (P) 16. The number of TH cells sharply increases between P16 and P20 and subsequently decreases to adult values. The absence of apoptotic markers in these cells suggests that the reduction in cell number is not due to cell death but is due to a decline in TH production. Cortical TH cells lack all additional catecholaminergic enzymes, and many coexpress GABA and calretinin, but little else is known about their phenotype or function. Because interneurons containing choline acetyltransferase (ChAT) or vasoactive intestinal peptide (VIP) share characteristics with cortical TH neurons, the coexpression of TH with ChAT or VIP was examined throughout the neocortex at P16, P20, and P30. The proportions of TH cell profiles double-labeled for ChAT or VIP significantly increased between P16 and P30. Based on their proximity to blood vessels, intrinsic cholinergic and VIPergic cells have been hypothesized to regulate cortical microcirculation. Labeling with the gliovascular marker aquaporin-4 revealed that at least half of the TH cells were apposed to microvessels at these ages, and many of these cells contained ChAT or VIP. Cortical TH neurons did not coproduce nitric oxide synthase. These results suggest that increasing proportions of cortical TH neurons express ChAT or VIP developmentally and that a subset of these TH neurons may regulate local blood flow. PMID:21295554

Cortical feedback control of olfactory bulb circuits.

PubMed

Boyd, Alison M; Sturgill, James F; Poo, Cindy; Isaacson, Jeffry S

2012-12-20

Olfactory cortex pyramidal cells integrate sensory input from olfactory bulb mitral and tufted (M/T) cells and project axons back to the bulb. However, the impact of cortical feedback projections on olfactory bulb circuits is unclear. Here, we selectively express channelrhodopsin-2 in olfactory cortex pyramidal cells and show that cortical feedback projections excite diverse populations of bulb interneurons. Activation of cortical fibers directly excites GABAergic granule cells, which in turn inhibit M/T cells. However, we show that cortical inputs preferentially target short axon cells that drive feedforward inhibition of granule cells. In vivo, activation of olfactory cortex that only weakly affects spontaneous M/T cell firing strongly gates odor-evoked M/T cell responses: cortical activity suppresses odor-evoked excitation and enhances odor-evoked inhibition. Together, these results indicate that although cortical projections have diverse actions on olfactory bulb microcircuits, the net effect of cortical feedback on M/T cells is an amplification of odor-evoked inhibition. Copyright © 2012 Elsevier Inc. All rights reserved.

Stimulation of Cortical Myosin Phosphorylation by p114RhoGEF Drives Cell Migration and Tumor Cell Invasion

PubMed Central

Zihni, Ceniz; Harris, Andrew R.; Bailly, Maryse; Charras, Guillaume T.; Balda, Maria S.; Matter, Karl

2012-01-01

Actinomyosin activity is an important driver of cell locomotion and has been shown to promote collective cell migration of epithelial sheets as well as single cell migration and tumor cell invasion. However, the molecular mechanisms underlying activation of cortical myosin to stimulate single cell movement, and the relationship between the mechanisms that drive single cell locomotion and those that mediate collective cell migration of epithelial sheets are incompletely understood. Here, we demonstrate that p114RhoGEF, an activator of RhoA that associates with non-muscle myosin IIA, regulates collective cell migration of epithelial sheets and tumor cell invasion. Depletion of p114RhoGEF resulted in specific spatial inhibition of myosin activation at cell-cell contacts in migrating epithelial sheets and the cortex of migrating single cells, but only affected double and not single phosphorylation of myosin light chain. In agreement, overall elasticity and contractility of the cells, processes that rely on persistent and more constant forces, were not affected, suggesting that p114RhoGEF mediates process-specific myosin activation. Locomotion was p114RhoGEF-dependent on Matrigel, which favors more roundish cells and amoeboid-like actinomyosin-driven movement, but not on fibronectin, which stimulates flatter cells and lamellipodia-driven, mesenchymal-like migration. Accordingly, depletion of p114RhoGEF led to reduced RhoA, but increased Rac activity. Invasion of 3D matrices was p114RhoGEF-dependent under conditions that do not require metalloproteinase activity, supporting a role of p114RhoGEF in myosin-dependent, amoeboid-like locomotion. Our data demonstrate that p114RhoGEF drives cortical myosin activation by stimulating myosin light chain double phosphorylation and, thereby, collective cell migration of epithelial sheets and amoeboid-like motility of tumor cells. PMID:23185572

Interneuron-mediated inhibition synchronizes neuronal activity during slow oscillation.

PubMed

Chen, Jen-Yung; Chauvette, Sylvain; Skorheim, Steven; Timofeev, Igor; Bazhenov, Maxim

2012-08-15

The signature of slow-wave sleep in the electroencephalogram (EEG) is large-amplitude fluctuation of the field potential, which reflects synchronous alternation of activity and silence across cortical neurons. While initiation of the active cortical states during sleep slow oscillation has been intensively studied, the biological mechanisms which drive the network transition from an active state to silence remain poorly understood. In the current study, using a combination of in vivo electrophysiology and thalamocortical network simulation, we explored the impact of intrinsic and synaptic inhibition on state transition during sleep slow oscillation. We found that in normal physiological conditions, synaptic inhibition controls the duration and the synchrony of active state termination. The decline of interneuron-mediated inhibition led to asynchronous downward transition across the cortical network and broke the regular slow oscillation pattern. Furthermore, in both in vivo experiment and computational modelling, we revealed that when the level of synaptic inhibition was reduced significantly, it led to a recovery of synchronized oscillations in the form of seizure-like bursting activity. In this condition, the fast active state termination was mediated by intrinsic hyperpolarizing conductances. Our study highlights the significance of both intrinsic and synaptic inhibition in manipulating sleep slow rhythms.

Interneuron-mediated inhibition synchronizes neuronal activity during slow oscillation

PubMed Central

Chen, Jen-Yung; Chauvette, Sylvain; Skorheim, Steven; Timofeev, Igor; Bazhenov, Maxim

2012-01-01

The signature of slow-wave sleep in the electroencephalogram (EEG) is large-amplitude fluctuation of the field potential, which reflects synchronous alternation of activity and silence across cortical neurons. While initiation of the active cortical states during sleep slow oscillation has been intensively studied, the biological mechanisms which drive the network transition from an active state to silence remain poorly understood. In the current study, using a combination of in vivo electrophysiology and thalamocortical network simulation, we explored the impact of intrinsic and synaptic inhibition on state transition during sleep slow oscillation. We found that in normal physiological conditions, synaptic inhibition controls the duration and the synchrony of active state termination. The decline of interneuron-mediated inhibition led to asynchronous downward transition across the cortical network and broke the regular slow oscillation pattern. Furthermore, in both in vivo experiment and computational modelling, we revealed that when the level of synaptic inhibition was reduced significantly, it led to a recovery of synchronized oscillations in the form of seizure-like bursting activity. In this condition, the fast active state termination was mediated by intrinsic hyperpolarizing conductances. Our study highlights the significance of both intrinsic and synaptic inhibition in manipulating sleep slow rhythms. PMID:22641778

Parallel processing by cortical inhibition enables context-dependent behavior.

PubMed

Kuchibhotla, Kishore V; Gill, Jonathan V; Lindsay, Grace W; Papadoyannis, Eleni S; Field, Rachel E; Sten, Tom A Hindmarsh; Miller, Kenneth D; Froemke, Robert C

2017-01-01

Physical features of sensory stimuli are fixed, but sensory perception is context dependent. The precise mechanisms that govern contextual modulation remain unknown. Here, we trained mice to switch between two contexts: passively listening to pure tones and performing a recognition task for the same stimuli. Two-photon imaging showed that many excitatory neurons in auditory cortex were suppressed during behavior, while some cells became more active. Whole-cell recordings showed that excitatory inputs were affected only modestly by context, but inhibition was more sensitive, with PV + , SOM + , and VIP + interneurons balancing inhibition and disinhibition within the network. Cholinergic modulation was involved in context switching, with cholinergic axons increasing activity during behavior and directly depolarizing inhibitory cells. Network modeling captured these findings, but only when modulation coincidently drove all three interneuron subtypes, ruling out either inhibition or disinhibition alone as sole mechanism for active engagement. Parallel processing of cholinergic modulation by cortical interneurons therefore enables context-dependent behavior.

Novel AAV-based rat model of forebrain synucleinopathy shows extensive pathologies and progressive loss of cholinergic interneurons.

PubMed

Aldrin-Kirk, Patrick; Davidsson, Marcus; Holmqvist, Staffan; Li, Jia-Yi; Björklund, Tomas

2014-01-01

Synucleinopathies, characterized by intracellular aggregation of α-synuclein protein, share a number of features in pathology and disease progression. However, the vulnerable cell population differs significantly between the disorders, despite being caused by the same protein. While the vulnerability of dopamine cells in the substantia nigra to α-synuclein over-expression, and its link to Parkinson's disease, is well studied, animal models recapitulating the cortical degeneration in dementia with Lewy-bodies (DLB) are much less mature. The aim of this study was to develop a first rat model of widespread progressive synucleinopathy throughout the forebrain using adeno-associated viral (AAV) vector mediated gene delivery. Through bilateral injection of an AAV6 vector expressing human wild-type α-synuclein into the forebrain of neonatal rats, we were able to achieve widespread, robust α-synuclein expression with preferential expression in the frontal cortex. These animals displayed a progressive emergence of hyper-locomotion and dysregulated response to the dopaminergic agonist apomorphine. The animals receiving the α-synuclein vector displayed significant α-synuclein pathology including intra-cellular inclusion bodies, axonal pathology and elevated levels of phosphorylated α-synuclein, accompanied by significant loss of cortical neurons and a progressive reduction in both cortical and striatal ChAT positive interneurons. Furthermore, we found evidence of α-synuclein sequestered by IBA-1 positive microglia, which was coupled with a distinct change in morphology. In areas of most prominent pathology, the total α-synuclein levels were increased to, on average, two-fold, which is similar to the levels observed in patients with SNCA gene triplication, associated with cortical Lewy body pathology. This study provides a novel rat model of progressive cortical synucleinopathy, showing for the first time that cholinergic interneurons are vulnerable to �

Are Striatal Tyrosine Hydroxylase Interneurons Dopaminergic?

PubMed Central

Xenias, Harry S.; Ibáñez-Sandoval, Osvaldo; Koós, Tibor

2015-01-01

Striatal GABAergic interneurons that express the gene for tyrosine hydroxylase (TH) have been identified previously by several methods. Although generally assumed to be dopaminergic, possibly serving as a compensatory source of dopamine (DA) in Parkinson's disease, this assumption has never been tested directly. In TH–Cre mice whose nigrostriatal pathway had been eliminated unilaterally with 6-hydroxydopamine, we injected a Cre-dependent virus coding for channelrhodopsin-2 and enhanced yellow fluorescent protein unilaterally into the unlesioned midbrain or bilaterally into the striatum. Fast-scan cyclic voltammetry in striatal slices revealed that both optical and electrical stimulation readily elicited DA release in control striata but not from contralateral striata when nigrostriatal neurons were transduced. In contrast, neither optical nor electrical stimulation could elicit striatal DA release in either the control or lesioned striata when the virus was injected directly into the striatum transducing only striatal TH interneurons. This demonstrates that striatal TH interneurons do not release DA. Fluorescence immunocytochemistry in enhanced green fluorescent protein (EGFP)–TH mice revealed colocalization of DA, l-amino acid decarboxylase, the DA transporter, and vesicular monoamine transporter-2 with EGFP in midbrain dopaminergic neurons but not in any of the striatal EGFP–TH interneurons. Optogenetic activation of striatal EGFP–TH interneurons produced strong GABAergic inhibition in all spiny neurons tested. These results indicate that striatal TH interneurons are not dopaminergic but rather are a type of GABAergic interneuron that expresses TH but none of the other enzymes or transporters necessary to operate as dopaminergic neurons and exert widespread GABAergic inhibition onto direct and indirect spiny neurons. PMID:25904808

Reduction in cortical parvalbumin expression due to intermittent theta-burst stimulation correlates with maturation of the perineuronal nets in young rats.

PubMed

Mix, Annika; Hoppenrath, Kathrin; Funke, Klaus

2015-01-01

We recently showed that intermittent theta-burst stimulation (iTBS) using transcranial magnetic stimulation strongly reduces the number of rat neocortical interneurons expressing glutamic acid decarboxylase 67 kDa (GAD67) and parvalbumin (PV), indicating changed activity of fast-spiking (FS) interneurons. In advance of in vitro studies intended to characterize changes in electrical properties of FS interneurons under these conditions, we tested whether the iTBS effect is age-dependent. Conscious Sprague-Dawley rats aged between 28 and 90 days received three blocks of iTBS at 15 min intervals. We found that iTBS-related reduction in PV+ cells was absent up to an age of 32 days, then gradually increased, and approached a maximum of about 40% reduction at an age of about 40 days. The relative number of cells expressing PV (PV+, 8-9%) did not change with age in sham-controls and also the increase in cortical c-Fos expression induced by iTBS was not principally age-dependent. However, a prominent growth of the perineuronal nets, typically surrounding the PV+ cells, exactly paralleled the increase in the iTBS effect. Based on these findings, we conclude that the functional development of the inhibitory network of PV+ interneurons with regard to intracortical synaptic connectivity is not sufficiently matured in rats younger than 35 d to enable activity-dependent modifications during iTBS. Outgrowth of the perineuronal nets and associated maturation of excitatory cortical inputs, as is characteristic for the critical cortical period, may take place before PV+ interneurons can be sufficiently activated via repetitive transcranial magnetic stimulation, allowing plastic changes of molecular phenotype and likely also synaptic plasticity. © 2014 Wiley Periodicals, Inc.

A Circuit for Motor Cortical Modulation of Auditory Cortical Activity

PubMed Central

Nelson, Anders; Schneider, David M.; Takatoh, Jun; Sakurai, Katsuyasu; Wang, Fan

2013-01-01

Normal hearing depends on the ability to distinguish self-generated sounds from other sounds, and this ability is thought to involve neural circuits that convey copies of motor command signals to various levels of the auditory system. Although such interactions at the cortical level are believed to facilitate auditory comprehension during movements and drive auditory hallucinations in pathological states, the synaptic organization and function of circuitry linking the motor and auditory cortices remain unclear. Here we describe experiments in the mouse that characterize circuitry well suited to transmit motor-related signals to the auditory cortex. Using retrograde viral tracing, we established that neurons in superficial and deep layers of the medial agranular motor cortex (M2) project directly to the auditory cortex and that the axons of some of these deep-layer cells also target brainstem motor regions. Using in vitro whole-cell physiology, optogenetics, and pharmacology, we determined that M2 axons make excitatory synapses in the auditory cortex but exert a primarily suppressive effect on auditory cortical neuron activity mediated in part by feedforward inhibition involving parvalbumin-positive interneurons. Using in vivo intracellular physiology, optogenetics, and sound playback, we also found that directly activating M2 axon terminals in the auditory cortex suppresses spontaneous and stimulus-evoked synaptic activity in auditory cortical neurons and that this effect depends on the relative timing of motor cortical activity and auditory stimulation. These experiments delineate the structural and functional properties of a corticocortical circuit that could enable movement-related suppression of auditory cortical activity. PMID:24005287

Classification of neocortical interneurons using affinity propagation.

PubMed

Santana, Roberto; McGarry, Laura M; Bielza, Concha; Larrañaga, Pedro; Yuste, Rafael

2013-01-01

In spite of over a century of research on cortical circuits, it is still unknown how many classes of cortical neurons exist. In fact, neuronal classification is a difficult problem because it is unclear how to designate a neuronal cell class and what are the best characteristics to define them. Recently, unsupervised classifications using cluster analysis based on morphological, physiological, or molecular characteristics, have provided quantitative and unbiased identification of distinct neuronal subtypes, when applied to selected datasets. However, better and more robust classification methods are needed for increasingly complex and larger datasets. Here, we explored the use of affinity propagation, a recently developed unsupervised classification algorithm imported from machine learning, which gives a representative example or exemplar for each cluster. As a case study, we applied affinity propagation to a test dataset of 337 interneurons belonging to four subtypes, previously identified based on morphological and physiological characteristics. We found that affinity propagation correctly classified most of the neurons in a blind, non-supervised manner. Affinity propagation outperformed Ward's method, a current standard clustering approach, in classifying the neurons into 4 subtypes. Affinity propagation could therefore be used in future studies to validly classify neurons, as a first step to help reverse engineer neural circuits.

Molecular layer interneurons of the cerebellum: developmental and morphological aspects.

PubMed

Sotelo, Constantino

2015-10-01

During the past 25 years, our knowledge on the development of basket and stellate cells (molecular layer interneurons [MLIs]) has completely changed, not only regarding their origin from the ventricular zone, corresponding to the primitive cerebellar neuroepithelium, instead of the external granular layer, but above all by providing an almost complete account of the genetic regulations (transcription factors and other genes) involved in their differentiation and synaptogenesis. Moreover, it has been shown that MLIs' precursors (dividing neuroblasts) and not young postmitotic neurons, as in other germinal neuroepithelia, leave the germinative zone and migrate all along a complex and lengthy path throughout the presumptive cerebellar white matter, which provides suitable niches exerting epigenetic influences on their ultimate neuronal identities. Recent studies carried out on the anatomical-functional properties of adult MLIs emphasize the importance of these interneurons in regulating PC inhibition, and point out the crucial role played by electrical synaptic transmission between MLIs as well as ephaptic interactions between them and Purkinje cells at the pinceaux level, in the regulation of this inhibition.

Extended Interneuronal Network of the Dentate Gyrus.

PubMed

Szabo, Gergely G; Du, Xi; Oijala, Mikko; Varga, Csaba; Parent, Jack M; Soltesz, Ivan

2017-08-08

Local interneurons control principal cells within individual brain areas, but anecdotal observations indicate that interneuronal axons sometimes extend beyond strict anatomical boundaries. Here, we use the case of the dentate gyrus (DG) to show that boundary-crossing interneurons with cell bodies in CA3 and CA1 constitute a numerically significant and diverse population that relays patterns of activity generated within the CA regions back to granule cells. These results reveal the existence of a sophisticated retrograde GABAergic circuit that fundamentally extends the canonical interneuronal network. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Further studies on cortical tangential migration in wild type and Pax-6 mutant mice.

PubMed

Jiménez, D; López-Mascaraque, L; de Carlos, J A; Valverde, F

2002-01-01

In this study we present new data concerning the tangential migration from the medial and lateral ganglionic eminences (MGE and LGE) to the cerebral cortex during development. We have used Calbindin as a useful marker to follow the itinerary of tangential migratory cells during early developmental stages in wild-type and Pax-6 homozygous mutant mice. In the wild-type mice, at early developmental stages, migrating cells advance through the intermediate zone (IZ) and preplate (PP). At more advanced stages, migrating cells were present in the subplate (SP) and cortical plate (CP) to reach the entire developing cerebral cortex. We found that, in the homozygous mutant mice (Pax-6(Sey-Neu)/Pax-6(Sey-Neu)), this tangential migration is severely affected at early developmental stages: migrating cells were absent in the IZ, which were only found some days later, suggesting that in the mutant mice, there is a temporal delay in tangential migration. We have also defined some possible mechanisms to explain certain migratory routes from the basal telencephalon to the cerebral cortex. We describe the existence of two factors, which we consider to be essential for the normal migration; the first one is the cell adhesion molecule PSA-NCAM, whose role in other migratory systems is well known. The second factor is Robo-2, whose expression delimits a channel for the passage of migratory cells from the basal telencephalon to the cerebral cortex.

Behavior-dependent specialization of identified hippocampal interneurons

PubMed Central

Lapray, Damien; Lasztoczi, Balint; Lagler, Michael; Viney, Tim James; Katona, Linda; Valenti, Ornella; Hartwich, Katja; Borhegyi, Zsolt; Somogyi, Peter; Klausberger, Thomas

2012-01-01

A large variety of GABAergic interneurons control information processing in hippocampal circuits governing the formation of neuronal representations. Whether distinct hippocampal interneuron types contribute differentially to information-processing during behavior is not known. We employed a novel technique for recording and labeling interneurons and pyramidal cells in drug-free, freely-moving rats. Recorded parvalbumin-expressing basket interneurons innervate somata and proximal pyramidal cell dendrites, whereas nitric-oxide-synthase- and neuropeptide-Y-expressing ivy cells provide synaptic and extrasynaptic dendritic modulation. Basket and ivy cells showed distinct spike timing dynamics, firing at different rates and times during theta and ripple oscillations. Basket but not ivy cells changed their firing rates during movement, sleep and quiet wakefulness, suggesting that basket cells coordinate cell assemblies in a behavioral state-contingent manner, whereas persistently-firing ivy cells might control network excitability and homeostasis. Different interneuron types provide GABA to specific subcellular domains at defined times and rates, thus differentially controlling network activity during behavior. PMID:22864613

The Neural Cell Adhesion Molecule (NCAM) Promotes Clustering and Activation of EphA3 Receptors in GABAergic Interneurons to Induce Ras Homolog Gene Family, Member A (RhoA)/Rho-associated protein kinase (ROCK)-mediated Growth Cone Collapse*

PubMed Central

Sullivan, Chelsea S.; Kümper, Maike; Temple, Brenda S.; Maness, Patricia F.

2016-01-01

Establishment of a proper balance of excitatory and inhibitory connectivity is achieved during development of cortical networks and adjusted through synaptic plasticity. The neural cell adhesion molecule (NCAM) and the receptor tyrosine kinase EphA3 regulate the perisomatic synapse density of inhibitory GABAergic interneurons in the mouse frontal cortex through ephrin-A5-induced growth cone collapse. In this study, it was demonstrated that binding of NCAM and EphA3 occurred between the NCAM Ig2 domain and EphA3 cysteine-rich domain (CRD). The binding interface was further refined through molecular modeling and mutagenesis and shown to be comprised of complementary charged residues in the NCAM Ig2 domain (Arg-156 and Lys-162) and the EphA3 CRD (Glu-248 and Glu-264). Ephrin-A5 induced co-clustering of surface-bound NCAM and EphA3 in GABAergic cortical interneurons in culture. Receptor clustering was impaired by a charge reversal mutation that disrupted NCAM/EphA3 association, emphasizing the importance of the NCAM/EphA3 binding interface for cluster formation. NCAM enhanced ephrin-A5-induced EphA3 autophosphorylation and activation of RhoA GTPase, indicating a role for NCAM in activating EphA3 signaling through clustering. NCAM-mediated clustering of EphA3 was essential for ephrin-A5-induced growth cone collapse in cortical GABAergic interneurons, and RhoA and a principal effector, Rho-associated protein kinase, mediated the collapse response. This study delineates a mechanism in which NCAM promotes ephrin-A5-dependent clustering of EphA3 through interaction of the NCAM Ig2 domain and the EphA3 CRD, stimulating EphA3 autophosphorylation and RhoA signaling necessary for growth cone repulsion in GABAergic interneurons in vitro, which may extend to remodeling of axonal terminals of interneurons in vivo. PMID:27803162

Cortical Proteins are Chemokinetic to Cells from the Medial Ganglionic Eminence

DTIC Science & Technology

2011-05-28

et al., 2009). Disruption of interneuron migration can lead to improper distribution within the cortex and is associated with schizophrenia, autism ...include the neurotrophins; the growth factors NRG1 and GDNF, the chemokine, SDF-1 and neurotransmitters, glutamate, GABA, and dopamine (Stumm et al...Bhide PG ( Dopamine receptor activation modulates GABA neuron migration from the basal forebrain to the cerebral cortex. J Neurosci 27:3813-3822.2007

Distinct learning-induced changes in stimulus selectivity and interactions of GABAergic interneuron classes in visual cortex.

PubMed

Khan, Adil G; Poort, Jasper; Chadwick, Angus; Blot, Antonin; Sahani, Maneesh; Mrsic-Flogel, Thomas D; Hofer, Sonja B

2018-06-01

How learning enhances neural representations for behaviorally relevant stimuli via activity changes of cortical cell types remains unclear. We simultaneously imaged responses of pyramidal cells (PYR) along with parvalbumin (PV), somatostatin (SOM), and vasoactive intestinal peptide (VIP) inhibitory interneurons in primary visual cortex while mice learned to discriminate visual patterns. Learning increased selectivity for task-relevant stimuli of PYR, PV and SOM subsets but not VIP cells. Strikingly, PV neurons became as selective as PYR cells, and their functional interactions reorganized, leading to the emergence of stimulus-selective PYR-PV ensembles. Conversely, SOM activity became strongly decorrelated from the network, and PYR-SOM coupling before learning predicted selectivity increases in individual PYR cells. Thus, learning differentially shapes the activity and interactions of multiple cell classes: while SOM inhibition may gate selectivity changes, PV interneurons become recruited into stimulus-specific ensembles and provide more selective inhibition as the network becomes better at discriminating behaviorally relevant stimuli.

Dizocilpine (MK-801) induces distinct changes of N-methyl-D-aspartic acid receptor subunits in parvalbumin-containing interneurons in young adult rat prefrontal cortex.

PubMed

Xi, Dong; Zhang, Wentong; Wang, Huai-Xing; Stradtman, George G; Gao, Wen-Jun

2009-11-01

N-methyl-D-aspartic acid receptor (NMDAR) hypofunction has long been implicated in schizophrenia and NMDARs on gamma-aminobutyric acid (GABA)ergic interneurons are proposed to play an essential role in the pathogenesis. However, controversial results have been reported regarding the regulation of NMDAR expression, and direct evidence of how NMDAR antagonists act on specific subpopulations of prefrontal interneurons is missing. We investigated the effects of the NMDAR antagonist dizocilpine (MK-801) on the expression of NMDAR subtypes in the identified interneurons in young adult rat prefrontal cortex (PFC) by using laser microdissection and real-time polymerase chain reaction, combined with Western blotting and immunofluorescent staining. We found that MK-801 induced distinct changes of NMDAR subunits in the parvalbumin-immunoreactive (PV-ir) interneurons vs. pyramidal neurons in the PFC circuitry. The messenger RNA (mRNA) expression of all NMDAR subtypes, including NR1 and NR2A to 2D, exhibited inverted-U dose-dependent changes in response to MK-801 treatment in the PFC. In contrast, subunit mRNAs of NMDARs in PV-ir interneurons were significantly down-regulated at low doses, unaltered at medium doses, and significantly decreased again at high doses, suggesting a biphasic dose response to MK-801. The differential effects of MK-801 in mRNA expression of NMDAR subunits were consistent with the protein expression of NR2A and NR2B subunits revealed with Western blotting and double immunofluorescent staining. These results suggest that PV-containing interneurons in the PFC exhibit a distinct responsiveness to NMDAR antagonism and that NMDA antagonist can differentially and dose-dependently regulate the functions of pyramidal neurons and GABAergic interneurons in the prefrontal cortical circuitry.

Sim1 is required for the migration and axonal projections of V3 interneurons in the developing mouse spinal cord.

PubMed

Blacklaws, Jake; Deska-Gauthier, Dylan; Jones, Christopher T; Petracca, Yanina L; Liu, Mingwei; Zhang, Han; Fawcett, James P; Glover, Joel C; Lanuza, Guillermo M; Zhang, Ying

2015-09-01

V3 spinal interneurons (INs) are a group of excitatory INs that play a crucial role in producing balanced and stable gaits in vertebrate animals. In the developing mouse spinal cord, V3 INs arise from the most ventral progenitor domain and form anatomically distinctive subpopulations in adult spinal cords. They are marked by the expression of transcription factor Sim1 postmitotically, but the function of Sim1 in V3 development remains unknown. Here, we used Sim1(Cre) ;tdTomato mice to trace the fate of V3 INs in a Sim1 mutant versus control genetic background during development. In Sim1 mutants, V3 INs are produced normally and maintain a similar position and organization as in wild types before E12.5. Further temporal analysis revealed that the V3 INs in the mutants failed to migrate properly to form V3 subgroups along the dorsoventral axis of the spinal cord. At birth, in the Sim1 mutant the number of V3 INs in the ventral subgroup was normal, but they were significantly reduced in the dorsal subgroup with a concomitant increase in the intermediate subgroup. Retrograde labeling at lumbar level revealed that loss of Sim1 led to a reduction in extension of contralateral axon projections both at E14.5 and P0 without affecting ipsilateral axon projections. These results demonstrate that Sim1 is essential for proper migration and the guidance of commissural axons of the spinal V3 INs. © 2015 Wiley Periodicals, Inc.

Cortical orofacial motor representation in Old World monkeys, great apes, and humans. II. Stereologic analysis of chemoarchitecture.

PubMed

Sherwood, Chet C; Holloway, Ralph L; Erwin, Joseph M; Hof, Patrick R

2004-01-01

This study presents a comparative stereologic investigation of neurofilament protein- and calcium-binding protein-immunoreactive neurons within the region of orofacial representation of primary motor cortex (Brodmann's area 4) in several catarrhine primate species (Macaca fascicularis, Papio anubis, Pongo pygmaeus, Gorilla gorilla, Pan troglodytes, and Homo sapiens). Results showed that the density of interneurons involved in vertical interlaminar processing (i.e., calbindin- and calretinin-immunoreactive neurons) as well pyramidal neurons that supply heavily-myelinated projections (i.e., neurofilament protein-immunoreactive neurons) are correlated with overall neuronal density, whereas interneurons making transcolumnar connections (i.e., parvalbumin-immunoreactive neurons) do not exhibit such a relationship. These results suggest that differential scaling rules apply to different neuronal subtypes depending on their functional role in cortical circuitry. For example, cortical columns across catarrhine species appear to involve a similar conserved network of intracolumnar inhibitory interconnections, as represented by the distribution of calbindin- and calretinin-immunoreactive neurons. The subpopulation of horizontally-oriented wide-arbor interneurons, on the other hand, increases in density relative to other interneuron subpopulations in large brains. Due to these scaling trends, the region of orofacial representation of primary motor cortex in great apes and humans is characterized by a greater proportion of neurons enriched in neurofilament protein and parvalbumin compared to the Old World monkeys examined. These modifications might contribute to the voluntary dexterous control of orofacial muscles in great ape and human communication. Copyright 2004 S. Karger AG, Basel

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

Changes in cell migration and survival in the olfactory bulb of the pcd/pcd mouse.

PubMed

Valero, J; Weruaga, E; Murias, A R; Recio, J S; Curto, G G; Gómez, C; Alonso, J R

2007-06-01

Postnatally, the Purkinje cell degeneration mutant mice lose the main projecting neurons of the main olfactory bulb (OB): mitral cells (MC). In adult animals, progenitor cells from the rostral migratory stream (RMS) differentiate into bulbar interneurons that modulate MC activity. In the present work, we studied changes in proliferation, tangential migration, radial migration patterns, and the survival of these newly generated neurons in this neurodegeneration animal model. The animals were injected with bromodeoxyuridine 2 weeks or 2 months before killing in order to label neuroblast incorporation into the OB and to analyze the survival of these cells after differentiation, respectively. Both the organization and cellular composition of the RMS and the differentiation of the newly generated neurons in the OB were studied using specific markers of glial cells, neuroblasts, and mature neurons. No changes were observed in the cell proliferation rate nor in their tangential migration through the RMS, indicating that migrating neuroblasts are only weakly responsive to the alteration in their target region, the OB. However, the absence of MC does elicit differences in the final destination of the newly generated interneurons. Moreover, the loss of MC also produces changes in the survival of the newly generated interneurons, in accordance with the dramatic decrease in the number of synaptic targets available.

Spillover-mediated feedforward-inhibition functionally segregates interneuron activity

PubMed Central

Coddington, Luke T.; Rudolph, Stephanie; Lune, Patrick Vande; Overstreet-Wadiche, Linda; Wadiche, Jacques I.

2013-01-01

Summary Neurotransmitter spillover represents a form of neural transmission not restricted to morphologically defined synaptic connections. Communication between climbing fibers (CFs) and molecular layer interneurons (MLIs) in the cerebellum is mediated exclusively by glutamate spillover. Here, we show how CF stimulation functionally segregates MLIs based on their location relative to glutamate release. Excitation of MLIs that reside within the domain of spillover diffusion coordinates inhibition of MLIs outside the diffusion limit. CF excitation of MLIs is dependent on extrasynaptic NMDA receptors that enhance the spatial and temporal spread of CF signaling. Activity mediated by functionally segregated MLIs converges onto neighboring Purkinje cells (PCs) to generate a long-lasting biphasic change in inhibition. These data demonstrate how glutamate release from single CFs modulates excitability of neighboring PCs, thus expanding the influence of CFs on cerebellar cortical activity in a manner not predicted by anatomical connectivity. PMID:23707614

Impairments in Motor Neurons, Interneurons and Astrocytes Contribute to Hyperexcitability in ALS: Underlying Mechanisms and Paths to Therapy.

PubMed

Do-Ha, Dzung; Buskila, Yossi; Ooi, Lezanne

2018-02-01

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the loss of motor neurons leading to progressive paralysis and death. Using transcranial magnetic stimulation (TMS) and nerve excitability tests, several clinical studies have identified that cortical and peripheral hyperexcitability are among the earliest pathologies observed in ALS patients. The changes in the electrophysiological properties of motor neurons have been identified in both sporadic and familial ALS patients, despite the diverse etiology of the disease. The mechanisms behind the change in neuronal signalling are not well understood, though current findings implicate intrinsic changes in motor neurons and dysfunction of cells critical in regulating motor neuronal excitability, such as astrocytes and interneurons. Alterations in ion channel expression and/or function in motor neurons has been associated with changes in cortical and peripheral nerve excitability. In addition to these intrinsic changes in motor neurons, inhibitory signalling through GABAergic interneurons is also impaired in ALS, likely contributing to increased neuronal excitability. Astrocytes have also recently been implicated in increasing neuronal excitability in ALS by failing to adequately regulate glutamate levels and extracellular K + concentration at the synaptic cleft. As hyperexcitability is a common and early feature of ALS, it offers a therapeutic and diagnostic target. Thus, understanding the underlying pathways and mechanisms leading to hyperexcitability in ALS offers crucial insight for future development of ALS treatments.

Social context differentially modulates activity of two interneuron populations in an avian basal ganglia nucleus

PubMed Central

2016-01-01

Basal ganglia circuits are critical for the modulation of motor performance across behavioral states. In zebra finches, a cortical-basal ganglia circuit dedicated to singing is necessary for males to adjust their song performance and transition between spontaneous singing, when they are alone (“undirected” song), and a performance state, when they sing to a female (“female-directed” song). However, we know little about the role of different basal ganglia cell types in this behavioral transition or the degree to which behavioral context modulates the activity of different neuron classes. To investigate whether interneurons in the songbird basal ganglia encode information about behavioral state, I recorded from two interneuron types, fast-spiking interneurons (FSI) and external pallidal (GPe) neurons, in the songbird basal ganglia nucleus area X during both female-directed and undirected singing. Both cell types exhibited higher firing rates, more frequent bursting, and greater trial-by-trial variability in firing when male zebra finches produced undirected songs compared with when they produced female-directed songs. However, the magnitude and direction of changes to the firing rate, bursting, and variability of spiking between when birds sat silently and when they sang undirected and female-directed song varied between FSI and GPe neurons. These data indicate that social modulation of activity important for eliciting changes in behavioral state is present in multiple cell types within area X and suggests that social interactions may adjust circuit dynamics during singing at multiple points within the circuit. PMID:27628208

Essential and nonredundant roles for Diaphanous formins in cortical microtubule capture and directed cell migration.

PubMed

Daou, Pascale; Hasan, Salma; Breitsprecher, Dennis; Baudelet, Emilie; Camoin, Luc; Audebert, Stéphane; Goode, Bruce L; Badache, Ali

2014-03-01

Formins constitute a large family of proteins that regulate the dynamics and organization of both the actin and microtubule cytoskeletons. Previously we showed that the formin mDia1 helps tether microtubules at the cell cortex, acting downstream of the ErbB2 receptor tyrosine kinase. Here we further study the contributions of mDia1 and its two most closely related formins, mDia2 and mDia3, to cortical microtubule capture and ErbB2-dependent breast carcinoma cell migration. We find that depletion of each of these three formins strongly disrupts chemotaxis without significantly affecting actin-based structures. Further, all three formins are required for formation of cortical microtubules in a nonredundant manner, and formin proteins defective in actin polymerization remain active for microtubule capture. Using affinity purification and mass spectrometry analysis, we identify differential binding partners of the formin-homology domain 2 (FH2) of mDia1, mDia2, and mDia3, which may explain their nonredundant roles in microtubule capture. The FH2 domain of mDia1 specifically interacts with Rab6-interacting protein 2 (Rab6IP2). Further, mDia1 is required for cortical localization of Rab6IP2, and concomitant depletion of Rab6IP2 and IQGAP1 severely disrupts cortical capture of microtubules, demonstrating the coinvolvement of mDia1, IQGAP1, and Rab6IP2 in microtubule tethering at the leading edge.

Essential and nonredundant roles for Diaphanous formins in cortical microtubule capture and directed cell migration

PubMed Central

Daou, Pascale; Hasan, Salma; Breitsprecher, Dennis; Baudelet, Emilie; Camoin, Luc; Audebert, Stéphane; Goode, Bruce L.; Badache, Ali

2014-01-01

Formins constitute a large family of proteins that regulate the dynamics and organization of both the actin and microtubule cytoskeletons. Previously we showed that the formin mDia1 helps tether microtubules at the cell cortex, acting downstream of the ErbB2 receptor tyrosine kinase. Here we further study the contributions of mDia1 and its two most closely related formins, mDia2 and mDia3, to cortical microtubule capture and ErbB2-dependent breast carcinoma cell migration. We find that depletion of each of these three formins strongly disrupts chemotaxis without significantly affecting actin-based structures. Further, all three formins are required for formation of cortical microtubules in a nonredundant manner, and formin proteins defective in actin polymerization remain active for microtubule capture. Using affinity purification and mass spectrometry analysis, we identify differential binding partners of the formin-homology domain 2 (FH2) of mDia1, mDia2, and mDia3, which may explain their nonredundant roles in microtubule capture. The FH2 domain of mDia1 specifically interacts with Rab6-interacting protein 2 (Rab6IP2). Further, mDia1 is required for cortical localization of Rab6IP2, and concomitant depletion of Rab6IP2 and IQGAP1 severely disrupts cortical capture of microtubules, demonstrating the coinvolvement of mDia1, IQGAP1, and Rab6IP2 in microtubule tethering at the leading edge. PMID:24403606

Foxp1 Regulates Cortical Radial Migration and Neuronal Morphogenesis in Developing Cerebral Cortex

PubMed Central

Li, Xue; Xiao, Jian; Fröhlich, Henning; Tu, Xiaomeng; Li, Lianlian; Xu, Yue; Cao, Huateng; Qu, Jia; Rappold, Gudrun A.; Chen, Jie-Guang

2015-01-01

FOXP1 is a member of FOXP subfamily transcription factors. Mutations in FOXP1 gene have been found in various development-related cognitive disorders. However, little is known about the etiology of these symptoms, and specifically the function of FOXP1 in neuronal development. Here, we report that suppression of Foxp1 expression in mouse cerebral cortex led to a neuronal migration defect, which was rescued by overexpression of Foxp1. Mice with Foxp1 knockdown exhibited ectopic neurons in deep layers of the cortex postnatally. The neuronal differentiation of Foxp1-downregulated cells was normal. However, morphological analysis showed that the neurons with Foxp1 deficiency had an inhibited axonal growth in vitro and a weakened transition from multipolar to bipolar in vivo. Moreover, we found that the expression of Foxp1 modulated the dendritic maturation of neurons at a late postnatal date. Our results demonstrate critical roles of Foxp1 in the radial migration and morphogenesis of cortical neurons during development. This study may shed light on the complex relationship between neuronal development and the related cognitive disorders. PMID:26010426

Hilar GABAergic Interneuron Activity Controls Spatial Learning and Memory Retrieval

PubMed Central

Andrews-Zwilling, Yaisa; Gillespie, Anna K.; Kravitz, Alexxai V.; Nelson, Alexandra B.; Devidze, Nino; Lo, Iris; Yoon, Seo Yeon; Bien-Ly, Nga; Ring, Karen; Zwilling, Daniel; Potter, Gregory B.; Rubenstein, John L. R.; Kreitzer, Anatol C.; Huang, Yadong

2012-01-01

Background Although extensive research has demonstrated the importance of excitatory granule neurons in the dentate gyrus of the hippocampus in normal learning and memory and in the pathogenesis of amnesia in Alzheimer's disease (AD), the role of hilar GABAergic inhibitory interneurons, which control the granule neuron activity, remains unclear. Methodology and Principal Findings We explored the function of hilar GABAergic interneurons in spatial learning and memory by inhibiting their activity through Cre-dependent viral expression of enhanced halorhodopsin (eNpHR3.0)—a light-driven chloride pump. Hilar GABAergic interneuron-specific expression of eNpHR3.0 was achieved by bilaterally injecting adeno-associated virus containing a double-floxed inverted open-reading frame encoding eNpHR3.0 into the hilus of the dentate gyrus of mice expressing Cre recombinase under the control of an enhancer specific for GABAergic interneurons. In vitro and in vivo illumination with a yellow laser elicited inhibition of hilar GABAergic interneurons and consequent activation of dentate granule neurons, without affecting pyramidal neurons in the CA3 and CA1 regions of the hippocampus. We found that optogenetic inhibition of hilar GABAergic interneuron activity impaired spatial learning and memory retrieval, without affecting memory retention, as determined in the Morris water maze test. Importantly, optogenetic inhibition of hilar GABAergic interneuron activity did not alter short-term working memory, motor coordination, or exploratory activity. Conclusions and Significance Our findings establish a critical role for hilar GABAergic interneuron activity in controlling spatial learning and memory retrieval and provide evidence for the potential contribution of GABAergic interneuron impairment to the pathogenesis of amnesia in AD. PMID:22792368

Selective functional interactions between excitatory and inhibitory cortical neurons and differential contribution to persistent activity of the slow oscillation.

PubMed

Tahvildari, Babak; Wölfel, Markus; Duque, Alvaro; McCormick, David A

2012-08-29

The neocortex depends upon a relative balance of recurrent excitation and inhibition for its operation. During spontaneous Up states, cortical pyramidal cells receive proportional barrages of excitatory and inhibitory synaptic potentials. Many of these synaptic potentials arise from the activity of nearby neurons, although the identity of these cells is relatively unknown, especially for those underlying the generation of inhibitory synaptic events. To address these fundamental questions, we developed an in vitro submerged slice preparation of the mouse entorhinal cortex that generates robust and regular spontaneous recurrent network activity in the form of the slow oscillation. By performing whole-cell recordings from multiple cell types identified with green fluorescent protein expression and electrophysiological and/or morphological properties, we show that distinct functional subpopulations of neurons exist in the entorhinal cortex, with large variations in contribution to the generation of balanced excitation and inhibition during the slow oscillation. The most active neurons during the slow oscillation are excitatory pyramidal and inhibitory fast spiking interneurons, receiving robust barrages of both excitatory and inhibitory synaptic potentials. Weak action potential activity was observed in stellate excitatory neurons and somatostatin-containing interneurons. In contrast, interneurons containing neuropeptide Y, vasoactive intestinal peptide, or the 5-hydroxytryptamine (serotonin) 3a receptor, were silent. Our data demonstrate remarkable functional specificity in the interactions between different excitatory and inhibitory cortical neuronal subtypes, and suggest that it is the large recurrent interaction between pyramidal neurons and fast spiking interneurons that is responsible for the generation of persistent activity that characterizes the depolarized states of the cortex.

POSTNATAL PHENOTYPE AND LOCALIZATION OF SPINAL CORD V1 DERIVED INTERNEURONS

PubMed Central

Alvarez, Francisco J.; Jonas, Philip C.; Sapir, Tamar; Hartley, Robert; Berrocal, Maria C.; Geiman, Eric J.; Todd, Andrew J.; Goulding, Martyn

2010-01-01

Developmental studies identified four classes (V0, V1, V2, V3) of embryonic interneurons in the ventral spinal cord. Very little however is known about their adult phenotypes. In order to further characterize interneuron cell types in the adult, the location, neurotransmitter phenotype, calcium-buffering protein expression and axon distributions of V1-derived neurons in the mouse spinal cord was determined. In the mature (P20 and older) spinal cord, most V1-derived neurons are located in lateral LVII and in LIX, few in medial LVII and none in LVIII. Approximately 40% express calbindin and/or parvalbumin, while few express calretinin. Of seven groups of ventral interneurons identified according to calcium-buffering protein expression, two groups (1 and 4) correspond with V1-derived neurons. Group 1 are Renshaw cells and intensely express calbindin and coexpress parvalbumin and calretinin. They represent 9% of the V1 population. Group 4 express only parvalbumin and represent 27% of V1-derived neurons. V1-derived group 4 neurons receive contacts from primary sensory afferents and are therefore proprioceptive interneurons and the most ventral neurons in this group receive convergent calbindin-IR Renshaw cell inputs. This subgroup resembles Ia inhibitory interneurons (IaINs) and represents 13% of V1-derived neurons. Adult V1-interneuron axons target LIX and LVII and some enter the deep dorsal horn. V1-axons do not cross the midline. V1 derived axonal varicosities were mostly (>80%) glycinergic and a third were GABAergic. None were glutamatergic or cholinergic. In summary, V1 interneurons develop into ipsilaterally projecting, inhibitory interneurons that include Renshaw cells, Ia inhibitory interneurons and other unidentified proprioceptive interneurons. PMID:16255029

GABA interneurons mediate the rapid antidepressant-like effects of scopolamine

PubMed Central

Wohleb, Eric S.; Wu, Min; Gerhard, Danielle M.; Taylor, Seth R.; Picciotto, Marina R.; Alreja, Meenakshi; Duman, Ronald S.

2016-01-01

Major depressive disorder (MDD) is a recurring psychiatric illness that causes substantial health and socioeconomic burdens. Clinical reports have revealed that scopolamine, a nonselective muscarinic acetylcholine receptor antagonist, produces rapid antidepressant effects in individuals with MDD. Preclinical models suggest that these rapid antidepressant effects can be recapitulated with blockade of M1-type muscarinic acetylcholine receptors (M1-AChR); however, the cellular mechanisms underlying activity-dependent synaptic and behavioral responses to scopolamine have not been determined. Here, we demonstrate that the antidepressant-like effects of scopolamine are mediated by GABA interneurons in the medial prefrontal cortex (mPFC). Both GABAergic (GAD67+) interneurons and glutamatergic (CaMKII+) interneurons in the mPFC expressed M1-AChR. In mice, viral-mediated knockdown of M1-AChR specifically in GABAergic neurons, but not glutamatergic neurons, in the mPFC attenuated the antidepressant-like effects of scopolamine. Immunohistology and electrophysiology showed that somatostatin (SST) interneurons in the mPFC express M1-AChR at higher levels than parvalbumin interneurons. Moreover, knockdown of M1-AChR in SST interneurons in the mPFC demonstrated that M1-AChR expression in these neurons is required for the rapid antidepressant-like effects of scopolamine. These data indicate that SST interneurons in the mPFC are a promising pharmacological target for developing rapid-acting antidepressant therapies. PMID:27270172

GABA interneurons mediate the rapid antidepressant-like effects of scopolamine.

PubMed

Wohleb, Eric S; Wu, Min; Gerhard, Danielle M; Taylor, Seth R; Picciotto, Marina R; Alreja, Meenakshi; Duman, Ronald S

2016-07-01

Major depressive disorder (MDD) is a recurring psychiatric illness that causes substantial health and socioeconomic burdens. Clinical reports have revealed that scopolamine, a nonselective muscarinic acetylcholine receptor antagonist, produces rapid antidepressant effects in individuals with MDD. Preclinical models suggest that these rapid antidepressant effects can be recapitulated with blockade of M1-type muscarinic acetylcholine receptors (M1-AChR); however, the cellular mechanisms underlying activity-dependent synaptic and behavioral responses to scopolamine have not been determined. Here, we demonstrate that the antidepressant-like effects of scopolamine are mediated by GABA interneurons in the medial prefrontal cortex (mPFC). Both GABAergic (GAD67+) interneurons and glutamatergic (CaMKII+) interneurons in the mPFC expressed M1-AChR. In mice, viral-mediated knockdown of M1-AChR specifically in GABAergic neurons, but not glutamatergic neurons, in the mPFC attenuated the antidepressant-like effects of scopolamine. Immunohistology and electrophysiology showed that somatostatin (SST) interneurons in the mPFC express M1-AChR at higher levels than parvalbumin interneurons. Moreover, knockdown of M1-AChR in SST interneurons in the mPFC demonstrated that M1-AChR expression in these neurons is required for the rapid antidepressant-like effects of scopolamine. These data indicate that SST interneurons in the mPFC are a promising pharmacological target for developing rapid-acting antidepressant therapies.

Multi-dimensional classification of GABAergic interneurons with Bayesian network-modeled label uncertainty.

PubMed

Mihaljević, Bojan; Bielza, Concha; Benavides-Piccione, Ruth; DeFelipe, Javier; Larrañaga, Pedro

2014-01-01

Interneuron classification is an important and long-debated topic in neuroscience. A recent study provided a data set of digitally reconstructed interneurons classified by 42 leading neuroscientists according to a pragmatic classification scheme composed of five categorical variables, namely, of the interneuron type and four features of axonal morphology. From this data set we now learned a model which can classify interneurons, on the basis of their axonal morphometric parameters, into these five descriptive variables simultaneously. Because of differences in opinion among the neuroscientists, especially regarding neuronal type, for many interneurons we lacked a unique, agreed-upon classification, which we could use to guide model learning. Instead, we guided model learning with a probability distribution over the neuronal type and the axonal features, obtained, for each interneuron, from the neuroscientists' classification choices. We conveniently encoded such probability distributions with Bayesian networks, calling them label Bayesian networks (LBNs), and developed a method to predict them. This method predicts an LBN by forming a probabilistic consensus among the LBNs of the interneurons most similar to the one being classified. We used 18 axonal morphometric parameters as predictor variables, 13 of which we introduce in this paper as quantitative counterparts to the categorical axonal features. We were able to accurately predict interneuronal LBNs. Furthermore, when extracting crisp (i.e., non-probabilistic) predictions from the predicted LBNs, our method outperformed related work on interneuron classification. Our results indicate that our method is adequate for multi-dimensional classification of interneurons with probabilistic labels. Moreover, the introduced morphometric parameters are good predictors of interneuron type and the four features of axonal morphology and thus may serve as objective counterparts to the subjective, categorical axonal features.

Targeted Interneuron Ablation in the Mouse Hippocampus Can Cause Spontaneous Recurrent Seizures

PubMed Central

2017-01-01

Abstract The death of GABAergic interneurons has long been hypothesized to contribute to acquired epilepsy. These experiments tested the hypothesis that focal interneuron lesions cause acute seizures [i.e., status epilepticus (SE)] and/or chronic epilepsy [i.e., persistent spontaneous recurrent seizures (SRSs)]. To selectively ablate interneurons, Gad2-ires-Cre mice were injected unilaterally in the CA1 area of the dorsal hippocampus with an adeno-associated virus containing the diphtheria toxin receptor (DTR). Simultaneously, an electrode, connected to a miniature telemetry device, was positioned at the injection site for chronic recordings of local field potentials (LFPs). Two weeks after virus transfection, intraperitoneal injection of DT consistently caused focal, specific, and extensive ablation of interneurons. Long-term, continuous monitoring revealed that all mice with DT-induced interneuron lesions had SRSs. Seizures lasted tens of seconds and interseizure intervals were several hours (or days); therefore, these interneuron lesions did not induce SE. The SRSs occurred 3-5 d after DT treatment, which is the estimated time required for DT-induced cell death; therefore, induction of SRSs occurred without the latent period typical of acquired epilepsy. In five of six DT-treated mice, SRSs stopped within days, suggesting that the DT-induced interneuron lesions did not usually cause epilepsy. In one mouse, however, SRSs occurred for ≥34 d after interneuron ablation, similar to epilepsy after experimental SE. Sham control mice had no detectable seizures, confirming that the SRSs were due to ablation of interneurons. These data show that selective interneuron ablation consistently caused SRSs but not SE; and, at least under the conditions used here, interneuron lesions rarely led to persistent SRSs (i.e., epilepsy). PMID:28785726

Loss of embryonic MET signaling alters profiles of hippocampal interneurons.

PubMed

Martins, Gabriela J; Plachez, Céline; Powell, Elizabeth M

2007-01-01

Hippocampal interneurons arise in the ventral forebrain and migrate dorsally in response to cues, including hepatocyte growth factor/scatter factor which signals via its receptor MET. Examination of the hippocampus in adult mice in which MET had been inactivated in the embryonic proliferative zones showed an increase in parvalbumin-expressing cells in the dentate gyrus, but a loss of these cells in the CA3 region. An overall loss of calretinin-expressing cells was seen throughout the hippocampus. A similar CA3 deficit of parvalbumin and calretinin cells was observed when MET was eliminated only in postmitotic cells. These data suggest that MET is required for the proper hippocampal development, and embryonic perturbations lead to long-term anatomical defects with possible learning and memory dysfunction.

Leading Process Branch Instability in Lis1+/− Nonradially Migrating Interneurons

PubMed Central

Gopal, Pallavi P.; Simonet, Jacqueline C.; Shapiro, William

2010-01-01

Mammalian forebrain development requires extensive migration, yet the mechanisms through which migrating neurons sense and respond to guidance cues are not well understood. Similar to the axon growth cone, the leading process and branches of neurons may guide migration, but the cytoskeletal events that regulate branching are unknown. We have previously shown that loss of microtubule-associated protein Lis1 reduces branching during migration compared with wild-type neurons. Using time-lapse imaging of Lis1+/− and Lis1+/+ cells migrating from medial ganglionic eminence explant cultures, we show that the branching defect is not due to a failure to initiate branches but a defect in the stabilization of new branches. The leading processes of Lis1+/− neurons have reduced expression of stabilized, acetylated microtubules compared with Lis1+/+ neurons. To determine whether Lis1 modulates branch stability through its role as the noncatalytic β regulatory subunit of platelet-activating factor (PAF) acetylhydrolase 1b, exogenous PAF was applied to wild-type cells. Excess PAF added to wild-type neurons phenocopies the branch instability observed in Lis1+/− neurons, and a PAF antagonist rescues leading process branching in Lis1+/− neurons. These data highlight a role for Lis1, acting through the PAF pathway, in leading process branching and microtubule stabilization. PMID:19861636

Increased Cortical Inhibition in Autism-Linked Neuroligin-3R451C Mice Is Due in Part to Loss of Endocannabinoid Signaling.

PubMed

Speed, Haley E; Masiulis, Irene; Gibson, Jay R; Powell, Craig M

2015-01-01

A single, maternally inherited, X-linked point mutation leading to an arginine to cysteine substitution at amino acid 451 (R451C) of Neuroligin 3 (NLGN3R451C) is a likely cause of autism in two brothers. Knockin mice expressing the Nlgn3R451C mutation in place of wild-type Nlgn3 demonstrate increased inhibitory synaptic strength in somatosensory cortex, resulting in an excitatory/inhibitory (E/I) imbalance that is potentially relevant for autism-associated behavioral deficits characteristic of these mice. We have replicated the increase in evoked inhibitory postsynaptic currents (eIPSCs) onto layer II/III cortical pyramidal neurons. We also find that increased frequency of spontaneous mIPSCs in Nlgn3R451C mice occurs in the absence of action potential-driven transmission. This suggests the E/I imbalance is due to changes at the synapse level, as opposed to the network level. Next, we use paired whole-cell recordings in an attempt to identify specific interneuron subtypes affected by the Nlgn3R451C mutation. Curiously, we observe no change in the amplitude of cell-to-cell, unitary IPSCs (uIPSCs) from parvalbumin-positive (PV) or somatostatin-positive (SOM) interneurons onto pyramidal neurons. We also observe no change in the number or density of PV and SOM interneurons in LII/III of somatosensory cortex. This effectively rules out a role for these particular interneurons in the increased inhibitory synaptic transmission, pointing to perhaps alternative interneuron subtypes. Lastly, impaired endocannabinoid signaling has been implicated in hippocampal synaptic dysfunction in Nlgn3R451C mice, but has not been investigated at cortical synapses. We find that bath application of the CB1 antagonist, AM 251 in WT mice eliminates the Nlgn3R451C increase in eIPSC amplitude and mIPSC frequency, indicating that increased inhibitory transmission in mutant mice is due, at least in part, to a loss of endocannabinoid signaling through CB1 receptors likely acting at interneurons

Increased Cortical Inhibition in Autism-Linked Neuroligin-3R451C Mice Is Due in Part to Loss of Endocannabinoid Signaling

PubMed Central

Speed, Haley E.; Masiulis, Irene; Gibson, Jay R.; Powell, Craig M.

2015-01-01

A single, maternally inherited, X-linked point mutation leading to an arginine to cysteine substitution at amino acid 451 (R451C) of Neuroligin 3 (NLGN3R451C) is a likely cause of autism in two brothers. Knockin mice expressing the Nlgn3R451C mutation in place of wild-type Nlgn3 demonstrate increased inhibitory synaptic strength in somatosensory cortex, resulting in an excitatory/inhibitory (E/I) imbalance that is potentially relevant for autism-associated behavioral deficits characteristic of these mice. We have replicated the increase in evoked inhibitory postsynaptic currents (eIPSCs) onto layer II/III cortical pyramidal neurons. We also find that increased frequency of spontaneous mIPSCs in Nlgn3R451C mice occurs in the absence of action potential-driven transmission. This suggests the E/I imbalance is due to changes at the synapse level, as opposed to the network level. Next, we use paired whole-cell recordings in an attempt to identify specific interneuron subtypes affected by the Nlgn3R451C mutation. Curiously, we observe no change in the amplitude of cell-to-cell, unitary IPSCs (uIPSCs) from parvalbumin-positive (PV) or somatostatin-positive (SOM) interneurons onto pyramidal neurons. We also observe no change in the number or density of PV and SOM interneurons in LII/III of somatosensory cortex. This effectively rules out a role for these particular interneurons in the increased inhibitory synaptic transmission, pointing to perhaps alternative interneuron subtypes. Lastly, impaired endocannabinoid signaling has been implicated in hippocampal synaptic dysfunction in Nlgn3R451C mice, but has not been investigated at cortical synapses. We find that bath application of the CB1 antagonist, AM 251 in WT mice eliminates the Nlgn3R451C increase in eIPSC amplitude and mIPSC frequency, indicating that increased inhibitory transmission in mutant mice is due, at least in part, to a loss of endocannabinoid signaling through CB1 receptors likely acting at interneurons

Cornu Ammonis Regions–Antecedents of Cortical Layers?

PubMed Central

Mercer, Audrey; Thomson, Alex M.

2017-01-01

Studying neocortex and hippocampus in parallel, we are struck by the similarities. All three to four layered allocortices and the six layered mammalian neocortex arise in the pallium. All receive and integrate multiple cortical and subcortical inputs, provide multiple outputs and include an array of neuronal classes. During development, each cell positions itself to sample appropriate local and distant inputs and to innervate appropriate targets. Simpler cortices had already solved the need to transform multiple coincident inputs into serviceable outputs before neocortex appeared in mammals. Why then do phylogenetically more recent cortices need multiple pyramidal cell layers? A simple answer is that more neurones can compute more complex functions. The dentate gyrus and hippocampal CA regions—which might be seen as hippocampal antecedents of neocortical layers—lie side by side, albeit around a tight bend. Were the millions of cells of rat neocortex arranged in like fashion, the surface area of the CA pyramidal cell layers would be some 40 times larger. Even if evolution had managed to fold this immense sheet into the space available, the distances between neurones that needed to be synaptically connected would be huge and to maintain the speed of information transfer, massive, myelinated fiber tracts would be needed. How much more practical to stack the “cells that fire and wire together” into narrow columns, while retaining the mechanisms underlying the extraordinary precision with which circuits form. This demonstrably efficient arrangement presents us with challenges, however, not the least being to categorize the baffling array of neuronal subtypes in each of five “pyramidal layers.” If we imagine the puzzle posed by this bewildering jumble of apical dendrites, basal dendrites and axons, from many different pyramidal and interneuronal classes, that is encountered by a late-arriving interneurone insinuating itself into a functional circuit, we can

Cultured networks of excitatory projection neurons and inhibitory interneurons for studying human cortical neurotoxicity

PubMed Central

Xu, Jin-Chong; Fan, Jing; Wang, Xueqing; Eacker, Stephen M.; Kam, Tae-In; Chen, Li; Yin, Xiling; Zhu, Juehua; Chi, Zhikai; Jiang, Haisong; Chen, Rong; Dawson, Ted M.; Dawson, Valina L.

2017-01-01

Translating neuroprotective treatments from discovery in cell and animal models to the clinic has proven challenging. To reduce the gap between basic studies of neurotoxicity and neuroprotection and clinically relevant therapies, we developed a human cortical neuron culture system from human embryonic stem cells (ESCs) or inducible pluripotent stem cells (iPSCs) that generated both excitatory and inhibitory neuronal networks resembling the composition of the human cortex. This methodology used timed administration of retinoic acid (RA) to FOXG1 neural precursor cells leading to differentiation of neuronal populations representative of the six cortical layers with both excitatory and inhibitory neuronal networks that were functional and homeostatically stable. In human cortical neuron cultures, excitotoxicity or ischemia due to oxygen and glucose deprivation led to cell death that was dependent on N-methyl-D-aspartate (NMDA) receptors, nitric oxide (NO), and the poly (ADP-ribose) polymerase (PARP)-dependent cell death, a cell death pathway designated parthanatos to separate it from apoptosis, necroptosis and other forms of cell death. Neuronal cell death was attenuated by PARP inhibitors that are currently in clinical trials for cancer treatment. This culture system provides a new platform for the study of human cortical neurotoxicity and suggests that PARP inhibitors may be useful for ameliorating excitotoxic and ischemic cell death in human neurons. PMID:27053772

The Mediodorsal Thalamus Drives Feedforward Inhibition in the Anterior Cingulate Cortex via Parvalbumin Interneurons

PubMed Central

Delevich, Kristen; Tucciarone, Jason; Huang, Z. Josh

2015-01-01

Although the medial prefrontal cortex (mPFC) is classically defined by its reciprocal connections with the mediodorsal thalamic nucleus (MD), the nature of information transfer between MD and mPFC is poorly understood. In sensory thalamocortical pathways, thalamic recruitment of feedforward inhibition mediated by fast-spiking, putative parvalbumin-expressing (PV) interneurons is a key feature that enables cortical neurons to represent sensory stimuli with high temporal fidelity. Whether a similar circuit mechanism is in place for the projection from the MD (a higher-order thalamic nucleus that does not receive direct input from the periphery) to the mPFC is unknown. Here we show in mice that inputs from the MD drive disynaptic feedforward inhibition in the dorsal anterior cingulate cortex (dACC) subregion of the mPFC. In particular, we demonstrate that axons arising from MD neurons directly synapse onto and excite PV interneurons that in turn mediate feedforward inhibition of pyramidal neurons in layer 3 of the dACC. This feedforward inhibition in the dACC limits the time window during which pyramidal neurons integrate excitatory synaptic inputs and fire action potentials, but in a manner that allows for greater flexibility than in sensory cortex. These findings provide a foundation for understanding the role of MD-PFC circuit function in cognition. PMID:25855185

Basal Forebrain Gating by Somatostatin Neurons Drives Prefrontal Cortical Activity.

PubMed

Espinosa, Nelson; Alonso, Alejandra; Morales, Cristian; Espinosa, Pedro; Chávez, Andrés E; Fuentealba, Pablo

2017-11-17

The basal forebrain provides modulatory input to the cortex regulating brain states and cognitive processing. Somatostatin-expressing neurons constitute a heterogeneous GABAergic population known to functionally inhibit basal forebrain cortically projecting cells thus favoring sleep and cortical synchronization. However, it remains unclear if somatostatin cells can regulate population activity patterns in the basal forebrain and modulate cortical dynamics. Here, we demonstrate that somatostatin neurons regulate the corticopetal synaptic output of the basal forebrain impinging on cortical activity and behavior. Optogenetic inactivation of somatostatin neurons in vivo rapidly modified neural activity in the basal forebrain, with the consequent enhancement and desynchronization of activity in the prefrontal cortex, reflected in both neuronal spiking and network oscillations. Cortical activation was partially dependent on cholinergic transmission, suppressing slow waves and potentiating gamma oscillations. In addition, recruitment dynamics was cell type-specific, with interneurons showing similar temporal profiles, but stronger responses than pyramidal cells. Finally, optogenetic stimulation of quiescent animals during resting periods prompted locomotor activity, suggesting generalized cortical activation and increased arousal. Altogether, we provide physiological and behavioral evidence indicating that somatostatin neurons are pivotal in gating the synaptic output of the basal forebrain, thus indirectly controlling cortical operations via both cholinergic and non-cholinergic mechanisms. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Novel Fast Adapting Interneurons Mediate Cholinergic-Induced Fast GABAA IPSCs In Striatal Spiny Neurons

PubMed Central

Faust, Thomas W.; Assous, Maxime; Shah, Fulva; Tepper, James M.; Koós, Tibor

2015-01-01

Previous work suggests that neostriatal cholinergic interneurons control the activity of several classes of GABAergic interneurons through fast nicotinic receptor mediated synaptic inputs. Although indirect evidence has suggested the existence of several classes of interneurons controlled by this mechanism only one such cell type, the neuropeptide-Y expressing neurogliaform neuron, has been identified to date. Here we tested the hypothesis that in addition to the neurogliaform neurons that elicit slow GABAergic inhibitory responses, another interneuron type exists in the striatum that receives strong nicotinic cholinergic input and elicits conventional fast GABAergic synaptic responses in projection neurons. We obtained in vitro slice recordings from double transgenic mice in which Channelrhodopsin-2 was natively expressed in cholinergic neurons and a population of serotonin receptor-3a-Cre expressing GABAergic interneurons were visualized with tdTomato. We show that among the targeted GABAergic interneurons a novel type of interneuron, termed the fast-adapting interneuron, can be identified that is distinct from previously known interneurons based on immunocytochemical and electrophysiological criteria. We show using optogenetic activation of cholinergic inputs that fast-adapting interneurons receive a powerful supra-threshold nicotinic cholinergic input in vitro. Moreover, fast adapting neurons are densely connected to projection neurons and elicit fast, GABAA receptor mediated inhibitory postsynaptic responses. The nicotinic receptor mediated activation of fast-adapting interneurons may constitute an important mechanism through which cholinergic interneurons control the activity of projection neurons and perhaps the plasticity of their synaptic inputs when animals encounter reinforcing or otherwise salient stimuli. PMID:25865337

Dorsal CA1 interneurons contribute to acute stress-induced spatial memory deficits.

PubMed

Yu, Jing-Ying; Fang, Ping; Wang, Chi; Wang, Xing-Xing; Li, Kun; Gong, Qian; Luo, Ben-Yan; Wang, Xiao-Dong

2018-06-01

Exposure to severely stressful experiences disrupts the activity of neuronal circuits and impairs declarative memory. GABAergic interneurons coordinate neuronal network activity, but their involvement in stress-evoked memory loss remains to be elucidated. Here, we provide evidence that interneurons in area CA1 of the dorsal hippocampus partially modulate acute stress-induced memory deficits. In adult male mice, both acute forced swim stress and restraint stress impaired hippocampus-dependent spatial memory and increased the density of c-fos-positive interneurons in the dorsal CA1. Selective activation of dorsal CA1 interneurons by chemogenetics disrupted memory performance in the spatial object recognition task. In comparison, anxiety-related behavior, spatial working memory and novel object recognition memory remained intact when dorsal CA1 interneurons were overactivated. Moreover, chemogenetic activation of dorsal CA1 interneurons suppressed the activity of adjacent pyramidal neurons, whereas a single exposure to forced swim stress but not restraint stress increased the activity of CA1 pyramidal neurons. However, chemogenetic inhibition of dorsal CA1 interneurons led to spatial memory impairments and failed to attenuate acute stress-induced memory loss. These findings suggest that acute stress may overactivate interneurons in the dorsal CA1, which reduces the activity of pyramidal neurons and in turn disrupts long-term memory. Copyright © 2018 Elsevier Ltd. All rights reserved.

Heterogeneity of the Axon Initial Segment in Interneurons and Pyramidal Cells of Rodent Visual Cortex

PubMed Central

Höfflin, Felix; Jack, Alexander; Riedel, Christian; Mack-Bucher, Julia; Roos, Johannes; Corcelli, Corinna; Schultz, Christian; Wahle, Petra; Engelhardt, Maren

2017-01-01

The microdomain that orchestrates action potential initiation in neurons is the axon initial segment (AIS). It has long been considered to be a rather homogeneous domain at the very proximal axon hillock with relatively stable length, particularly in cortical pyramidal cells. However, studies in other brain regions paint a different picture. In hippocampal CA1, up to 50% of axons emerge from basal dendrites. Further, in about 30% of thick-tufted layer V pyramidal neurons in rat somatosensory cortex, axons have a dendritic origin. Consequently, the AIS is separated from the soma. Recent in vitro and in vivo studies have shown that cellular excitability is a function of AIS length/position and somatodendritic morphology, undermining a potentially significant impact of AIS heterogeneity for neuronal function. We therefore investigated neocortical axon morphology and AIS composition, hypothesizing that the initial observation of seemingly homogeneous AIS is inadequate and needs to take into account neuronal cell types. Here, we biolistically transfected cortical neurons in organotypic cultures to visualize the entire neuron and classify cell types in combination with immunolabeling against AIS markers. Using confocal microscopy and morphometric analysis, we investigated axon origin, AIS position, length, diameter as well as distance to the soma. We find a substantial AIS heterogeneity in visual cortical neurons, classified into three groups: (I) axons with somatic origin with proximal AIS at the axon hillock; (II) axons with somatic origin with distal AIS, with a discernible gap between the AIS and the soma; and (III) axons with dendritic origin (axon-carrying dendrite cell, AcD cell) and an AIS either starting directly at the axon origin or more distal to that point. Pyramidal cells have significantly longer AIS than interneurons. Interneurons with vertical columnar axonal projections have significantly more distal AIS locations than all other cells with their

Cortical Neural Computation by Discrete Results Hypothesis

PubMed Central

Castejon, Carlos; Nuñez, Angel

2016-01-01

One of the most challenging problems we face in neuroscience is to understand how the cortex performs computations. There is increasing evidence that the power of the cortical processing is produced by populations of neurons forming dynamic neuronal ensembles. Theoretical proposals and multineuronal experimental studies have revealed that ensembles of neurons can form emergent functional units. However, how these ensembles are implicated in cortical computations is still a mystery. Although cell ensembles have been associated with brain rhythms, the functional interaction remains largely unclear. It is still unknown how spatially distributed neuronal activity can be temporally integrated to contribute to cortical computations. A theoretical explanation integrating spatial and temporal aspects of cortical processing is still lacking. In this Hypothesis and Theory article, we propose a new functional theoretical framework to explain the computational roles of these ensembles in cortical processing. We suggest that complex neural computations underlying cortical processing could be temporally discrete and that sensory information would need to be quantized to be computed by the cerebral cortex. Accordingly, we propose that cortical processing is produced by the computation of discrete spatio-temporal functional units that we have called “Discrete Results” (Discrete Results Hypothesis). This hypothesis represents a novel functional mechanism by which information processing is computed in the cortex. Furthermore, we propose that precise dynamic sequences of “Discrete Results” is the mechanism used by the cortex to extract, code, memorize and transmit neural information. The novel “Discrete Results” concept has the ability to match the spatial and temporal aspects of cortical processing. We discuss the possible neural underpinnings of these functional computational units and describe the empirical evidence supporting our hypothesis. We propose that fast

Cortical Neural Computation by Discrete Results Hypothesis.

PubMed

Castejon, Carlos; Nuñez, Angel

2016-01-01

One of the most challenging problems we face in neuroscience is to understand how the cortex performs computations. There is increasing evidence that the power of the cortical processing is produced by populations of neurons forming dynamic neuronal ensembles. Theoretical proposals and multineuronal experimental studies have revealed that ensembles of neurons can form emergent functional units. However, how these ensembles are implicated in cortical computations is still a mystery. Although cell ensembles have been associated with brain rhythms, the functional interaction remains largely unclear. It is still unknown how spatially distributed neuronal activity can be temporally integrated to contribute to cortical computations. A theoretical explanation integrating spatial and temporal aspects of cortical processing is still lacking. In this Hypothesis and Theory article, we propose a new functional theoretical framework to explain the computational roles of these ensembles in cortical processing. We suggest that complex neural computations underlying cortical processing could be temporally discrete and that sensory information would need to be quantized to be computed by the cerebral cortex. Accordingly, we propose that cortical processing is produced by the computation of discrete spatio-temporal functional units that we have called "Discrete Results" (Discrete Results Hypothesis). This hypothesis represents a novel functional mechanism by which information processing is computed in the cortex. Furthermore, we propose that precise dynamic sequences of "Discrete Results" is the mechanism used by the cortex to extract, code, memorize and transmit neural information. The novel "Discrete Results" concept has the ability to match the spatial and temporal aspects of cortical processing. We discuss the possible neural underpinnings of these functional computational units and describe the empirical evidence supporting our hypothesis. We propose that fast-spiking (FS

Cholinergic Interneurons Are Differentially Distributed in the Human Striatum

PubMed Central

Bernácer, Javier; Prensa, Lucía; Giménez-Amaya, José Manuel

2007-01-01

Background The striatum (caudate nucleus, CN, and putamen, Put) is a group of subcortical nuclei involved in planning and executing voluntary movements as well as in cognitive processes. Its neuronal composition includes projection neurons, which connect the striatum with other structures, and interneurons, whose main roles are maintaining the striatal organization and the regulation of the projection neurons. The unique electrophysiological and functional properties of the cholinergic interneurons give them a crucial modulating function on the overall striatal response. Methodology/Principle Findings This study was carried out using stereological methods to examine the volume and density (cells/mm3) of these interneurons, as visualized by choline acetyltransferase (ChAT) immunoreactivity, in the following territories of the CN and Put of nine normal human brains: 1) precommissural head; 2) postcommissural head; 3) body; 4) gyrus and 5) tail of the CN; 6) precommissural and 7) postcommissural Put. The distribution of ChAT interneurons was analyzed with respect to the topographical, functional and chemical territories of the dorsal striatum. The CN was more densely populated by cholinergic neurons than the Put, and their density increased along the anteroposterior axis of the striatum with the CN body having the highest neuronal density. The associative territory of the dorsal striatum was by far the most densely populated. The striosomes of the CN precommissural head and the postcommissural Put contained the greatest number of ChAT-ir interneurons. The intrastriosomal ChAT-ir neurons were abundant on the periphery of the striosomes throughout the striatum. Conclusions/Significance All these data reveal that cholinergic interneurons are differentially distributed in the distinct topographical and functional territories of the human dorsal striatum, as well as in its chemical compartments. This heterogeneity may indicate that the posterior aspects of the CN require a

Thalamocortical Projection Neuron and Interneuron Numbers in the Visual Thalamic Nuclei of the Adult C57BL/6 Mouse.

PubMed

Evangelio, Marian; García-Amado, María; Clascá, Francisco

2018-01-01

A key parameter to constrain predictive, bottom-up circuit models of a given brain domain is the number and position of the neuronal populations involved. These include not only the neurons whose bodies reside within the domain, but also the neurons in distant regions that innervate the domain. The mouse visual cortex receives its main subcortical input from the dorsal lateral geniculate nucleus (dLGN) and the lateral posterior (LP) complex of the thalamus. The latter consists of three different nuclei: lateral posterior lateral (LPL), lateral posterior medial rostral (LPMR), and lateral posterior medial caudal (LPMC), each exhibiting specific patterns of connections with the various visual cortical areas. Here, we have determined the number of thalamocortical projection neurons and interneurons in the LP complex and dLGN of the adult C57BL/6 male mouse. We combined Nissl staining and histochemical and immunolabeling methods for consistently delineating nuclei borders, and applied unbiased stereological cell counting methods. Thalamic interneurons were identified using GABA immunolabeling. The C57BL/6 dLGN contains ∼21,200 neurons, while LP complex contains ∼31,000 total neurons. The dLGN and LP are the only nuclei of the mouse dorsal thalamus containing substantial numbers GABA-immunoreactive interneurons. These interneurons, however, are scarcer than previously estimated; they are 5.6% of dLGN neurons and just 1.9% of the LP neurons. It can be thus inferred that the dLGN contains ∼20,000 and the LP complex ∼30,400 thalamocortical projection neurons (∼12,000 in LPL, 15,200 in LPMR, and 4,200 in LPMC). The present dataset is relevant for constraining models of mouse visual thalamocortical circuits, as well as for quantitative comparisons between genetically modified mouse strains, or across species.

Thalamocortical Projection Neuron and Interneuron Numbers in the Visual Thalamic Nuclei of the Adult C57BL/6 Mouse

PubMed Central

Evangelio, Marian; García-Amado, María; Clascá, Francisco

2018-01-01

A key parameter to constrain predictive, bottom-up circuit models of a given brain domain is the number and position of the neuronal populations involved. These include not only the neurons whose bodies reside within the domain, but also the neurons in distant regions that innervate the domain. The mouse visual cortex receives its main subcortical input from the dorsal lateral geniculate nucleus (dLGN) and the lateral posterior (LP) complex of the thalamus. The latter consists of three different nuclei: lateral posterior lateral (LPL), lateral posterior medial rostral (LPMR), and lateral posterior medial caudal (LPMC), each exhibiting specific patterns of connections with the various visual cortical areas. Here, we have determined the number of thalamocortical projection neurons and interneurons in the LP complex and dLGN of the adult C57BL/6 male mouse. We combined Nissl staining and histochemical and immunolabeling methods for consistently delineating nuclei borders, and applied unbiased stereological cell counting methods. Thalamic interneurons were identified using GABA immunolabeling. The C57BL/6 dLGN contains ∼21,200 neurons, while LP complex contains ∼31,000 total neurons. The dLGN and LP are the only nuclei of the mouse dorsal thalamus containing substantial numbers GABA-immunoreactive interneurons. These interneurons, however, are scarcer than previously estimated; they are 5.6% of dLGN neurons and just 1.9% of the LP neurons. It can be thus inferred that the dLGN contains ∼20,000 and the LP complex ∼30,400 thalamocortical projection neurons (∼12,000 in LPL, 15,200 in LPMR, and 4,200 in LPMC). The present dataset is relevant for constraining models of mouse visual thalamocortical circuits, as well as for quantitative comparisons between genetically modified mouse strains, or across species. PMID:29706872

Cortical GluN2B deletion attenuates punished suppression of food reward-seeking.

PubMed

Radke, Anna K; Nakazawa, Kazu; Holmes, Andrew

2015-10-01

Compulsive behavior, which is a hallmark of psychiatric disorders such as addiction and obsessive-compulsive disorder, engages corticostriatal circuits. Previous studies indicate a role for corticostriatal N-methyl-D-aspartate receptors (NMDARs) in mediating compulsive-like responding for drugs of abuse, but the specific receptor subunits controlling reward-seeking in the face of punishment remain unclear. The current study assessed the involvement of corticostriatal GluN2B-containing NMDARs in measures of persistent and punished food reward-seeking. Mice with genetic deletion of GluN2B in one of three distinct neuronal populations, cortical principal neurons, forebrain interneurons, or striatal medium spiny neurons, were tested for (1) sustained food reward-seeking when reward was absent, (2) reward-seeking under a progressive ratio schedule of reinforcement, and (3) persistent reward-seeking after a footshock punishment. Mutant mice with genetic deletion of GluN2B in cortical principal neurons demonstrated attenuated suppression of reward-seeking during punishment. These mice performed normally on other behavioral measures, including an assay for pain sensitivity. Mutants with interneuronal or striatal GluN2B deletions were normal on all behavioral assays. Current findings offer novel evidence that loss of GluN2B-containing NMDARs expressed on principal neurons in the cortex results in reduced punished food reward-seeking. These data support the involvement of GluN2B subunit in cortical circuits regulating cognitive flexibility in a variety of settings, with implications for understanding the basis of inflexible behavior in neuropsychiatric disorders including obsessive-compulsive disorders (OCD) and addictions.

Rab3A, a possible marker of cortical granules, participates in cortical granule exocytosis in mouse eggs

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

Bello, Oscar Daniel; Cappa, Andrea Isabel; Paola, Matilde de

Fusion of cortical granules with the oocyte plasma membrane is the most significant event to prevent polyspermy. This particular exocytosis, also known as cortical reaction, is regulated by calcium and its molecular mechanism is still not known. Rab3A, a member of the small GTP-binding protein superfamily, has been implicated in calcium-dependent exocytosis and is not yet clear whether Rab3A participates in cortical granules exocytosis. Here, we examine the involvement of Rab3A in the physiology of cortical granules, particularly, in their distribution during oocyte maturation and activation, and their participation in membrane fusion during cortical granule exocytosis. Immunofluorescence and Western blotmore » analysis showed that Rab3A and cortical granules have a similar migration pattern during oocyte maturation, and that Rab3A is no longer detected after cortical granule exocytosis. These results suggested that Rab3A might be a marker of cortical granules. Overexpression of EGFP-Rab3A colocalized with cortical granules with a Pearson correlation coefficient of +0.967, indicating that Rab3A and cortical granules have almost a perfect colocalization in the egg cortical region. Using a functional assay, we demonstrated that microinjection of recombinant, prenylated and active GST-Rab3A triggered cortical granule exocytosis, indicating that Rab3A has an active role in this secretory pathway. To confirm this active role, we inhibited the function of endogenous Rab3A by microinjecting a polyclonal antibody raised against Rab3A prior to parthenogenetic activation. Our results showed that Rab3A antibody microinjection abolished cortical granule exocytosis in parthenogenetically activated oocytes. Altogether, our findings confirm that Rab3A might function as a marker of cortical granules and participates in cortical granule exocytosis in mouse eggs. - Highlights: • Rab3A has a similar migration pattern to cortical granules in mouse oocytes. • Rab3A can be a

Activity-Dependent Changes in the Firing Properties of Neocortical Fast-Spiking Interneurons in the Absence of Large Changes in Gene Expression

PubMed Central

Miller, Mark N.; Okaty, Benjamin W.; Kato, Saori; Nelson, Sacha B.

2010-01-01

The diverse cell types that comprise neocortical circuits each have characteristic integrative and firing properties that are specialized to perform specific functions within the network. Parvalbumin-positive fast-spiking (FS) interneurons are a particularly specialized cortical cell-type that controls the dynamics of ongoing activity and prevents runaway excitation by virtue of remarkably high firing rates, a feature that is permitted by narrow action potentials and the absence of spike-frequency adaptation. Although several neuronal intrinsic membrane properties undergo activity-dependent plasticity, the role of network activity in shaping and maintaining specialized, cell-type-specific firing properties is unknown. We tested whether the specialized firing properties of mature FS interneurons are sensitive to activity perturbations by inactivating a portion of motor cortex in vivo for 48 hours and measuring resulting plasticity of FS intrinsic and firing properties with whole-cell recording in acute slices. Many of the characteristic properties of FS interneurons, including non-adapting high-frequency spiking and narrow action potentials, were profoundly affected by activity deprivation both at an age just after maturation of FS firing properties and also a week after their maturation. Using microarray screening, we determined that although normal maturation of FS electrophysiological specializations is accompanied by large-scale transcriptional changes, the effects of deprivation on the same specializations involve more modest transcriptional changes, and may instead be primarily mediated by post-transcriptional mechanisms. PMID:21154910

Distinct Translaminar Glutamatergic Circuits to GABAergic Interneurons in the Neonatal Auditory Cortex.

PubMed

Deng, Rongkang; Kao, Joseph P Y; Kanold, Patrick O

2017-05-09

GABAergic activity is important in neocortical development and plasticity. Because the maturation of GABAergic interneurons is regulated by neural activity, the source of excitatory inputs to GABAergic interneurons plays a key role in development. We show, by laser-scanning photostimulation, that layer 4 and layer 5 GABAergic interneurons in the auditory cortex in neonatal mice (interneurons showed two spatial patterns of translaminar connection: inputs originating predominantly from supragranular or from supragranular and infragranular layers, including the subplate, which relays early thalamocortical activity. Sensory deprivation altered the development of translaminar inputs. Thus, distinct translaminar circuits to GABAergic interneurons exist throughout development, and the maturation of excitatory synapses is input-specific. Glutamatergic signaling from subplate and intracortical sources likely plays a role in the maturation of GABAergic interneurons. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Cerebral-buccal pathways in Aplysia californica: synaptic connections, cooperative interneuronal effects and feedback during buccal motor programs.

PubMed

Sánchez, J A; Kirk, M D

2001-12-01

Ingestion of seaweed by Aplysia is in part mediated by cerebral-buccal interneurons that drive rhythmic motor output from the buccal ganglia and in some cases cerebral-buccal interneurons act as members of the feeding central pattern generator. Here we document cooperative interactions between cerebral-buccal interneuron 2 and cerebral-buccal interneuron 12, characterize synaptic input to cerebral-buccal interneuron 2 and cerebral-buccal interneuron 12 from buccal peripheral nerve 2,3, describe a synaptic connection between cerebral-buccal interneuron 1 and buccal neuron B34, further characterize connections made by cerebral-buccal interneurons 2 and -12 with B34 and B61/62, and describe a novel, inhibitory connection made by cerebral-buccal interneuron 2 with a buccal neuron. When cerebral-buccal interneurons 2 and 12 were driven synchronously at low frequencies, ingestion-like buccal motor programs were elicited, and if either was driven alone, indirect synaptic input was recruited in the other cerebral-buccal interneuron. Stimulation of BN2,3 recruited both ingestion and rejection-like motor programs without firing in cerebral-buccal interneurons 2 or 12. During motor programs elicited by cerebral-buccal interneurons 2 or 12, high-voltage stimulation of BN2,3 inhibited firing in both cerebral-buccal interneurons. Our results suggest that cerebral-buccal interneurons 2 and 12 use cooperative interactions to modulate buccal motor programs, yet firing in cerebral-buccal interneurons 2 or 12 is not necessary for recruiting motor programs by buccal peripheral nerve BN2,3, even in preparations with intact cerebral-buccal pathways.

Fast oscillations in cortical-striatal networks switch frequency following rewarding events and stimulant drugs.

PubMed

Berke, J D

2009-09-01

Oscillations may organize communication between components of large-scale brain networks. Although gamma-band oscillations have been repeatedly observed in cortical-basal ganglia circuits, their functional roles are not yet clear. Here I show that, in behaving rats, distinct frequencies of ventral striatal local field potential oscillations show coherence with different cortical inputs. The approximately 50 Hz gamma oscillations that normally predominate in awake ventral striatum are coherent with piriform cortex, whereas approximately 80-100 Hz high-gamma oscillations are coherent with frontal cortex. Within striatum, entrainment to gamma rhythms is selective to fast-spiking interneurons, with distinct fast-spiking interneuron populations entrained to different gamma frequencies. Administration of the psychomotor stimulant amphetamine or the dopamine agonist apomorphine causes a prolonged decrease in approximately 50 Hz power and increase in approximately 80-100 Hz power. The same frequency switch is observed for shorter epochs spontaneously in awake, undrugged animals and is consistently provoked for < 1 s following reward receipt. Individual striatal neurons can participate in these brief high-gamma bursts with, or without, substantial changes in firing rate. Switching between discrete oscillatory states may allow different modes of information processing during decision-making and reinforcement-based learning, and may also be an important systems-level process by which stimulant drugs affect cognition and behavior.

Cell Type-specific Intrinsic Perithreshold Oscillations in Hippocampal GABAergic Interneurons.

PubMed

Kang, Young-Jin; Lewis, Hannah Elisabeth Smashey; Young, Mason William; Govindaiah, Gubbi; Greenfield, Lazar John; Garcia-Rill, Edgar; Lee, Sang-Hun

2018-04-15

The hippocampus plays a critical role in learning, memory, and spatial processing through coordinated network activity including theta and gamma oscillations. Recent evidence suggests that hippocampal subregions (e.g., CA1) can generate these oscillations at the network level, at least in part, through GABAergic interneurons. However, it is unclear whether specific GABAergic interneurons generate intrinsic theta and/or gamma oscillations at the single-cell level. Since major types of CA1 interneurons (i.e., parvalbumin-positive basket cells (PVBCs), cannabinoid type 1 receptor-positive basket cells (CB 1 BCs), Schaffer collateral-associated cells (SCAs), neurogliaform cells and ivy cells) are thought to play key roles in network theta and gamma oscillations in the hippocampus, we tested the hypothesis that these cells generate intrinsic perithreshold oscillations at the single-cell level. We performed whole-cell patch-clamp recordings from GABAergic interneurons in the CA1 region of the mouse hippocampus in the presence of synaptic blockers to identify intrinsic perithreshold membrane potential oscillations. The majority of PVBCs (83%), but not the other interneuron subtypes, produced intrinsic perithreshold gamma oscillations if the membrane potential remained above -45 mV. In contrast, CB 1 BCs, SCAs, neurogliaform cells, ivy cells, and the remaining PVBCs (17%) produced intrinsic theta, but not gamma, oscillations. These oscillations were prevented by blockers of persistent sodium current. These data demonstrate that the major types of hippocampal interneurons produce distinct frequency bands of intrinsic perithreshold membrane oscillations. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

MicroRNA-134 activity in somatostatin interneurons regulates H-Ras localization by repressing the palmitoylation enzyme, DHHC9.

PubMed

Chai, Sunghee; Cambronne, Xiaolu A; Eichhorn, Stephen W; Goodman, Richard H

2013-10-29

MicroRNA-134 (miR-134) serves as a widely accepted model for microRNA function in synaptic plasticity. In this model, synaptic activity stimulates miR-134 expression, which then regulates dendrite growth and spine formation. By using a ratiometric microRNA sensor, we found, unexpectedly, that miR-134 activity in cortical neurons was restricted to interneurons. Using an assay designed to trap microRNA-mRNA complexes, we determined that miR-134 interacted directly with the mRNA encoding the palmitoylation enzyme, DHHC9. This enzyme is known to palmitoylate H-Ras, a modification required for proper membrane trafficking. Treatment with bicuculline, a GABAA receptor antagonist, decreased DHHC9 expression in somatostatin-positive interneurons and membrane localization of an H-Ras reporter in a manner that depended on miR-134. Thus, although miR-134 has been proposed to affect all types of neurons, we showed that functionally active miR-134 is produced in only a selected population of neurons where it influences the expression of targets, such as DHHC9, that regulate membrane targeting of critical signaling molecules.

Kv7 potassium channel subunits and M currents in cultured hippocampal interneurons.

PubMed

Grigorov, Alexej; Moskalyuk, Anastasia; Kravchenko, Mykola; Veselovsky, Nikolai; Verkhratsky, Alexei; Fedulova, Svetlana

2014-09-01

Potassium channels of the Kv7 family that mediate the non-inactivating M current regulate the excitability of many types of neurons in the central nervous system, including some in the hippocampus. We report here that individual interneurons from newborn rat hippocampi in long-term culture strongly express messenger RNA specific for Kv7.2 and Kv7.3 and, to a lesser extent, Kv7.5 channel subunits but not for the Kv7.4 subunit. An M-like current was electrophysiologically identified in two subpopulations of interneurons distinct in their spiking behaviour (regular or fast spiking). The M-channel enhancer retigabine reduced interneuronal excitability by constraining the number of action potentials generated during imposed depolarisations; this effect was inhibited by specific the M-channel blocking drugs. In paired synaptically connected interneuron-target cell recordings, anatomically localised applications of retigabine indicated that M channels were present in both the interneuron soma and its GABA-ergic inhibitory axon. We conclude that M-channel subunits and functional M channels are broadly expressed in hippocampal interneurons and their axons and are potentially capable of strongly regulating their firing properties.

Intracerebroventricular kainic acid administration to neonatal rats alters interneuron development in the hippocampus.

PubMed

Dong, Hongxin; Csernansky, Cynthia A; Chu, Yunxiang; Csernansky, John G

2003-10-10

The effects of neonatal exposure to excitotoxins on the development of interneurons have not been well characterized, but may be relevant to the pathogenesis of neuropsychiatric disorders. In this study, the excitotoxin, kainic acid (KA) was administered to rats at postnatal day 7 (P7) by intracerebroventricular (i.c.v.) infusion. At P14, P25, P40 and P60, Nissl staining and immunohistochemical studies with the interneuron markers, glutamic acid decarboxylase (GAD-67), calbindin-D28k (CB) and parvalbumin (PV) were performed in the hippocampus. In control animals, the total number of interneurons, as well as the number of interneurons stained with GAD-67, CB and PV, was nearly constant from P14 through P60. In KA-treated rats, Nissl staining, GAD-67 staining, and CB staining revealed a progressive decline in the overall number of interneurons in the CA1 and CA3 subfields from P14 to P60. In contrast, PV staining in KA-treated rats showed initial decreases in the number of interneurons in the CA1 and CA3 subfields at P14 followed by increases that approached control levels by P60. These results suggest that, in general, early exposure to the excitotoxin KA decreases the number of hippocampal interneurons, but has a more variable effect on the specific population of interneurons labeled by PV. The functional impact of these changes may be relevant to the pathogenesis of neuropsychiatric disorders, such as schizophrenia.

GABAA Receptor-Mediated Activity in a Model of Cortical Dysplasia

DTIC Science & Technology

2012-06-29

epilepsy, autism and schizophrenia, and results from failure of immature neurons to appropriately migrate to their cortical targets. We developed a...schizophrenia, and autism , and results from failure of immature neurons to appropriately migrate and reach their cortical targets (Taylor et al., 1971; Choi and...2012) autism (Fatemi et al., 2006 , 2009; Chao et al., 2010; Oblak et al., 2010; Chattopaddhyaya and Di Cristo, 2012; Kang and Barnes; 2012), and X

Interneuronal Mechanism for Tinbergen’s Hierarchical Model of Behavioral Choice

PubMed Central

Pirger, Zsolt; Crossley, Michael; László, Zita; Naskar, Souvik; Kemenes, György; O’Shea, Michael; Benjamin, Paul R.; Kemenes, Ildikó

2014-01-01

Summary Recent studies of behavioral choice support the notion that the decision to carry out one behavior rather than another depends on the reconfiguration of shared interneuronal networks [1]. We investigated another decision-making strategy, derived from the classical ethological literature [2, 3], which proposes that behavioral choice depends on competition between autonomous networks. According to this model, behavioral choice depends on inhibitory interactions between incompatible hierarchically organized behaviors. We provide evidence for this by investigating the interneuronal mechanisms mediating behavioral choice between two autonomous circuits that underlie whole-body withdrawal [4, 5] and feeding [6] in the pond snail Lymnaea. Whole-body withdrawal is a defensive reflex that is initiated by tactile contact with predators. As predicted by the hierarchical model, tactile stimuli that evoke whole-body withdrawal responses also inhibit ongoing feeding in the presence of feeding stimuli. By recording neurons from the feeding and withdrawal networks, we found no direct synaptic connections between the interneuronal and motoneuronal elements that generate the two behaviors. Instead, we discovered that behavioral choice depends on the interaction between two unique types of interneurons with asymmetrical synaptic connectivity that allows withdrawal to override feeding. One type of interneuron, the Pleuro-Buccal (PlB), is an extrinsic modulatory neuron of the feeding network that completely inhibits feeding when excited by touch-induced monosynaptic input from the second type of interneuron, Pedal-Dorsal12 (PeD12). PeD12 plays a critical role in behavioral choice by providing a synaptic pathway joining the two behavioral networks that underlies the competitive dominance of whole-body withdrawal over feeding. PMID:25155505

Fyn kinase mediates cortical actin ring depolymerization required for mast cell migration in response to TGF-β in mice.

PubMed

Ramírez-Valadez, Karla A; Vázquez-Victorio, Genaro; Macías-Silva, Marina; González-Espinosa, Claudia

2017-08-01

Transforming growth factor-β (TGF-β) is a potent mast cell (MC) chemoattractant able to modulate local inflammatory reactions. The molecular mechanism leading to TGF-β-directed MC migration is not fully described. Here we analyzed the role of the Src family protein kinase Fyn on the main TGF-β-induced cytoskeletal changes leading to MC migration. Utilizing bone marrow-derived mast cells (BMMCs) from WT and Fyn-deficient mice we found that BMMC migration to TGF-β was impaired in the absence of the kinase. TGF-β caused depolymerization of the cortical actin ring and changes on the phosphorylation of cofilin, LIMK and CAMKII only in WT cells. Defective cofilin activation and phosphorylation of regulatory proteins was detected in Fyn-deficient BMMCs and this finding correlated with a lower activity of the catalytic subunit of the phosphatase PP2A. Diminished TGF-β-induced chemotaxis of Fyn-deficient cells was also observed in an in vivo model of MC migration (bleomycin-induced scleroderma). Our results show that Fyn kinase is an important positive effector of TGF-β-induced chemotaxis through the control of PP2A activity and this is relevant to pathological processes that are related to TGF-β-dependent mast cell migration. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Distribution of neurons expressing tyrosine hydroxylase in the human cerebral cortex

PubMed Central

Benavides-Piccione, Ruth; DeFelipe, Javier

2007-01-01

Since the very first detailed description of the different types of cortical interneurons by Cajal, the tremendous variation in the morphology, physiology and neurochemical properties of these cells has become apparent. However, it still remains unclear whether all types of interneurons are present in all cortical areas and species. Here we have focused on tyrosine hydroxylase (TH)-immunoreactive cortical interneurons, which although only present in certain species, are particularly abundant in the human neocortex. We argue that this type of interneuron is more widespread in the human neocortex than in any other species examined so far and that, therefore, it is probably involved in a larger variety of cortical circuits. In addition, notable regional variation can be seen in relation to these interneurons. These differences further emphasize the variability in the design of microcircuits between cortical areas and species, and they probably reflect an evolutionary adaptation of cortical circuits to particular functions. PMID:17593221

Hilar Interneuron Vulnerability Distinguishes Aged Rats With Memory Impairment

PubMed Central

Spiegel, Amy M.; Koh, Ming Teng; Vogt, Nicholas M.; Rapp, Peter R.; Gallagher, Michela

2016-01-01

Hippocampal interneuron populations are reportedly vulnerable to normal aging. The relationship between interneuron network integrity and age-related memory impairment, however, has not been tested directly. That question was addressed in the present study using a well-characterized model in which outbred, aged, male Long-Evans rats exhibit a spectrum of individual differences in hippocampal-dependent memory. Selected interneuron populations in the hippocampus were visualized for stereological quantification with a panel of immunocytochemical markers, including glutamic acid decarboxylase-67 (GAD67), somatostatin, and neuropeptide Y. The overall pattern of results was that, although the numbers of GAD67- and somatostatin-positive interneurons declined with age across multiple fields of the hippocampus, alterations specifically related to the cognitive outcome of aging were observed exclusively in the hilus of the dentate gyrus. Because the total number of NeuN-immunoreactive hilar neurons was unaffected, the decline observed with other markers likely reflects a loss of target protein rather than neuron death. In support of that interpretation, treatment with the atypical antiepileptic levetiracetam at a low dose shown previously to improve behavioral performance fully restored hilar SOM expression in aged, memory-impaired rats. Age-related decreases in GAD67- and somatostatin-immunoreactive neuron number beyond the hilus were regionally selective and spared the CA1 field of the hippocampus entirely. Together these findings confirm the vulnerability of hippocampal interneurons to normal aging and highlight that the integrity of a specific subpopulation in the hilus is coupled with age-related memory impairment. PMID:23749483

Dynamic interneuron-principal cell interplay leads to a specific pattern of in vitro ictogenesis.

PubMed

Lévesque, Maxime; Chen, Li-Yuan; Hamidi, Shabnam; Avoli, Massimo

2018-07-01

Ictal discharges induced by 4-aminopyridine in the in vitro rodent entorhinal cortex present with either low-voltage fast or sudden onset patterns. The role of interneurons in initiating low-voltage fast onset ictal discharges is well established but the processes leading to sudden onset ictal discharges remain unclear. We analysed here the participation of interneurons (n = 75) and principal cells (n = 13) in the sudden onset pattern by employing in vitro tetrode wire recordings in the entorhinal cortex of brain slices from Sprague-Dawley rats. Ictal discharges emerged from a background of frequently occurring interictal spikes that were associated to a specific interneuron/principal cell interplay. High rates of interneuron firing occurred 12 ms before interictal spike onset while principal cells fired later during low interneuron firing. In contrast, the onset of sudden ictal discharges was characterized by increased firing from principal cells 627 ms before ictal onset whereas interneurons increased their firing rates 161 ms before ictal onset. Our data show that sudden onset ictogenesis is associated with frequently occurring interictal spikes resting on the interplay between interneurons and principal cells while ictal discharges stem from enhanced principal cell firing leading to increased interneuron activity. These findings indicate that specific patterns of interactions between interneurons and principal cells shape interictal and ictal discharges with sudden onset in the rodent entorhinal cortex. We propose that specific neuronal interactions lead to the generation of distinct onset patterns in focal epileptic disorders. Copyright © 2018 Elsevier Inc. All rights reserved.

Pyramidal cell-interneuron interactions underlie hippocampal ripple oscillations.

PubMed

Stark, Eran; Roux, Lisa; Eichler, Ronny; Senzai, Yuta; Royer, Sebastien; Buzsáki, György

2014-07-16

High-frequency ripple oscillations, observed most prominently in the hippocampal CA1 pyramidal layer, are associated with memory consolidation. The cellular and network mechanisms underlying the generation, frequency control, and spatial coherence of the rhythm are poorly understood. Using multisite optogenetic manipulations in freely behaving rodents, we found that depolarization of a small group of nearby pyramidal cells was sufficient to induce high-frequency oscillations, whereas closed-loop silencing of pyramidal cells or activation of parvalbumin- (PV) or somatostatin-immunoreactive interneurons aborted spontaneously occurring ripples. Focal pharmacological blockade of GABAA receptors abolished ripples. Localized PV interneuron activation paced ensemble spiking, and simultaneous induction of high-frequency oscillations at multiple locations resulted in a temporally coherent pattern mediated by phase-locked interneuron spiking. These results constrain competing models of ripple generation and indicate that temporally precise local interactions between excitatory and inhibitory neurons support ripple generation in the intact hippocampus. Copyright © 2014 Elsevier Inc. All rights reserved.

Pyramidal Cell-Interneuron Interactions Underlie Hippocampal Ripple Oscillations

PubMed Central

Stark, Eran; Roux, Lisa; Eichler, Ronny; Senzai, Yuta; Royer, Sebastien; Buzsáki, György

2015-01-01

SUMMARY High-frequency ripple oscillations, observed most prominently in the hippocampal CA1 pyramidal layer, are associated with memory consolidation. The cellular and network mechanisms underlying the generation, frequency control, and spatial coherence of the rhythm are poorly understood. Using multisite optogenetic manipulations in freely behaving rodents, we found that depolarization of a small group of nearby pyramidal cells was sufficient to induce high-frequency oscillations, whereas closed-loop silencing of pyramidal cells or activation of parvalbumin-(PV) or somatostatin-immunoreactive interneurons aborted spontaneously occurring ripples. Focal pharmacological blockade of GABAA receptors abolished ripples. Localized PV inter-neuron activation paced ensemble spiking, and simultaneous induction of high-frequency oscillations at multiple locations resulted in a temporally coherent pattern mediated by phase-locked inter-neuron spiking. These results constrain competing models of ripple generation and indicate that temporally precise local interactions between excitatory and inhibitory neurons support ripple generation in the intact hippocampus. PMID:25033186

Genetic dissection of GABAergic neural circuits in mouse neocortex

PubMed Central

Taniguchi, Hiroki

2014-01-01

Diverse and flexible cortical functions rely on the ability of neural circuits to perform multiple types of neuronal computations. GABAergic inhibitory interneurons significantly contribute to this task by regulating the balance of activity, synaptic integration, spiking, synchrony, and oscillation in a neural ensemble. GABAergic interneurons display a high degree of cellular diversity in morphology, physiology, connectivity, and gene expression. A considerable number of subtypes of GABAergic interneurons diversify modes of cortical inhibition, enabling various types of information processing in the cortex. Thus, comprehensively understanding fate specification, circuit assembly, and physiological function of GABAergic interneurons is a key to elucidate the principles of cortical wiring and function. Recent advances in genetically encoded molecular tools have made a breakthrough to systematically study cortical circuitry at the molecular, cellular, circuit, and whole animal levels. However, the biggest obstacle to fully applying the power of these to analysis of GABAergic circuits was that there were no efficient and reliable methods to express them in subtypes of GABAergic interneurons. Here, I first summarize cortical interneuron diversity and current understanding of mechanisms, by which distinct classes of GABAergic interneurons are generated. I then review recent development in genetically encoded molecular tools for neural circuit research, and genetic targeting of GABAergic interneuron subtypes, particularly focusing on our recent effort to develop and characterize Cre/CreER knockin lines. Finally, I highlight recent success in genetic targeting of chandelier cells, the most unique and distinct GABAergic interneuron subtype, and discuss what kind of questions need to be addressed to understand development and function of cortical inhibitory circuits. PMID:24478631

Excitatory interneurons dominate sensory processing in the spinal substantia gelatinosa of rat

PubMed Central

Santos, Sónia F A; Rebelo, Sandra; Derkach, Victor A; Safronov, Boris V

2007-01-01

Substantia gelatinosa (SG, lamina II) is a spinal cord region where most unmyelinated primary afferents terminate and the central nociceptive processing begins. It is formed by several distinct groups of interneurons whose functional properties and synaptic connections are poorly understood, in part, because recordings from synaptically coupled pairs of SG neurons are quite challenging due to a very low probability of finding connected cells. Here, we describe an efficient method for identifying synaptically coupled interneurons in rat spinal cord slices and characterizing their excitatory or inhibitory function. Using tight-seal whole-cell recordings and a cell-attached stimulation technique, we routinely tested about 1500 SG interneurons, classifying 102 of them as monosynaptically connected to neurons in lamina I–III. Surprisingly, the vast majority of SG interneurons (n = 87) were excitatory and glutamatergic, while only 15 neurons were inhibitory. According to their intrinsic firing properties, these 102 SG neurons were also classified as tonic (n = 49), adapting (n = 17) or delayed-firing neurons (n = 36). All but two tonic neurons and all adapting neurons were excitatory interneurons. Of 36 delayed-firing neurons, 23 were excitatory and 13 were inhibitory. We conclude that sensory integration in the intrinsic SG neuronal network is dominated by excitatory interneurons. Such organization of neuronal circuitries in the spinal SG can be important for nociceptive encoding. PMID:17331995

Neuronal Migration Dynamics in the Developing Ferret Cortex.

PubMed

Gertz, Caitlyn C; Kriegstein, Arnold R

2015-10-21

During mammalian neocortical development, newborn excitatory and inhibitory neurons must migrate over long distances to reach their final positions within the cortical plate. In the lissencephalic rodent brain, pyramidal neurons are born in the ventricular and subventricular zones of the pallium and migrate along radial glia fibers to reach the appropriate cortical layer. Although much less is known about neuronal migration in species with a gyrencephalic cortex, retroviral studies in the ferret and primate suggest that, unlike the rodent, pyramidal neurons do not follow strict radial pathways and instead can disperse horizontally. However, the means by which pyramidal neurons laterally disperse remain unknown. In this study, we identified a viral labeling technique for visualizing neuronal migration in the ferret, a gyrencephalic carnivore, and found that migration was predominantly radial at early postnatal ages. In contrast, neurons displayed more tortuous migration routes with a decreased frequency of cortical plate-directed migration at later stages of neurogenesis concomitant with the start of brain folding. This was accompanied by neurons migrating sequentially along several different radial glial fibers, suggesting a mode by which pyramidal neurons may laterally disperse in a folded cortex. These findings provide insight into the migratory behavior of neurons in gyrencephalic species and provide a framework for using nonrodent model systems for studying neuronal migration disorders. Elucidating neuronal migration dynamics in the gyrencephalic, or folded, cortex is important for understanding neurodevelopmental disorders. Similar to the rodent, we found that neuronal migration was predominantly radial at early postnatal ages in the gyrencephalic ferret cortex. Interestingly, ferret neurons displayed more tortuous migration routes and a decreased frequency of radial migration at later ages coincident with the start of cortical folding. We found that ferret

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

Parvalbumin-expressing interneurons coordinate hippocampal network dynamics required for memory consolidation

NASA Astrophysics Data System (ADS)

Ognjanovski, Nicolette; Schaeffer, Samantha; Wu, Jiaxing; Mofakham, Sima; Maruyama, Daniel; Zochowski, Michal; Aton, Sara J.

2017-04-01

Activity in hippocampal area CA1 is essential for consolidating episodic memories, but it is unclear how CA1 activity patterns drive memory formation. We find that in the hours following single-trial contextual fear conditioning (CFC), fast-spiking interneurons (which typically express parvalbumin (PV)) show greater firing coherence with CA1 network oscillations. Post-CFC inhibition of PV+ interneurons blocks fear memory consolidation. This effect is associated with loss of two network changes associated with normal consolidation: (1) augmented sleep-associated delta (0.5-4 Hz), theta (4-12 Hz) and ripple (150-250 Hz) oscillations; and (2) stabilization of CA1 neurons' functional connectivity patterns. Rhythmic activation of PV+ interneurons increases CA1 network coherence and leads to a sustained increase in the strength and stability of functional connections between neurons. Our results suggest that immediately following learning, PV+ interneurons drive CA1 oscillations and reactivation of CA1 ensembles, which directly promotes network plasticity and long-term memory formation.

Temporal integration and 1/f power scaling in a circuit model of cerebellar interneurons.

PubMed

Maex, Reinoud; Gutkin, Boris

2017-07-01

Inhibitory interneurons interconnected via electrical and chemical (GABA A receptor) synapses form extensive circuits in several brain regions. They are thought to be involved in timing and synchronization through fast feedforward control of principal neurons. Theoretical studies have shown, however, that whereas self-inhibition does indeed reduce response duration, lateral inhibition, in contrast, may generate slow response components through a process of gradual disinhibition. Here we simulated a circuit of interneurons (stellate and basket cells) of the molecular layer of the cerebellar cortex and observed circuit time constants that could rise, depending on parameter values, to >1 s. The integration time scaled both with the strength of inhibition, vanishing completely when inhibition was blocked, and with the average connection distance, which determined the balance between lateral and self-inhibition. Electrical synapses could further enhance the integration time by limiting heterogeneity among the interneurons and by introducing a slow capacitive current. The model can explain several observations, such as the slow time course of OFF-beam inhibition, the phase lag of interneurons during vestibular rotation, or the phase lead of Purkinje cells. Interestingly, the interneuron spike trains displayed power that scaled approximately as 1/ f at low frequencies. In conclusion, stellate and basket cells in cerebellar cortex, and interneuron circuits in general, may not only provide fast inhibition to principal cells but also act as temporal integrators that build a very short-term memory. NEW & NOTEWORTHY The most common function attributed to inhibitory interneurons is feedforward control of principal neurons. In many brain regions, however, the interneurons are densely interconnected via both chemical and electrical synapses but the function of this coupling is largely unknown. Based on large-scale simulations of an interneuron circuit of cerebellar cortex, we

Serotonin regulates voltage-dependent currents in type Ie(A) and Ii interneurons of Hermissenda

PubMed Central

Jin, Nan Ge

2011-01-01

Serotonin (5-HT) has both direct and modulatory actions on central neurons contributing to behavioral arousal and cellular-synaptic plasticity in diverse species. In Hermissenda, 5-HT produces changes in intrinsic excitability of different types of identified interneurons in the circumesophageal nervous system. Using whole cell patch-clamp techniques we have examined membrane conductance changes produced by 5-HT that contribute to intrinsic excitability in two identified classes of interneurons, types Ii and IeA. Whole cell currents were examined before and after 5-HT application to the isolated nervous system. A 4-aminopyridine-sensitive transient outward K+ current [IK(A)], a tetraethylammonium-sensitive delayed rectifier K+ current [IK(V)], an inward rectifier K+ current [IK(IR)], and a hyperpolarization-activated current (Ih) were characterized. 5-HT decreased the amplitude of IK(A) and IK(V) in both type Ii and IeA interneurons. However, differences in 5-HT's effects on the activation-inactivation kinetics were observed in different types of interneurons. 5-HT produced a depolarizing shift in the activation curve of IK(V) and a hyperpolarizing shift in the inactivation curve of IK(A) in type Ii interneurons. In contrast, 5-HT produced a depolarizing shift in the activation curve and a hyperpolarizing shift in the inactivation curve of both IK(V) and IK(A) in type IeA interneurons. In addition, 5-HT decreased the amplitude of IK(IR) in type Ii interneurons and increased the amplitude of Ih in type IeA interneurons. These results indicate that 5-HT-dependent changes in IK(A), IK(V), IK(IR), and Ih contribute to multiple mechanisms that synergistically support modulation of increased intrinsic excitability associated with different functional classes of identified type I interneurons. PMID:21813747

Dynamic, cell type-specific roles for GABAergic interneurons in a mouse model of optogenetically inducible seizures

PubMed Central

Khoshkhoo, Sattar; Vogt, Daniel; Sohal, Vikaas S.

2016-01-01

SUMMARY GABAergic interneurons play critical roles in seizures, but it remains unknown whether these vary across interneuron subtypes or evolve during a seizure. This uncertainty stems from the unpredictable timing of seizures in most models, which limits neuronal imaging or manipulations around the seizure onset. Here, we describe a mouse model for optogenetic seizure induction. Combining this with calcium imaging, we find that seizure onset rapidly recruits parvalbumin (PV), somatostatin (SOM), and vasoactive intestinal peptitde (VIP)-expressing interneurons, whereas excitatory neurons are recruited several seconds later. Optogenetically inhibiting VIP interneurons consistently increased seizure threshold and reduced seizure duration. Inhibiting PV+ and SOM+ interneurons had mixed effects on seizure initiation, but consistently reduced seizure duration. Thus, while their roles may evolve during seizures, PV+ and SOM+ interneurons ultimately help maintain ongoing seizures. These results show how an optogenetically-induced seizure model can be leveraged to pinpoint a new target for seizure control: VIP interneurons. PMID:28041880

Maternal Immune Activation Leads to Selective Functional Deficits in Offspring Parvalbumin Interneurons

PubMed Central

Canetta, Sarah; Bolkan, Scott; Padilla-Coreano, Nancy; Song, LouJin; Sahn, Ryan; Harrison, Neil; Gordon, Joshua A.; Brown, Alan; Kellendonk, Christoph

2015-01-01

Summary Abnormalities in prefrontal GABAergic transmission, particularly in fast-spiking interneurons that express parvalbumin (PV), are hypothesized to contribute to the pathophysiology of multiple psychiatric disorders including schizophrenia, bipolar disorder, anxiety disorders and depression. While primarily histological abnormalities have been observed in patients and in animal models of psychiatric disease, evidence for abnormalities in functional neurotransmission at the level of specific interneuron populations has been lacking in animal models and is difficult to establish in human patients. Using an animal model of a psychiatric disease risk factor, prenatal maternal immune activation (MIA), we found reduced functional GABAergic transmission in the medial prefrontal cortex (mPFC) of adult MIA offspring. Decreased transmission was selective for interneurons expressing PV, and was not observed in calretinin-expressing neurons. This deficit in PV function in MIA offspring was associated with increased anxiety-like behavior and impairments in attentional set shifting, but did not affect working memory. Furthermore, cell-type specific optogenetic inhibition of mPFC PV interneurons was sufficient to impair attentional set shifting and enhance anxiety levels. Finally, we found that in vivo mPFC gamma oscillations, which are supported by PV interneuron function, were linearly correlated with the degree of anxiety displayed in adult mice, and that this correlation was disrupted in MIA offspring. These results demonstrate a selective functional vulnerability of PV interneurons to maternal immune activation, leading to affective and cognitive symptoms that have high relevance for schizophrenia and other psychiatric disorders. PMID:26830140

GABAergic interneurons: The orchestra or the conductor in fear learning and memory?

PubMed

Lucas, Elizabeth K; Clem, Roger L

2017-12-02

Fear conditioning is a form of associative learning that is fundamental to survival and involves potentiation of activity in excitatory projection neurons (PNs). Current models stipulate that the mechanisms underlying this process involve plasticity of PN synapses, which exhibit strengthening in response to fear conditioning. However, excitatory PNs are extensively modulated by a diverse array of GABAergic interneurons whose contributions to acquisition, storage, and expression of fear memory remain poorly understood. Here we review emerging evidence that genetically-defined interneurons play important subtype-specific roles in processing of fear-related stimuli and that these dynamics shape PN firing through both inhibition and disinhibition. Furthermore, interneurons exhibit structural, molecular, and electrophysiological evidence of fear learning-induced synaptic plasticity. These studies warrant discarding the notion of interneurons as passive bystanders in long-term memory. Copyright © 2017. Published by Elsevier Inc.

Brain-wide Maps Reveal Stereotyped Cell-Type-Based Cortical Architecture and Subcortical Sexual Dimorphism.

PubMed

Kim, Yongsoo; Yang, Guangyu Robert; Pradhan, Kith; Venkataraju, Kannan Umadevi; Bota, Mihail; García Del Molino, Luis Carlos; Fitzgerald, Greg; Ram, Keerthi; He, Miao; Levine, Jesse Maurica; Mitra, Partha; Huang, Z Josh; Wang, Xiao-Jing; Osten, Pavel

2017-10-05

The stereotyped features of neuronal circuits are those most likely to explain the remarkable capacity of the brain to process information and govern behaviors, yet it has not been possible to comprehensively quantify neuronal distributions across animals or genders due to the size and complexity of the mammalian brain. Here we apply our quantitative brain-wide (qBrain) mapping platform to document the stereotyped distributions of mainly inhibitory cell types. We discover an unexpected cortical organizing principle: sensory-motor areas are dominated by output-modulating parvalbumin-positive interneurons, whereas association, including frontal, areas are dominated by input-modulating somatostatin-positive interneurons. Furthermore, we identify local cell type distributions with more cells in the female brain in 10 out of 11 sexually dimorphic subcortical areas, in contrast to the overall larger brains in males. The qBrain resource can be further mined to link stereotyped aspects of neuronal distributions to known and unknown functions of diverse brain regions. Copyright © 2017 Elsevier Inc. All rights reserved.

DREADD in parvalbumin interneurons of the dentate gyrus modulates anxiety, social interaction and memory extinction.

PubMed

Zou, D; Chen, L; Deng, D; Jiang, D; Dong, F; McSweeney, C; Zhou, Y; Liu, L; Chen, G; Wu, Y; Mao, Y

2016-01-01

Parvalbumin (PV)-positive interneurons in the hippocampus play a critical role in animal memory, such as spatial working memory. However, how PV-positive interneurons in the subregions of the hippocampus affect animal behaviors remains poorly defined. Here, we achieved specific and reversible activation of PV-positive interneurons using designer receptors exclusively activated by designer drugs (DREADD) technology. Inducible DREADD expression was demonstrated in vitro in cultured neurons, in which co-transfection of the hM3D-Gq-mCherry vector with a Cre plasmid resulted in a cellular response to hM3Dq ligand clozapine-N-oxide (CNO) stimulation. In addition, the dentate gyrus (DG) of PV-Cre mice received bilateral injection of control lentivirus or lentivirus expressing double floxed hM3D-Gq-mCherry. Selective activation of PV-positive interneurons in the DG did not affect locomotor activity or depression-related behavior in mice. Interestingly, stimulation of PV-positive interneurons induced an anxiolytic effect. Activation of PVpositive interneurons appears to impair social interaction to novelty, but has no effect on social motivation. However, this defect is likely due to the anxiolytic effect as the exploratory behavior of mice expressing hM3DGq is significantly increased. Mice expressing hM3D-Gq did not affect novel object recognition. Activation of PV-positive interneurons in the DG maintains intact cued and contextual fear memory but facilitates fear extinction. Collectively, our results demonstrated that proper control of PV interneurons activity in the DG is critical for regulation of the anxiety, social interaction and fear extinction. These results improve our fundamental understanding of the physiological role of PV-positive interneurons in the hippocampus.

Preparation of the cortical reaction: maturation-dependent migration of SNARE proteins, clathrin, and complexin to the porcine oocyte's surface blocks membrane traffic until fertilization.

PubMed

Tsai, Pei-Shiue; van Haeften, Theo; Gadella, Bart M

2011-02-01

The cortical reaction is a calcium-dependent exocytotic process in which the content of secretory granules is released into the perivitellin space immediately after fertilization, which serves to prevent polyspermic fertilization. In this study, we investigated the involvement and the organization of SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins in the docking and fusion of the cortical granule membrane with the oolemma in porcine oocytes. During meiotic maturation, secretory vesicles that were labeled with a granule-specific binding lectin, peanut agglutinin (PNA), migrated toward the oocyte's surface. This surface-orientated redistribution behavior was also observed for the oocyte-specific SNARE proteins SNAP23 and VAMP1 that colocalized with the PNA-labeled structures in the cortex area just under the oolemma and with the exclusive localization area of complexin (a trans-SNARE complex-stabilizing protein). The coming together of these proteins serves to prevent the spontaneous secretion of the docked cortical granules and to prepare the oocyte's surface for the cortical reaction, which should probably be immediately compensated for by a clathrin-mediated endocytosis. In vitro fertilization resulted in the secretion of the cortical granule content and the concomitant release of complexin and clathrin into the oocyte's cytosol, and this is considered to stimulate the observed endocytosis of SNARE-containing membrane vesicles.

Unit Activity of Hippocampal Interneurons before Spontaneous Seizures in an Animal Model of Temporal Lobe Epilepsy

PubMed Central

Toyoda, Izumi; Fujita, Satoshi; Thamattoor, Ajoy K.

2015-01-01

Mechanisms of seizure initiation are unclear. To evaluate the possible roles of inhibitory neurons, unit recordings were obtained in the dentate gyrus, CA3, CA1, and subiculum of epileptic pilocarpine-treated rats as they experienced spontaneous seizures. Most interneurons in the dentate gyrus, CA1, and subiculum increased their firing rate before seizures, and did so with significant consistency from seizure to seizure. Identification of CA1 interneuron subtypes based on firing characteristics during theta and sharp waves suggested that a parvalbumin-positive basket cell and putative bistratified cells, but not oriens lacunosum moleculare cells, were activated preictally. Preictal changes occurred much earlier than those described by most previous in vitro studies. Preictal activation of interneurons began earliest (>4 min before seizure onset), increased most, was most prevalent in the subiculum, and was minimal in CA3. Preictal inactivation of interneurons was most common in CA1 (27% of interneurons) and included a putative ivy cell and parvalbumin-positive basket cell. Increased or decreased preictal activity correlated with whether interneurons fired faster or slower, respectively, during theta activity. Theta waves were more likely to occur before seizure onset, and increased preictal firing of subicular interneurons correlated with theta activity. Preictal changes by other hippocampal interneurons were largely independent of theta waves. Within seconds of seizure onset, many interneurons displayed a brief pause in firing and a later, longer drop that was associated with reduced action potential amplitude. These findings suggest that many interneurons inactivate during seizures, most increase their activity preictally, but some fail to do so at the critical time before seizure onset. PMID:25904809

Circuit variability interacts with excitatory-inhibitory diversity of interneurons to regulate network encoding capacity.

PubMed

Tsai, Kuo-Ting; Hu, Chin-Kun; Li, Kuan-Wei; Hwang, Wen-Liang; Chou, Ya-Hui

2018-05-23

Local interneurons (LNs) in the Drosophila olfactory system exhibit neuronal diversity and variability, yet it is still unknown how these features impact information encoding capacity and reliability in a complex LN network. We employed two strategies to construct a diverse excitatory-inhibitory neural network beginning with a ring network structure and then introduced distinct types of inhibitory interneurons and circuit variability to the simulated network. The continuity of activity within the node ensemble (oscillation pattern) was used as a readout to describe the temporal dynamics of network activity. We found that inhibitory interneurons enhance the encoding capacity by protecting the network from extremely short activation periods when the network wiring complexity is very high. In addition, distinct types of interneurons have differential effects on encoding capacity and reliability. Circuit variability may enhance the encoding reliability, with or without compromising encoding capacity. Therefore, we have described how circuit variability of interneurons may interact with excitatory-inhibitory diversity to enhance the encoding capacity and distinguishability of neural networks. In this work, we evaluate the effects of different types and degrees of connection diversity on a ring model, which may simulate interneuron networks in the Drosophila olfactory system or other biological systems.

Renshaw cell interneuron specialization is controlled by a temporally restricted transcription factor program

PubMed Central

Stam, Floor J.; Hendricks, Timothy J.; Zhang, Jingming; Geiman, Eric J.; Francius, Cedric; Labosky, Patricia A.; Clotman, Frederic; Goulding, Martyn

2012-01-01

The spinal cord contains a diverse array of physiologically distinct interneuron cell types that subserve specialized roles in somatosensory perception and motor control. The mechanisms that generate these specialized interneuronal cell types from multipotential spinal progenitors are not known. In this study, we describe a temporally regulated transcriptional program that controls the differentiation of Renshaw cells (RCs), an anatomically and functionally discrete spinal interneuron subtype. We show that the selective activation of the Onecut transcription factors Oc1 and Oc2 during the first wave of V1 interneuron neurogenesis is a key step in the RC differentiation program. The development of RCs is additionally dependent on the forkhead transcription factor Foxd3, which is more broadly expressed in postmitotic V1 interneurons. Our demonstration that RCs are born, and activate Oc1 and Oc2 expression, in a narrow temporal window leads us to posit that neuronal diversity in the developing spinal cord is established by the composite actions of early spatial and temporal determinants. PMID:22115757

Cracking Down on Inhibition: Selective Removal of GABAergic Interneurons from Hippocampal Networks

PubMed Central

Antonucci, Flavia; Alpár, Alán; Kacza, Johannes; Caleo, Matteo; Verderio, Claudia; Giani, Alice; Martens, Henrik; Chaudhry, Farrukh A.; Allegra, Manuela; Grosche, Jens; Michalski, Dominik; Erck, Christian; Hoffmann, Anke; Härtig, Wolfgang

2012-01-01

Inhibitory (GABAergic) interneurons entrain assemblies of excitatory principal neurons to orchestrate information processing in the hippocampus. Disrupting the dynamic recruitment as well as the temporally precise activity of interneurons in hippocampal circuitries can manifest in epileptiform seizures, and impact specific behavioral traits. Despite the importance of GABAergic interneurons during information encoding in the brain, experimental tools to selectively manipulate GABAergic neurotransmission are limited. Here, we report the selective elimination of GABAergic interneurons by a ribosome inactivation approach through delivery of saporin-conjugated anti-vesicular GABA transporter antibodies (SAVAs) in vitro as well as in the mouse and rat hippocampus in vivo. We demonstrate the selective loss of GABAergic—but not glutamatergic—synapses, reduced GABA release, and a shift in excitation/inhibition balance in mixed cultures of hippocampal neurons exposed to SAVAs. We also show the focal and indiscriminate loss of calbindin+, calretinin+, parvalbumin/system A transporter 1+, somatostatin+, vesicular glutamate transporter 3 (VGLUT3)/cholecystokinin/CB1 cannabinoid receptor+ and neuropeptide Y+ local-circuit interneurons upon SAVA microlesions to the CA1 subfield of the rodent hippocampus, with interneuron debris phagocytosed by infiltrating microglia. SAVA microlesions did not affect VGLUT1+ excitatory afferents. Yet SAVA-induced rearrangement of the hippocampal circuitry triggered network hyperexcitability associated with the progressive loss of CA1 pyramidal cells and the dispersion of dentate granule cells. Overall, our data identify SAVAs as an effective tool to eliminate GABAergic neurons from neuronal circuits underpinning high-order behaviors and cognition, and whose manipulation can recapitulate pathogenic cascades of epilepsy and other neuropsychiatric illnesses. PMID:22323713

Maternal immune activation leads to selective functional deficits in offspring parvalbumin interneurons.

PubMed

Canetta, S; Bolkan, S; Padilla-Coreano, N; Song, L J; Sahn, R; Harrison, N L; Gordon, J A; Brown, A; Kellendonk, C

2016-07-01

Abnormalities in prefrontal gamma aminobutyric acid (GABA)ergic transmission, particularly in fast-spiking interneurons that express parvalbumin (PV), are hypothesized to contribute to the pathophysiology of multiple psychiatric disorders, including schizophrenia, bipolar disorder, anxiety disorders and depression. While primarily histological abnormalities have been observed in patients and in animal models of psychiatric disease, evidence for abnormalities in functional neurotransmission at the level of specific interneuron populations has been lacking in animal models and is difficult to establish in human patients. Using an animal model of a psychiatric disease risk factor, prenatal maternal immune activation (MIA), we found reduced functional GABAergic transmission in the medial prefrontal cortex (mPFC) of adult MIA offspring. Decreased transmission was selective for interneurons expressing PV, resulted from a decrease in release probability and was not observed in calretinin-expressing neurons. This deficit in PV function in MIA offspring was associated with increased anxiety-like behavior and impairments in attentional set shifting, but did not affect working memory. Furthermore, cell-type specific optogenetic inhibition of mPFC PV interneurons was sufficient to impair attentional set shifting and enhance anxiety levels. Finally, we found that in vivo mPFC gamma oscillations, which are supported by PV interneuron function, were linearly correlated with the degree of anxiety displayed in adult mice, and that this correlation was disrupted in MIA offspring. These results demonstrate a selective functional vulnerability of PV interneurons to MIA, leading to affective and cognitive symptoms that have high relevance for schizophrenia and other psychiatric disorders.

Neuropeptide Y as a possible homeostatic element for changes in cortical excitability induced by repetitive transcranial magnetic stimulation.

PubMed

Jazmati, Danny; Neubacher, Ute; Funke, Klaus

2018-02-24

Repetitive transcranial magnetic stimulation (rTMS) is able to modify cortical excitability. Rat rTMS studies revealed a modulation of inhibitory systems, in particular that of the parvalbumin-expressing (PV+) interneurons, when using intermittent theta-burst stimulation (iTBS). The potential disinhibitory action of iTBS raises the questions of how neocortical circuits stabilize excitatory-inhibitory balance within a physiological range. Neuropeptide Y (NPY) appears to be one candidate. Analysis of cortical expression of PV, NPY and vesicular glutamate transporter type 1 (vGluT1) by immunohistochemical means at the level of cell counts, mean neuropil expression and single cell pre-/postsynaptic expression, with and without intraventricular NPY-injection. Our results show that iTBS not only reduced the number of neurons with high-PV expression in a dose-dependent fashion, but also increased the cortical expression of NPY, discussed to reduce glutamatergic transmission, and this was further associated with a reduced vGluT1 expression, an indicator of glutamateric presynaptic activity. Interneurons showing a low-PV expression exhibit less presynaptic vGluT1 expression compared to those with a high-PV expression. Intraventricular application of NPY prior to iTBS prevented the iTBS-induced reduction in the number of high-PV neurons, the reduction in tissue vGluT1 level and that presynaptic to high-PV cells. We conclude that NPY, possibly via a global but also slow homeostatic control of glutamatergic transmission, modulates the strength and direction of the iTBS effects, likely preventing pathological imbalance of excitatory and inhibitory cortical activity but still allowing enough disinhibition beneficial for plastic changes as during learning. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Decreased number of interneurons and increased seizures in neuropilin 2 deficient mice: Implications for autism and epilepsy

PubMed Central

Gant, John C.; Thibault, Oliver; Blalock, Eric M.; Yang, Jun; Bachstetter, Adam; Kotick, James; Schauwecker, Paula E.; Hauser, Kurt F.; Smith, George M.; Mervis, Ron; Li, YanFang; Barnes, Gregory N.

2010-01-01

Summary Purpose Clinically, perturbations in the semaphorin signaling system have been associated with autism and epilepsy. The semaphorins have been implicated in guidance, migration, differentiation, and synaptic plasticity of neurons. The semaphorin 3F (Sema3F) ligand and its receptor, neuropilin 2 (NPN2) are highly expressed within limbic areas. NPN2 signaling may intimately direct the apposition of presynaptic and postsynaptic locations, facilitating the development and maturity of hippocampal synaptic function. To further understand the role of NPN2 signaling in central nevous system (CNS) plasticity, structural and functional alterations were assessed in NPN2 deficient mice. Methods In NPN2 deficient mice, we measured seizure susceptibility after kainic acid or pentylenetetrazol, neuronal excitability and synaptic throughput in slice preparations, principal and interneuron cell counts with immunocytochemical protocols, synaptosomal protein levels with immunoblots, and dendritic morphology with Golgi-staining. Results NPN2 deficient mice had shorter seizure latencies, increased vulnerability to seizure-related death, were more likely to develop spontaneous recurrent seizure activity after chemical challenge, and had an increased slope on input/output curves. Principal cell counts were unchanged, but GABA, parvalbumin, and neuropeptide Y interneuron cell counts were significantly reduced. Synaptosomal NPN2 protein levels and total number of GABAergic synapses were decreased in a gene dose-dependent fashion. CA1 pyramidal cells showed reduced dendritic length and complexity, as well as an increased number of dendritic spines. Discussion These data suggest the novel hypothesis that the Sema 3F signaling system's role in appropriate placement of subsets of hippocampal interneurons has critical downstream consequences for hippocampal function, resulting in a more seizure susceptible phenotype. PMID:18657176

Intermittent Theta-Burst Transcranial Magnetic Stimulation Alters Electrical Properties of Fast-Spiking Neocortical Interneurons in an Age-Dependent Fashion

PubMed Central

Hoppenrath, Kathrin; Härtig, Wolfgang; Funke, Klaus

2016-01-01

Modulation of human cortical excitability by repetitive transcranial magnetic stimulation (rTMS) appears to be in part related to changed activity of inhibitory systems. Our own studies showed that intermittent theta-burst stimulation (iTBS) applied via rTMS to rat cortex primarily affects the parvalbumin-expressing (PV) fast-spiking interneurons (FSIs), evident via a strongly reduced PV expression. We further found the iTBS effect on PV to be age-dependent since no reduction in PV could be induced before the perineuronal nets (PNNs) of FSIs start to grow around postnatal day (PD) 30. To elucidate possible iTBS-induced changes in the electrical properties of FSIs and cortical network activity during cortical critical period, we performed ex vivo—in vitro whole-cell patch clamp recordings from pre-labeled FSIs in the current study. FSIs of verum iTBS-treated rats displayed a higher excitability than sham-treated controls at PD29–38, evident as higher rates of induced action potential firing at low current injections (100–200 pA) and a more depolarized resting membrane potential. This effect was absent in younger (PD26–28) and older animals (PD40–62). Slices of verum iTBS-treated rats further showed higher rates of spontaneous excitatory postsynaptic currents (sEPSCs). Based on these and previous findings we conclude that FSIs are particularly sensitive to TBS during early cortical development, when FSIs show an activity-driven step of maturation which is paralleled by intense growth of the PNNs and subsequent closure of the cortical critical period. Although to be proven further, rTMS may be a possible early intervention to compensate for hypo-activity related mal-development of cortical neuronal circuits. PMID:27065812

Intermittent Theta-Burst Transcranial Magnetic Stimulation Alters Electrical Properties of Fast-Spiking Neocortical Interneurons in an Age-Dependent Fashion.

PubMed

Hoppenrath, Kathrin; Härtig, Wolfgang; Funke, Klaus

2016-01-01

Modulation of human cortical excitability by repetitive transcranial magnetic stimulation (rTMS) appears to be in part related to changed activity of inhibitory systems. Our own studies showed that intermittent theta-burst stimulation (iTBS) applied via rTMS to rat cortex primarily affects the parvalbumin-expressing (PV) fast-spiking interneurons (FSIs), evident via a strongly reduced PV expression. We further found the iTBS effect on PV to be age-dependent since no reduction in PV could be induced before the perineuronal nets (PNNs) of FSIs start to grow around postnatal day (PD) 30. To elucidate possible iTBS-induced changes in the electrical properties of FSIs and cortical network activity during cortical critical period, we performed ex vivo-in vitro whole-cell patch clamp recordings from pre-labeled FSIs in the current study. FSIs of verum iTBS-treated rats displayed a higher excitability than sham-treated controls at PD29-38, evident as higher rates of induced action potential firing at low current injections (100-200 pA) and a more depolarized resting membrane potential. This effect was absent in younger (PD26-28) and older animals (PD40-62). Slices of verum iTBS-treated rats further showed higher rates of spontaneous excitatory postsynaptic currents (sEPSCs). Based on these and previous findings we conclude that FSIs are particularly sensitive to TBS during early cortical development, when FSIs show an activity-driven step of maturation which is paralleled by intense growth of the PNNs and subsequent closure of the cortical critical period. Although to be proven further, rTMS may be a possible early intervention to compensate for hypo-activity related mal-development of cortical neuronal circuits.

Hybrid systems analysis of the control of burst duration by low-voltage-activated calcium current in leech heart interneurons.

PubMed

Olypher, Andrey; Cymbalyuk, Gennady; Calabrese, Ronald L

2006-12-01

The leech heartbeat CPG is paced by the alternating bursting of pairs of mutually inhibitory heart interneurons that form elemental half-center oscillators. We explore the control of burst duration in heart interneurons using a hybrid system, where a living, pharmacologically isolated, heart interneuron is connected with artificial synapses to a model heart interneuron running in real-time, by focusing on a low-voltage-activated (LVA) calcium current I(CaS). The transition from silence to bursting in this half-center oscillator occurs when the spike frequency of the bursting interneuron declines to a critical level, f(Final), at which the inhibited interneuron escapes owing to a build-up of the hyperpolarization-activated cation current, I(h). We varied I(CaS) inactivation time constant either in the living heart interneuron or in the model heart interneuron. In both cases, varying I(CaS) inactivation time constant did not affect f(Final) of either interneuron, but in the varied interneuron, the time constant of decline of spike frequency during bursts to f(Final) and thus the burst duration varied directly and nearly linearly with I(CaS) inactivation time constant. Bursts of the opposite, nonvaried interneuron did not change. We show also that control of burst duration by I(CaS) inactivation does not require synaptic interaction by reconstituting autonomous bursting in synaptically isolated living interneurons with injected I(CaS). Therefore inactivation of LVA calcium current is critically important for setting burst duration and thus period in a heart interneuron half-center oscillator and is potentially a general intrinsic mechanism for regulating burst duration in neurons.

Targeted ablation of cholinergic interneurons in the dorsolateral striatum produces behavioral manifestations of Tourette syndrome

PubMed Central

Xu, Meiyu; Kobets, Andrew; Du, Jung-Chieh; Lennington, Jessica; Li, Lina; Banasr, Mounira; Duman, Ronald S.; Vaccarino, Flora M.; DiLeone, Ralph J.; Pittenger, Christopher

2015-01-01

Gilles de la Tourette syndrome (TS) is characterized by tics, which are transiently worsened by stress, acute administration of dopaminergic drugs, and by subtle deficits in motor coordination and sensorimotor gating. It represents the most severe end of a spectrum of tic disorders that, in aggregate, affect ∼5% of the population. Available treatments are frequently inadequate, and the pathophysiology is poorly understood. Postmortem studies have revealed a reduction in specific striatal interneurons, including the large cholinergic interneurons, in severe disease. We tested the hypothesis that this deficit is sufficient to produce aspects of the phenomenology of TS, using a strategy for targeted, specific cell ablation in mice. We achieved ∼50% ablation of the cholinergic interneurons of the striatum, recapitulating the deficit observed in patients postmortem, without any effect on GABAergic markers or on parvalbumin-expressing fast-spiking interneurons. Interneuron ablation in the dorsolateral striatum (DLS), corresponding roughly to the human putamen, led to tic-like stereotypies after either acute stress or d-amphetamine challenge; ablation in the dorsomedial striatum, in contrast, did not. DLS interneuron ablation also led to a deficit in coordination on the rotorod, but not to any abnormalities in prepulse inhibition, a measure of sensorimotor gating. These results support the causal sufficiency of cholinergic interneuron deficits in the DLS to produce some, but not all, of the characteristic symptoms of TS. PMID:25561540

Pupil fluctuations track fast switching of cortical states during quiet wakefulness

PubMed Central

Reimer, Jacob; Froudarakis, Emmanouil; Cadwell, Cathryn R.; Yatsenko, Dimitri; Denfield, George H.; Tolias, Andreas S.

2014-01-01

Neural responses are modulated by brain state, which varies with arousal, attention, and behavior. In mice, running and whisking desynchronize the cortex and enhance sensory responses, but the quiescent periods between bouts of exploratory behaviors have not been well-studied. We found that these periods of “quiet wakefulness” were characterized by state fluctuations on a timescale of 1–2 seconds. Small fluctuations in pupil diameter tracked these state transitions in multiple cortical areas. During dilation, the intracellular membrane potential was desynchronized, sensory responses were enhanced, and population activity was less correlated. In contrast, constriction was characterized by increased low-frequency oscillations and higher ensemble correlations. Specific subtypes of cortical interneurons were differentially activated during dilation and constriction, consistent with their participation in the observed state changes. Pupillometry has been used to index attention and mental effort in humans, but the intracellular dynamics and differences in population activity underlying this phenomenon were previously unknown. PMID:25374359

The paired domain-containing nuclear factor pax[b] is expressed in specific commissural interneurons in zebrafish embryos.

PubMed

Mikkola, I; Fjose, A; Kuwada, J Y; Wilson, S; Guddal, P H; Krauss, S

1992-10-01

The zebrafish paired box (Pax) genes are expressed in the early neural tube and are thought to be transcription factors that regulate the differentiation of cells in the central nervous system (CNS). The protein product of one of these Pax genes, pax[b], is detectable as a nuclear antigen in all the regions of the embryo that transcribe the gene including the posterior midbrain, the nephritic primordium, the Wolffian duct, the optic stalk, and, in specific neurons, in the hindbrain and spinal cord. The timing and pattern of axonal outgrowth by the early pax[b]-positive neurons suggest that they are the commissural secondary ascending (CoSA) interneurons in the spinal cord; the primary commissural interneurons (MiD2c and MiD3c) in hindbrain rhombomeres mi2 and mi3; and a previously unclassified set of commissural interneurons that we termed the commissural caudalrhombomere ascending (CoCaA) interneurons in the caudal hindbrain. In contrast, the Mauthner interneurons do not express pax[b] early in development. Shortly after the appearance of the first pax[b]-positive interneurons, additional nuclei adjacent to the first pax[b]-positive interneurons become pax[b] positive. This pattern of expression suggests that the pax[b] protein may be involved in determining the identity of specific commissural interneurons.

Presynaptic miniature GABAergic currents in developing interneurons.

PubMed

Trigo, Federico F; Bouhours, Brice; Rostaing, Philippe; Papageorgiou, George; Corrie, John E T; Triller, Antoine; Ogden, David; Marty, Alain

2010-04-29

Miniature synaptic currents have long been known to represent random transmitter release under resting conditions, but much remains to be learned about their nature and function in central synapses. In this work, we describe a new class of miniature currents ("preminis") that arise by the autocrine activation of axonal receptors following random vesicular release. Preminis are prominent in gabaergic synapses made by cerebellar interneurons during the development of the molecular layer. Unlike ordinary miniature postsynaptic currents in the same cells, premini frequencies are strongly enhanced by subthreshold depolarization, suggesting that the membrane depolarization they produce belongs to a feedback loop regulating neurotransmitter release. Thus, preminis could guide the formation of the interneuron network by enhancing neurotransmitter release at recently formed synaptic contacts. Copyright 2010 Elsevier Inc. All rights reserved.

Involvement of pre- and postsynaptic NMDA receptors at local circuit interneuron connections in rat neocortex

PubMed Central

De-May, C.L.; Ali, A.B.

2013-01-01

To investigate the involvement of N-Methyl-D-aspartate (NMDA) receptors in local neocortical synaptic transmission, dual whole-cell recordings – combined with biocytin labelling – were obtained from bitufted adapting, multipolar adapting or multipolar non-adapting interneurons and pyramidal cells in layers II–V of rat (postnatal days 17–22) sensorimotor cortex. The voltage dependency of the amplitude of Excitatory postsynaptic potentials (EPSPs) received by the three types of interneuron appeared to coincide with the interneuron subclass; upon depolarisation, EPSPs received by multipolar non-adapting interneurons either decreased in amplitude or appeared insensitive, multipolar adapting interneuron EPSP amplitudes increased or appeared insensitive, whereas bitufted interneuron EPSP amplitudes increased or decreased. Connections were challenged with the NMDA receptor antagonist d-(−)-2-amino-5-phosphonopentanoic acid (d-AP5) (50 μM) revealing NMDA receptors to contribute to EPSPs received by all cell types, this also abolished the non-conventional voltage dependency. Reciprocal connections were frequent between pyramidal cells and multipolar interneurons, and inhibitory postsynaptic potentials (IPSPs) elicited in pyramidal cells by both multipolar adapting and multipolar non-adapting interneurons were sensitive to a significant reduction in amplitude by d-AP5. The involvement of presynaptic NMDA receptors was indicated by coefficient of variation analysis and an increase in the failures of transmission. Furthermore, by loading MK-801 into the pre- or postsynaptic neurons, we observed that a reduction in inhibition requires presynaptic and not postsynaptic NMDA receptors. These results suggest that NMDA receptors possess pre- and postsynaptic roles at selective neocortical synapses that are probably important in governing spike-timing and information flow. PMID:23079623

Zebrafish CiA interneurons are late-born primary neurons.

PubMed

Yeo, Sang-Yeob

2009-12-11

Pax2 is a neural-related transcription factor downstream of Notch signaling and is expressed in the developing spinal cord of zebrafish, including in CiA interneurons. However, the characteristics of pax2-positive neurons are largely unknown. The goal of this study was to characterize Pax2-positive neurons by examining their expression in embryos in which Notch function had been knocked down by mutation or injection of a morpholino or mRNA. I found that Pax2-positive CiA interneurons were late-differentiating primary neurons. pax2.1 was expressed in CoPA commissural neurons and CiA interneurons at 26 hpf. The number of pax2.1-positive cells increased in mind bomb mutant embryos or embryos injected with Su(H)1-MO, but not in cells injected with Xenopus Delta or Delta(stu) mRNA. These observations imply that Notch signaling plays a role in regulating the number of CiA neurons by preventing uncommitted precursors from acquiring a neuronal fate during vertebrate development.

A potential inhibitory function of draxin in regulating mouse trunk neural crest migration.

PubMed

Zhang, Sanbing; Su, Yuhong; Gao, Jinbao; Zhang, Chenbing; Tanaka, Hideaki

2017-01-01

Draxin is a repulsive axon guidance protein that plays important roles in the formation of three commissures in the central nervous system and dorsal interneuron 3 (dI3) in the chick spinal cord. In the present study, we report the expression pattern of mouse draxin in the embryonic mouse trunk spinal cord. In the presence of draxin, the longest net migration length of a migrating mouse trunk neural crest cell was significantly reduced. In addition, the relative number of apolar neural crest cells increased as the draxin treatment time increased. Draxin caused actin cytoskeleton rearrangement in the migrating trunk neural crest cells. Our data suggest that draxin may regulate mouse trunk neural crest cell migration by the rearrangement of cell actin cytoskeleton and by reducing the polarization activity of these cells subsequently.

Role of glutamic acid decarboxylase 67 in regulating cortical parvalbumin and GABA membrane transporter 1 expression: implications for schizophrenia.

PubMed

Curley, Allison A; Eggan, Stephen M; Lazarus, Matt S; Huang, Z Josh; Volk, David W; Lewis, David A

2013-02-01

Markers of GABA neurotransmission are altered in multiple regions of the neocortex in individuals with schizophrenia. Lower levels of glutamic acid decarboxylase 67 (GAD67) mRNA and protein, which is responsible for most cortical GABA synthesis, are accompanied by lower levels of GABA membrane transporter 1 (GAT1) mRNA. These alterations are thought to be most prominent in the parvalbumin (PV)-containing subclass of interneurons, which also contain lower levels of PV mRNA. Since GAT1 and PV each reduce the availability of GABA at postsynaptic receptors, lower levels of GAT1 and PV mRNAs have been hypothesized to represent compensatory responses to an upstream reduction in cortical GABA synthesis in schizophrenia. However, such cause-and-effect hypotheses cannot be directly tested in a human illness. Consequently, we used two mouse models with reduced GAD67 expression specifically in PV neurons (PV(GAD67+/-)) or in all interneurons (GABA(GAD67+/-)) and quantified GAD67, GAT1 and PV mRNA levels using methods identical to those employed in studies of schizophrenia. Cortical levels of PV or GAT1 mRNAs were not altered in PV(GAD67+/-) mice during postnatal development or in adulthood. Furthermore, cellular analyses confirmed the predicted reduction in GAD67 mRNA, but failed to show a deficit in PV mRNA in these animals. Levels of PV and GAT1 mRNAs were also unaltered in GABA(GAD67+/-) mice. Thus, mouse lines with cortical reductions in GAD67 mRNA that match or exceed those present in schizophrenia, and that differ in the developmental timing and cell type-specificity of the GAD67 deficit, failed to provide proof-of-concept evidence that lower PV and GAT1 expression in schizophrenia are a consequence of lower GAD67 expression. Together, these findings suggest that the correlated decrements in cortical GAD67, PV and GAT1 mRNAs in schizophrenia may be a common consequence of some other upstream factor. Copyright © 2012 Elsevier Inc. All rights reserved.

MGE-derived nNOS+ interneurons promote fear acquisition in nNOS-/- mice.

PubMed

Zhang, Lin; Yuan, Hong-Jin; Cao, Bo; Kong, Cheng-Cheng; Yuan, Fang; Li, Jun; Ni, Huan-Yu; Wu, Hai-Yin; Chang, Lei; Liu, Yan; Luo, Chun-Xia

2017-12-02

Neuronal nitric oxide synthase (nNOS) 1 , mainly responsible for NO release in central nervous system (CNS) 2 , plays a significant role in multiple physiological functions. However, the function of nNOS + interneurons in fear learning has not been much explored. Here we focused on the medial ganglionic eminences (MGE) 3 -derived nNOS + interneurons in fear learning. To determine the origin of nNOS + interneurons, we cultured neurons in vitro from MGE, cortex, lateral ganglionic eminence (LGE) 4 , caudal ganglionic eminences (CGE) 5 and preoptic area (POA) 6 . The results showed that MGE contained the most abundant precursors of nNOS + interneurons. Moreover, donor cells from E12.5 embryos demonstrated the highest positive rate of nNOS + interneurons compared with other embryonic periods (E11.5, E12, E13, E13.5 and E14). Additionally, these cells from E12.5 embryos showed long axonal and abundant dendritic arbors after 10 days culture, indicating the capability to disperse and integrate in host neural circuits after transplantation. To investigate the role of MGE-derived nNOS + interneurons in fear learning, donor MGE cells were transplanted into dentate gyrus (DG) 7 of nNOS knock-out (nNOS -/- ) or wild-type mice. Results showed that the transplantation of MGE cells promoted the acquisition of nNOS -/- but not the wild-type mice, suggesting the importance of nNOS + neurons in fear acquisition. Moreover, we transplanted MGE cells from nNOS -/- mice or wild-type mice into DG of the nNOS -/- mice and found that only MGE cells from wild-type mice but not the nNOS -/- mice rescued the deficit in acquisition of the nNOS -/- mice, further confirming the positive role of nNOS + neurons in fear learning. Copyright © 2017 Elsevier Inc. All rights reserved.

Differential binding of antibodies in PANDAS patients to cholinergic interneurons in the striatum.

PubMed

Frick, Luciana R; Rapanelli, Maximiliano; Jindachomthong, Kantiya; Grant, Paul; Leckman, James F; Swedo, Susan; Williams, Kyle; Pittenger, Christopher

2018-03-01

Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus, or PANDAS, is a syndrome of acute childhood onset of obsessive-compulsive disorder and other neuropsychiatric symptoms in the aftermath of an infection with Group A beta-hemolytic Streptococcus (GABHS). Its pathophysiology remains unclear. PANDAS has been proposed to result from cross-reactivity of antibodies raised against GABHS with brain antigens, but the targets of these antibodies are unclear and may be heterogeneous. We developed an in vivo assay in mice to characterize the cellular targets of antibodies in serum from individuals with PANDAS. We focus on striatal interneurons, which have been implicated in the pathogenesis of tic disorders. Sera from children with well-characterized PANDAS (n = 5) from a previously described clinical trial (NCT01281969), and matched controls, were infused into the striatum of mice; antibody binding to interneurons was characterized using immunofluorescence and confocal microscopy. Antibodies from children with PANDAS bound to ∼80% of cholinergic interneurons, significantly higher than the <50% binding seen with matched healthy controls. There was no elevated binding to two different populations of GABAergic interneurons (PV and nNOS-positive), confirming the specificity of this phenomenon. Elevated binding to cholinergic interneurons resolved in parallel with symptom improvement after treatment with intravenous immunoglobulin. Antibody-mediated dysregulation of striatal cholinergic interneurons may be a locus of pathology in PANDAS. Future clarification of the functional consequences of this specific binding may identify new opportunities for intervention in children with this condition. Copyright © 2017 Elsevier Inc. All rights reserved.

Effects of stimulation of phrenic afferents on cervical respiratory interneurones and phrenic motoneurones in cats.

PubMed Central

Iscoe, S; Duffin, J

1996-01-01

1. In ten decerebrate, paralysed and ventilated cats, we tested the hypothesis that cervical (C5) respiratory interneurones mediate inhibition of phrenic motoneurone activity resulting from single shocks to the phrenic nerve. 2. Stimulus intensities sufficient to activate all afferents elicited (latency, 4.0 +/- 0.9 ms, mean +/- S.D.) a graded suppression of ipsilateral, but not contralateral (five of seven cats) phrenic nerve activity lasting, in six of seven cats, more than 70 ms and interrupted by a brief (approximately 6-18 ms duration) excitation at latencies between 7 and 30 ms. 3. In twenty-five ipsilateral motoneurones, peristimulus time average of the membrane potentials (-61 +/- 10 mV) showed no effect in eleven; of the fourteen that responded, ten had initial EPSPs (latency, 17.6 +/- 3.0 ms) and four initial IPSPs (latencies, 2.25-4.3 ms). Only one motoneurone had both. No responses with latencies > 60 ms were observed. 4. Peristimulus time averages of extracellular activity of thirty ipsilateral interneurones, twenty-five firing in inspiration (I) and five in expiration (E), showed diverse responses. The initial response of I interneurones was an excitation in eleven, a suppression of activity in nine, and no response in five. Latencies of excitations ranged from 2 to 36.5 ms (median, 14 ms) with durations ranging from 2 to 7 ms (mean, 4.4 +/- 1.6 ms). Latencies of suppression of activity ranged from 2 to 29 ms (median, 10 ms). Two E interneurones were excited (latencies, 11 and 15 ms; durations, 3.5 and 2 ms), two inhibited (latencies, 2 and 12 ms; durations, > 40 and 17 ms, respectively), and one did not respond. 5. In nine interneurones (seven I, two E), peristimulus time averages of the membrane potentials (mean, -62 +/- 14 mV) revealed no effect on three (all I). Of the six that responded, four (three I) had initial IPSPs, two (one I, one E) initial EPSPs. EPSPs had latencies of 11.5 (I interneurone) and 22 ms (E interneurone); the latencies of the

Classifying GABAergic interneurons with semi-supervised projected model-based clustering.

PubMed

Mihaljević, Bojan; Benavides-Piccione, Ruth; Guerra, Luis; DeFelipe, Javier; Larrañaga, Pedro; Bielza, Concha

2015-09-01

A recently introduced pragmatic scheme promises to be a useful catalog of interneuron names. We sought to automatically classify digitally reconstructed interneuronal morphologies according to this scheme. Simultaneously, we sought to discover possible subtypes of these types that might emerge during automatic classification (clustering). We also investigated which morphometric properties were most relevant for this classification. A set of 118 digitally reconstructed interneuronal morphologies classified into the common basket (CB), horse-tail (HT), large basket (LB), and Martinotti (MA) interneuron types by 42 of the world's leading neuroscientists, quantified by five simple morphometric properties of the axon and four of the dendrites. We labeled each neuron with the type most commonly assigned to it by the experts. We then removed this class information for each type separately, and applied semi-supervised clustering to those cells (keeping the others' cluster membership fixed), to assess separation from other types and look for the formation of new groups (subtypes). We performed this same experiment unlabeling the cells of two types at a time, and of half the cells of a single type at a time. The clustering model is a finite mixture of Gaussians which we adapted for the estimation of local (per-cluster) feature relevance. We performed the described experiments on three different subsets of the data, formed according to how many experts agreed on type membership: at least 18 experts (the full data set), at least 21 (73 neurons), and at least 26 (47 neurons). Interneurons with more reliable type labels were classified more accurately. We classified HT cells with 100% accuracy, MA cells with 73% accuracy, and CB and LB cells with 56% and 58% accuracy, respectively. We identified three subtypes of the MA type, one subtype of CB and LB types each, and no subtypes of HT (it was a single, homogeneous type). We got maximum (adapted) Silhouette width and ARI values of

Transcriptional Networks Controlled by NKX2-1 in the Development of Forebrain GABAergic Neurons

DOE PAGES

Sandberg, Magnus; Flandin, Pierre; Silberberg, Shanni; ...

2016-09-21

The embryonic basal ganglia generates multiple projection neurons and interneuron subtypes from distinct progenitor domains. Combinatorial interactions of transcription factors and chromatin are thought to regulate gene expression. In the medial ganglionic eminence, the NKX2-1 transcription factor controls regional identity and, with LHX6, is necessary to specify pallidal projection neurons and forebrain interneurons. Here, we dissected the molecular functions of NKX2-1 by defining its chromosomal binding, regulation of gene expression, and epigenetic state. NKX2-1 binding at distal regulatory elements led to a repressed epigenetic state and transcriptional repression in the ventricular zone. Conversely, NKX2-1 is required to establish a permissivemore » chromatin state and transcriptional activation in the sub-ventricular and mantle zones. Moreover, combinatorial binding of NKX2-1 and LHX6 promotes transcriptionally permissive chromatin and activates genes expressed in cortical migrating interneurons. Our integrated approach gives a foundation for elucidating transcriptional networks guiding the development of the MGE and its descendants.« less

Anatomical and Electrophysiological Changes in Striatal TH Interneurons after Loss of the Nigrostriatal Dopaminergic Pathway

PubMed Central

Ünal, Bengi; Shah, Fulva; Kothari, Janish; Tepper, James M.

2013-01-01

Using transgenic mice that express enhanced green fluorescent protein (EGFP) under the control of the tyrosine hydroxylase (TH) promoter, we have previously shown that there are approximately 3000 striatal EGFP-TH interneurons per hemisphere in mice. Here we report that striatal TH-EGFP interneurons exhibit a small, transient but significant increase in number after unilateral destruction of the nigrostriatal dopaminergic pathway. The increase in cell number is accompanied by electrophysiological and morphological changes. The intrinsic electrophysiological properties of EGFP-TH interneurons ipsilateral to 6-OHDA lesion were similar to those originally reported in intact mice except for a significant reduction in the duration of a characteristic depolarization induced plateau potential. There was a significant change in the distribution of the four previously described electrophysiologically distinct subtypes of striatal TH interneurons. There was a concomitant increase in the frequency of both spontaneous excitatory and inhibitory postsynaptic currents, while their amplitudes did not change. Nigrostriatal lesions did not affect somatic size or dendritic length or branching, but resulted in an increase in the density of proximal dendritic spines and spine-like appendages in EGFP-TH interneurons. The changes indicate that electrophysiology properties and morphology of striatal EGFP-TH interneurons depend on endogenous levels of dopamine arising from the nigrostriatal pathway. Furthermore, these changes may serve to help compensate for the changes in activity of spiny projection neurons that occur following loss of the nigrostriatal innervation in experimental or in early idiopathic Parkinson’s disease by increasing feedforward GABAergic inhibition exerted by these interneurons. PMID:24173616

Anatomical and electrophysiological changes in striatal TH interneurons after loss of the nigrostriatal dopaminergic pathway.

PubMed

Ünal, Bengi; Shah, Fulva; Kothari, Janish; Tepper, James M

2015-01-01

Using transgenic mice that express enhanced green fluorescent protein (EGFP) under the control of the tyrosine hydroxylase (TH) promoter, we have previously shown that there are approximately 3,000 striatal EGFP-TH interneurons per hemisphere in mice. Here, we report that striatal TH-EGFP interneurons exhibit a small, transient but significant increase in number after unilateral destruction of the nigrostriatal dopaminergic pathway. The increase in cell number is accompanied by electrophysiological and morphological changes. The intrinsic electrophysiological properties of EGFP-TH interneurons ipsilateral to 6-OHDA lesion were similar to those originally reported in intact mice except for a significant reduction in the duration of a characteristic depolarization induced plateau potential. There was a significant change in the distribution of the four previously described electrophysiologically distinct subtypes of striatal TH interneurons. There was a concomitant increase in the frequency of both spontaneous excitatory and inhibitory post-synaptic currents, while their amplitudes did not change. Nigrostriatal lesions did not affect somatic size or dendritic length or branching, but resulted in an increase in the density of proximal dendritic spines and spine-like appendages in EGFP-TH interneurons. The changes indicate that electrophysiology properties and morphology of striatal EGFP-TH interneurons depend on endogenous levels of dopamine arising from the nigrostriatal pathway. Furthermore, these changes may serve to help compensate for the changes in activity of spiny projection neurons that occur following loss of the nigrostriatal innervation in experimental or in early idiopathic Parkinson's disease by increasing feedforward GABAergic inhibition exerted by these interneurons.

Striatal Cholinergic Interneurons Modulate Spike-Timing in Striosomes and Matrix by an Amphetamine-Sensitive Mechanism

PubMed Central

Crittenden, Jill R.; Lacey, Carolyn J.; Weng, Feng-Ju; Garrison, Catherine E.; Gibson, Daniel J.; Lin, Yingxi; Graybiel, Ann M.

2017-01-01

The striatum is key for action-selection and the motivation to move. Dopamine and acetylcholine release sites are enriched in the striatum and are cross-regulated, possibly to achieve optimal behavior. Drugs of abuse, which promote abnormally high dopamine release, disrupt normal action-selection and drive restricted, repetitive behaviors (stereotypies). Stereotypies occur in a variety of disorders including obsessive-compulsive disorder, autism, schizophrenia and Huntington's disease, as well as in addictive states. The severity of drug-induced stereotypy is correlated with induction of c-Fos expression in striosomes, a striatal compartment that is related to the limbic system and that directly projects to dopamine-producing neurons of the substantia nigra. These characteristics of striosomes contrast with the properties of the extra-striosomal matrix, which has strong sensorimotor and associative circuit inputs and outputs. Disruption of acetylcholine signaling in the striatum blocks the striosome-predominant c-Fos expression pattern induced by drugs of abuse and alters drug-induced stereotypy. The activity of striatal cholinergic interneurons is associated with behaviors related to sensory cues, and cortical inputs to striosomes can bias action-selection in the face of conflicting cues. The neurons and neuropil of striosomes and matrix neurons have observably separate distributions, both at the input level in the striatum and at the output level in the substantia nigra. Notably, cholinergic axons readily cross compartment borders, providing a potential route for local cross-compartment communication to maintain a balance between striosomal and matrix activity. We show here, by slice electrophysiology in transgenic mice, that repetitive evoked firing patterns in striosomal and matrix striatal projection neurons (SPNs) are interrupted by optogenetic activation of cholinergic interneurons either by the addition or the deletion of spikes. We demonstrate that this

Potentiation of NMDA receptor-mediated transmission in striatal cholinergic interneurons

PubMed Central

Oswald, Manfred J.; Schulz, Jan M.; Kelsch, Wolfgang; Oorschot, Dorothy E.; Reynolds, John N. J.

2015-01-01

Pauses in the tonic firing of striatal cholinergic interneurons (CINs) emerge during reward-related learning in response to conditioning of a neutral cue. We have previously reported that augmenting the postsynaptic response to cortical afferents in CINs is coupled to the emergence of a cell-intrinsic afterhyperpolarization (AHP) underlying pauses in tonic activity. Here we investigated in a bihemispheric rat-brain slice preparation the mechanisms of synaptic plasticity of excitatory afferents to CINs and the association with changes in the AHP. We found that high frequency stimulation (HFS) of commissural corticostriatal afferents from the contralateral hemisphere induced a robust long-term depression (LTD) of postsynaptic potentials (PSP) in CINs. Depression of the PSP of smaller magnitude and duration was observed in response to HFS of the ipsilateral white matter or cerebral cortex. In Mg2+-free solution HFS induced NMDA receptor-dependent potentiation of the PSP, evident in both the maximal slope and amplitude of the PSP. The increase in maximal slope corroborates previous findings, and was blocked by antagonism of either D1-like dopamine receptors with SCH23390 or D2-like dopamine receptors with sulpiride during HFS in Mg2+-free solution. Potentiation of the slower PSP amplitude component was due to augmentation of the NMDA receptor-mediated potential as this was completely reversed on subsequent application of the NMDA receptor antagonist AP5. HFS similarly potentiated NMDA receptor currents isolated by blockade of AMPA/kainate receptors with CNQX. The plasticity-induced increase in the slow PSP component was directly associated with an increase in the subsequent AHP. Thus plasticity of cortical afferent synapses is ideally suited to influence the cue-induced firing dynamics of CINs, particularly through potentiation of NMDA receptor-mediated synaptic transmission. PMID:25914618

Potentiation of NMDA receptor-mediated transmission in striatal cholinergic interneurons.

PubMed

Oswald, Manfred J; Schulz, Jan M; Kelsch, Wolfgang; Oorschot, Dorothy E; Reynolds, John N J

2015-01-01

Pauses in the tonic firing of striatal cholinergic interneurons (CINs) emerge during reward-related learning in response to conditioning of a neutral cue. We have previously reported that augmenting the postsynaptic response to cortical afferents in CINs is coupled to the emergence of a cell-intrinsic afterhyperpolarization (AHP) underlying pauses in tonic activity. Here we investigated in a bihemispheric rat-brain slice preparation the mechanisms of synaptic plasticity of excitatory afferents to CINs and the association with changes in the AHP. We found that high frequency stimulation (HFS) of commissural corticostriatal afferents from the contralateral hemisphere induced a robust long-term depression (LTD) of postsynaptic potentials (PSP) in CINs. Depression of the PSP of smaller magnitude and duration was observed in response to HFS of the ipsilateral white matter or cerebral cortex. In Mg(2+)-free solution HFS induced NMDA receptor-dependent potentiation of the PSP, evident in both the maximal slope and amplitude of the PSP. The increase in maximal slope corroborates previous findings, and was blocked by antagonism of either D1-like dopamine receptors with SCH23390 or D2-like dopamine receptors with sulpiride during HFS in Mg(2+)-free solution. Potentiation of the slower PSP amplitude component was due to augmentation of the NMDA receptor-mediated potential as this was completely reversed on subsequent application of the NMDA receptor antagonist AP5. HFS similarly potentiated NMDA receptor currents isolated by blockade of AMPA/kainate receptors with CNQX. The plasticity-induced increase in the slow PSP component was directly associated with an increase in the subsequent AHP. Thus plasticity of cortical afferent synapses is ideally suited to influence the cue-induced firing dynamics of CINs, particularly through potentiation of NMDA receptor-mediated synaptic transmission.

Structural-Functional Properties of Identified Excitatory and Inhibitory Interneurons within Pre-Bötzinger Complex Respiratory Microcircuits

PubMed Central

Koizumi, Hidehiko; Koshiya, Naohiro; Chia, Justine X.; Cao, Fang; Nugent, Joseph; Zhang, Ruli

2013-01-01

We comparatively analyzed cellular and circuit properties of identified rhythmic excitatory and inhibitory interneurons within respiratory microcircuits of the neonatal rodent pre-Bötzinger complex (pre-BötC), the structure generating inspiratory rhythm in the brainstem. We combined high-resolution structural–functional imaging, molecular assays for neurotransmitter phenotype identification in conjunction with electrophysiological property phenotyping, and morphological reconstruction of interneurons in neonatal rat and mouse slices in vitro. This approach revealed previously undifferentiated structural–functional features that distinguish excitatory and inhibitory interneuronal populations. We identified distinct subpopulations of pre-BötC glutamatergic, glycinergic, GABAergic, and glycine-GABA coexpressing interneurons. Most commissural pre-BötC inspiratory interneurons were glutamatergic, with a substantial subset exhibiting intrinsic oscillatory bursting properties. Commissural excitatory interneurons projected with nearly planar trajectories to the contralateral pre-BötC, many also with axon collaterals to areas containing inspiratory hypoglossal (XII) premotoneurons and motoneurons. Inhibitory neurons as characterized in the present study did not exhibit intrinsic oscillatory bursting properties, but were electrophysiologically distinguished by more pronounced spike frequency adaptation properties. Axons of many inhibitory neurons projected ipsilaterally also to regions containing inspiratory XII premotoneurons and motoneurons, whereas a minority of inhibitory neurons had commissural axonal projections. Dendrites of both excitatory and inhibitory interneurons were arborized asymmetrically, primarily in the coronal plane. The dendritic fields of inhibitory neurons were more spatially compact than those of excitatory interneurons. Our results are consistent with the concepts of a compartmental circuit organization, a bilaterally coupled excitatory

Long-term Reductions in the Population of GABAergic Interneurons in the Mouse Hippocampus following Developmental Ethanol Exposure.

PubMed

Bird, Clark W; Taylor, Devin H; Pinkowski, Natalie J; Chavez, G Jill; Valenzuela, C Fernando

2018-07-15

Developmental exposure to ethanol leads to a constellation of cognitive and behavioral abnormalities known as Fetal Alcohol Spectrum Disorders (FASDs). Many cell types throughout the central nervous system are negatively impacted by gestational alcohol exposure, including inhibitory, GABAergic interneurons. Little evidence exists, however, describing the long-term impact of fetal alcohol exposure on survival of interneurons within the hippocampal formation, which is critical for learning and memory processes that are impaired in individuals with FASDs. Mice expressing Venus yellow fluorescent protein in inhibitory interneurons were exposed to vaporized ethanol during the third trimester equivalent of human gestation (postnatal days 2-9), and the long-term effects on interneuron numbers were measured using unbiased stereology at P90. In adulthood, interneuron populations were reduced in every hippocampal region examined. Moreover, we found that a single exposure to ethanol at P7 caused robust activation of apoptotic neurodegeneration of interneurons in the hilus, granule cell layer, CA1 and CA3 regions of the hippocampus. These studies demonstrate that developmental ethanol exposure has a long-term impact on hippocampal interneuron survivability, and may provide a mechanism partially explaining deficits in hippocampal function and hippocampus-dependent behaviors in those afflicted with FASDs. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

Gamma rhythms link prefrontal interneuron dysfunction with cognitive inflexibility in Dlx5/6+/− mice

PubMed Central

Cho, Kathleen K.A.; Hoch, Renee; Lee, Anthony T.; Patel, Tosha; Rubenstein, John L.R.; Sohal, Vikaas S.

2015-01-01

SUMMARY Abnormalities in GABAergic interneurons, particularly fast-spiking interneurons (FSINs) that generate gamma (γ; ~30-120 Hz) oscillations, are hypothesized to disrupt prefrontal cortex (PFC)-dependent cognition in schizophrenia. Although γ rhythms are abnormal in schizophrenia, it remains unclear whether they directly influence cognition. Mechanisms underlying schizophrenia's typical post-adolescent onset also remain elusive. We addressed these issues using mice heterozygous for Dlx5/6, which regulate GABAergic interneuron development. In Dlx5/6+/− mice, FSINs become abnormal following adolescence, coinciding with the onset of cognitive inflexibility and deficient task-evoked γ oscillations. Inhibiting PFC interneurons in control mice reproduced these deficits, whereas stimulating them at γ-frequencies restored cognitive flexibility in adult Dlx5/6+/− mice. These pro-cognitive effects were frequency-specific and persistent. These findings elucidate a mechanism whereby abnormal FSIN development may contribute to the post-adolescent onset of schizophrenia endophenotypes. Furthermore, they demonstrate a causal, potentially therapeutic, role for PFC interneuron-driven gamma oscillations in cognitive domains at the core of schizophrenia. PMID:25754826

Spinal microcircuits comprising dI3 interneurons are necessary for motor functional recovery following spinal cord transection

PubMed Central

Bui, Tuan V; Stifani, Nicolas; Akay, Turgay; Brownstone, Robert M

2016-01-01

The spinal cord has the capacity to coordinate motor activities such as locomotion. Following spinal transection, functional activity can be regained, to a degree, following motor training. To identify microcircuits involved in this recovery, we studied a population of mouse spinal interneurons known to receive direct afferent inputs and project to intermediate and ventral regions of the spinal cord. We demonstrate that while dI3 interneurons are not necessary for normal locomotor activity, locomotor circuits rhythmically inhibit them and dI3 interneurons can activate these circuits. Removing dI3 interneurons from spinal microcircuits by eliminating their synaptic transmission left locomotion more or less unchanged, but abolished functional recovery, indicating that dI3 interneurons are a necessary cellular substrate for motor system plasticity following transection. We suggest that dI3 interneurons compare inputs from locomotor circuits with sensory afferent inputs to compute sensory prediction errors that then modify locomotor circuits to effect motor recovery. DOI: http://dx.doi.org/10.7554/eLife.21715.001 PMID:27977000

Selective Reduction of AMPA Currents onto Hippocampal Interneurons Impairs Network Oscillatory Activity

PubMed Central

Le Magueresse, Corentin; Monyer, Hannah

2012-01-01

Reduction of excitatory currents onto GABAergic interneurons in the forebrain results in impaired spatial working memory and altered oscillatory network patterns in the hippocampus. Whether this phenotype is caused by an alteration in hippocampal interneurons is not known because most studies employed genetic manipulations affecting several brain regions. Here we performed viral injections in genetically modified mice to ablate the GluA4 subunit of the AMPA receptor in the hippocampus (GluA4HC−/− mice), thereby selectively reducing AMPA receptor-mediated currents onto a subgroup of hippocampal interneurons expressing GluA4. This regionally selective manipulation led to a strong spatial working memory deficit while leaving reference memory unaffected. Ripples (125–250 Hz) in the CA1 region of GluA4HC−/− mice had larger amplitude, slower frequency and reduced rate of occurrence. These changes were associated with an increased firing rate of pyramidal cells during ripples. The spatial selectivity of hippocampal pyramidal cells was comparable to that of controls in many respects when assessed during open field exploration and zigzag maze running. However, GluA4 ablation caused altered modulation of firing rate by theta oscillations in both interneurons and pyramidal cells. Moreover, the correlation between the theta firing phase of pyramidal cells and position was weaker in GluA4HC−/− mice. These results establish the involvement of AMPA receptor-mediated currents onto hippocampal interneurons for ripples and theta oscillations, and highlight potential cellular and network alterations that could account for the altered working memory performance. PMID:22675480

Terminal Field and Firing Selectivity of Cholecystokinin-Expressing Interneurons in the Hippocampal CA3 Area

PubMed Central

Lasztóczi, Bálint; Tukker, John J.; Somogyi, Peter; Klausberger, Thomas

2015-01-01

Hippocampal oscillations reflect coordinated neuronal activity on many timescales. Distinct types of GABAergic interneuron participate in the coordination of pyramidal cells over different oscillatory cycle phases. In the CA3 area, which generates sharp waves and gamma oscillations, the contribution of identified GABAergic neurons remains to be defined. We have examined the firing of a family of cholecystokinin-expressing interneurons during network oscillations in urethane-anesthetized rats and compared them with firing of CA3 pyramidal cells. The position of the terminals of individual visualized interneurons was highly diverse, selective, and often spatially coaligned with either the entorhinal or the associational inputs to area CA3. The spike timing in relation to theta and gamma oscillations and sharp waves was correlated with the innervated pyramidal cell domain. Basket and dendritic-layer-innervating interneurons receive entorhinal and associational inputs and preferentially fire on the ascending theta phase, when pyramidal cell assemblies emerge. Perforant-path-associated cells, driven by recurrent collaterals of pyramidal cells fire on theta troughs, when established pyramidal cell assemblies are most active. In the CA3 area, slow and fast gamma oscillations occurred on opposite theta oscillation phases. Perforant-path-associated and some COUP-TFII-positive interneurons are strongly coupled to both fast and slow gamma oscillations, but basket and dendritic-layer-innervating cells are weakly coupled to fast gamma oscillations only. During sharp waves, different interneuron types are activated, inhibited, or remain unaffected. We suggest that specialization in pyramidal cell domain and glutamatergic input-specific operations, reflected in the position of GABAergic terminals, is the evolutionary drive underlying the diversity of cholecystokinin-expressing interneurons. PMID:22159120

Even-Skipped(+) Interneurons Are Core Components of a Sensorimotor Circuit that Maintains Left-Right Symmetric Muscle Contraction Amplitude.

PubMed

Heckscher, Ellie S; Zarin, Aref Arzan; Faumont, Serge; Clark, Matthew Q; Manning, Laurina; Fushiki, Akira; Schneider-Mizell, Casey M; Fetter, Richard D; Truman, James W; Zwart, Maarten F; Landgraf, Matthias; Cardona, Albert; Lockery, Shawn R; Doe, Chris Q

2015-10-21

Bilaterally symmetric motor patterns--those in which left-right pairs of muscles contract synchronously and with equal amplitude (such as breathing, smiling, whisking, and locomotion)--are widespread throughout the animal kingdom. Yet, surprisingly little is known about the underlying neural circuits. We performed a thermogenetic screen to identify neurons required for bilaterally symmetric locomotion in Drosophila larvae and identified the evolutionarily conserved Even-skipped(+) interneurons (Eve/Evx). Activation or ablation of Eve(+) interneurons disrupted bilaterally symmetric muscle contraction amplitude, without affecting the timing of motor output. Eve(+) interneurons are not rhythmically active and thus function independently of the locomotor CPG. GCaMP6 calcium imaging of Eve(+) interneurons in freely moving larvae showed left-right asymmetric activation that correlated with larval behavior. TEM reconstruction of Eve(+) interneuron inputs and outputs showed that the Eve(+) interneurons are at the core of a sensorimotor circuit capable of detecting and modifying body wall muscle contraction. Copyright © 2015 Elsevier Inc. All rights reserved.

Even-skipped+ interneurons are core components of a sensorimotor circuit that maintains left-right symmetric muscle contraction amplitude

PubMed Central

Heckscher, Ellie S.; Zarin, Aref Arzan; Faumont, Serge; Clark, Matthew Q.; Manning, Laurina; Fushiki, Akira; Schneider-Mizel, Casey M.; Fetter, Richard D.; Truman, James W.; Zwart, Maarten F.; Landgraf, Matthias; Cardona, Albert; Lockery, Shawn R.; Doe, Chris Q.

2015-01-01

Summary Bilaterally symmetric motor patterns—those in which left-right pairs of muscles contract synchronously and with equal amplitude (such as breathing, smiling, whisking, locomotion)—are widespread throughout the animal kingdom. Yet surprisingly little is known about the underlying neural circuits. We performed a thermogenetic screen to identify neurons required for bilaterally symmetric locomotion in Drosophila larvae, and identified the evolutionarily-conserved Even-skipped+ interneurons (Eve/Evx). Activation or ablation of Eve+ interneurons disrupted bilaterally symmetric muscle contraction amplitude, without affecting the timing of motor output. Eve+ interneurons are not rhythmically active, and thus function independently of the locomotor CPG. GCaMP6 calcium imaging of Eve+ interneurons in freely-moving larvae showed left-right asymmetric activation that correlated with larval behavior. TEM reconstruction of Eve+ interneuron inputs and outputs showed that the Eve+ interneurons are at the core of a sensorimotor circuit capable of detecting and modifying body wall muscle contraction. PMID:26439528

A Subtype of Olfactory Bulb Interneurons Is Required for Odor Detection and Discrimination Behaviors.

PubMed

Takahashi, Hiroo; Ogawa, Yoichi; Yoshihara, Sei-Ichi; Asahina, Ryo; Kinoshita, Masahito; Kitano, Tatsuro; Kitsuki, Michiko; Tatsumi, Kana; Okuda, Mamiko; Tatsumi, Kouko; Wanaka, Akio; Hirai, Hirokazu; Stern, Peter L; Tsuboi, Akio

2016-08-03

Neural circuits that undergo reorganization by newborn interneurons in the olfactory bulb (OB) are necessary for odor detection and discrimination, olfactory memory, and innate olfactory responses, including predator avoidance and sexual behaviors. The OB possesses many interneurons, including various types of granule cells (GCs); however, the contribution that each type of interneuron makes to olfactory behavioral control remains unknown. Here, we investigated the in vivo functional role of oncofetal trophoblast glycoprotein 5T4, a regulator for dendritic arborization of 5T4-expressing GCs (5T4 GCs), the level of which is reduced in the OB of 5T4 knock-out (KO) mice. Electrophysiological recordings with acute OB slices indicated that external tufted cells (ETCs) can be divided into two types, bursting and nonbursting. Optogenetic stimulation of 5T4 GCs revealed their connection to both bursting and nonbursting ETCs, as well as to mitral cells (MCs). Interestingly, nonbursting ETCs received fewer inhibitory inputs from GCs in 5T4 KO mice than from those in wild-type (WT) mice, whereas bursting ETCs and MCs received similar inputs in both mice. Furthermore, 5T4 GCs received significantly fewer excitatory inputs in 5T4 KO mice. Remarkably, in olfactory behavior tests, 5T4 KO mice had higher odor detection thresholds than the WT, as well as defects in odor discrimination learning. Therefore, the loss of 5T4 attenuates inhibitory inputs from 5T4 GCs to nonbursting ETCs and excitatory inputs to 5T4 GCs, contributing to disturbances in olfactory behavior. Our novel findings suggest that, among the various types of OB interneurons, the 5T4 GC subtype is required for odor detection and discrimination behaviors. Neuronal circuits in the brain include glutamatergic principal neurons and GABAergic interneurons. Although the latter is a minority cell type, they are vital for normal brain function because they regulate the activity of principal neurons. If interneuron function

Cholinergic systems are essential for late-stage maturation and refinement of motor cortical circuits

PubMed Central

Ramanathan, Dhakshin S.; Conner, James M.; Anilkumar, Arjun A.

2014-01-01

Previous studies reported that early postnatal cholinergic lesions severely perturb early cortical development, impairing neuronal cortical migration and the formation of cortical dendrites and synapses. These severe effects of early postnatal cholinergic lesions preclude our ability to understand the contribution of cholinergic systems to the later-stage maturation of topographic cortical representations. To study cholinergic mechanisms contributing to the later maturation of motor cortical circuits, we first characterized the temporal course of cortical motor map development and maturation in rats. In this study, we focused our attention on the maturation of cortical motor representations after postnatal day 25 (PND 25), a time after neuronal migration has been accomplished and cortical volume has reached adult size. We found significant maturation of cortical motor representations after this time, including both an expansion of forelimb representations in motor cortex and a shift from proximal to distal forelimb representations to an extent unexplainable by simple volume enlargement of the neocortex. Specific cholinergic lesions placed at PND 24 impaired enlargement of distal forelimb representations in particular and markedly reduced the ability to learn skilled motor tasks as adults. These results identify a novel and essential role for cholinergic systems in the late refinement and maturation of cortical circuits. Dysfunctions in this system may constitute a mechanism of late-onset neurodevelopmental disorders such as Rett syndrome and schizophrenia. PMID:25505106

Lack of Cdkl5 Disrupts the Organization of Excitatory and Inhibitory Synapses and Parvalbumin Interneurons in the Primary Visual Cortex.

PubMed

Pizzo, Riccardo; Gurgone, Antonia; Castroflorio, Enrico; Amendola, Elena; Gross, Cornelius; Sassoè-Pognetto, Marco; Giustetto, Maurizio

2016-01-01

Cyclin-dependent kinase-like 5 (CDKL5) mutations are found in severe neurodevelopmental disorders, including the Hanefeld variant of Rett syndrome (RTT; CDKL5 disorder). CDKL5 loss-of-function murine models recapitulate pathological signs of the human disease, such as visual attention deficits and reduced visual acuity. Here we investigated the cellular and synaptic substrates of visual defects by studying the organization of the primary visual cortex (V1) of Cdkl5 -/y mice. We found a severe reduction of c-Fos expression in V1 of Cdkl5 -/y mutants, suggesting circuit hypoactivity. Glutamatergic presynaptic structures were increased, but postsynaptic PSD-95 and Homer were significantly downregulated in CDKL5 mutants. Interneurons expressing parvalbumin, but not other types of interneuron, had a higher density in mutant V1, and were hyperconnected with pyramidal neurons. Finally, the developmental trajectory of pavalbumin-containing cells was also affected in Cdkl5 -/y mice, as revealed by fainter appearance perineuronal nets at the closure of the critical period (CP). The present data reveal an overall disruption of V1 cellular and synaptic organization that may cause a shift in the excitation/inhibition balance likely to underlie the visual deficits characteristic of CDKL5 disorder. Moreover, ablation of CDKL5 is likely to tamper with the mechanisms underlying experience-dependent refinement of cortical circuits during the CP of development.

Lack of Cdkl5 Disrupts the Organization of Excitatory and Inhibitory Synapses and Parvalbumin Interneurons in the Primary Visual Cortex

PubMed Central

Pizzo, Riccardo; Gurgone, Antonia; Castroflorio, Enrico; Amendola, Elena; Gross, Cornelius; Sassoè-Pognetto, Marco; Giustetto, Maurizio

2016-01-01

Cyclin-dependent kinase-like 5 (CDKL5) mutations are found in severe neurodevelopmental disorders, including the Hanefeld variant of Rett syndrome (RTT; CDKL5 disorder). CDKL5 loss-of-function murine models recapitulate pathological signs of the human disease, such as visual attention deficits and reduced visual acuity. Here we investigated the cellular and synaptic substrates of visual defects by studying the organization of the primary visual cortex (V1) of Cdkl5−/y mice. We found a severe reduction of c-Fos expression in V1 of Cdkl5−/y mutants, suggesting circuit hypoactivity. Glutamatergic presynaptic structures were increased, but postsynaptic PSD-95 and Homer were significantly downregulated in CDKL5 mutants. Interneurons expressing parvalbumin, but not other types of interneuron, had a higher density in mutant V1, and were hyperconnected with pyramidal neurons. Finally, the developmental trajectory of pavalbumin-containing cells was also affected in Cdkl5−/y mice, as revealed by fainter appearance perineuronal nets at the closure of the critical period (CP). The present data reveal an overall disruption of V1 cellular and synaptic organization that may cause a shift in the excitation/inhibition balance likely to underlie the visual deficits characteristic of CDKL5 disorder. Moreover, ablation of CDKL5 is likely to tamper with the mechanisms underlying experience-dependent refinement of cortical circuits during the CP of development. PMID:27965538

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.

Dissecting local circuits in vivo: integrated optogenetic and electrophysiology approaches for exploring inhibitory regulation of cortical activity.

PubMed

Cardin, Jessica A

2012-01-01

Local cortical circuit activity in vivo comprises a complex and flexible series of interactions between excitatory and inhibitory neurons. Our understanding of the functional interactions between these different neural populations has been limited by the difficulty of identifying and selectively manipulating the diverse and sparsely represented inhibitory interneuron classes in the intact brain. The integration of recently developed optical tools with traditional electrophysiological techniques provides a powerful window into the role of inhibition in regulating the activity of excitatory neurons. In particular, optogenetic targeting of specific cell classes reveals the distinct impacts of local inhibitory populations on other neurons in the surrounding local network. In addition to providing the ability to activate or suppress spiking in target cells, optogenetic activation identifies extracellularly recorded neurons by class, even when naturally occurring spike rates are extremely low. However, there are several important limitations on the use of these tools and the interpretation of resulting data. The purpose of this article is to outline the uses and limitations of optogenetic tools, along with current methods for achieving cell type-specific expression, and to highlight the advantages of an experimental approach combining optogenetics and electrophysiology to explore the role of inhibition in active networks. To illustrate the efficacy of these combined approaches, I present data comparing targeted manipulations of cortical fast-spiking, parvalbumin-expressing and low threshold-spiking, somatostatin-expressing interneurons in vivo. Copyright © 2011 Elsevier Ltd. All rights reserved.

Single CA3 pyramidal cells trigger sharp waves in vitro by exciting interneurones.

PubMed

Bazelot, Michaël; Teleńczuk, Maria T; Miles, Richard

2016-05-15

The CA3 hippocampal region generates sharp waves (SPW), a population activity associated with neuronal representations. The synaptic mechanisms responsible for the generation of these events still require clarification. Using slices maintained in an interface chamber, we found that the firing of single CA3 pyramidal cells triggers SPW like events at short latencies, similar to those for the induction of firing in interneurons. Multi-electrode records from the CA3 stratum pyramidale showed that pyramidal cells triggered events consisting of putative interneuron spikes followed by field IPSPs. SPW fields consisted of a repetition of these events at intervals of 4-8 ms. Although many properties of induced and spontaneous SPWs were similar, the triggered events tended to be initiated close to the stimulated cell. These data show that the initiation of SPWs in vitro is mediated via pyramidal cell synapses that excite interneurons. They do not indicate why interneuron firing is repeated during a SPW. Sharp waves (SPWs) are a hippocampal population activity that has been linked to neuronal representations. We show that SPWs in the CA3 region of rat hippocampal slices can be triggered by the firing of single pyramidal cells. Single action potentials in almost one-third of pyramidal cells initiated SPWs at latencies of 2-5 ms with probabilities of 0.07-0.76. Initiating pyramidal cells evoked field IPSPs (fIPSPs) at similar latencies when SPWs were not initiated. Similar spatial profiles for fIPSPs and middle components of SPWs suggested that SPW fields reflect repeated fIPSPs. Multiple extracellular records showed that the initiated SPWs tended to start near the stimulated pyramidal cell, whereas spontaneous SPWs could emerge at multiple sites. Single pyramidal cells could initiate two to six field IPSPs with distinct amplitude distributions, typically preceeded by a short-duration extracellular action potential. Comparison of these initiated fields with spontaneously

Molecular and electrophysiological characterization of GFP-expressing CA1 interneurons in GAD65-GFP mice.

PubMed

Wierenga, Corette J; Müllner, Fiona E; Rinke, Ilka; Keck, Tara; Stein, Valentin; Bonhoeffer, Tobias

2010-12-31

The use of transgenic mice in which subtypes of neurons are labeled with a fluorescent protein has greatly facilitated modern neuroscience research. GAD65-GFP mice, which have GABAergic interneurons labeled with GFP, are widely used in many research laboratories, although the properties of the labeled cells have not been studied in detail. Here we investigate these cells in the hippocampal area CA1 and show that they constitute ∼20% of interneurons in this area. The majority of them expresses either reelin (70±2%) or vasoactive intestinal peptide (VIP; 15±2%), while expression of parvalbumin and somatostatin is virtually absent. This strongly suggests they originate from the caudal, and not the medial, ganglionic eminence. GFP-labeled interneurons can be subdivided according to the (partially overlapping) expression of neuropeptide Y (42±3%), cholecystokinin (25±3%), calbindin (20±2%) or calretinin (20±2%). Most of these subtypes (with the exception of calretinin-expressing interneurons) target the dendrites of CA1 pyramidal cells. GFP-labeled interneurons mostly show delayed onset of firing around threshold, and regular firing with moderate frequency adaptation at more depolarized potentials.

Spatiotemporal dynamics of rhythmic spinal interneurons measured with two-photon calcium imaging and coherence analysis.

PubMed

Kwan, Alex C; Dietz, Shelby B; Zhong, Guisheng; Harris-Warrick, Ronald M; Webb, Watt W

2010-12-01

In rhythmic neural circuits, a neuron often fires action potentials with a constant phase to the rhythm, a timing relationship that can be functionally significant. To characterize these phase preferences in a large-scale, cell type-specific manner, we adapted multitaper coherence analysis for two-photon calcium imaging. Analysis of simulated data showed that coherence is a simple and robust measure of rhythmicity for calcium imaging data. When applied to the neonatal mouse hindlimb spinal locomotor network, the phase relationships between peak activity of >1,000 ventral spinal interneurons and motor output were characterized. Most interneurons showed rhythmic activity that was coherent and in phase with the ipsilateral motor output during fictive locomotion. The phase distributions of two genetically identified classes of interneurons were distinct from the ensemble population and from each other. There was no obvious spatial clustering of interneurons with similar phase preferences. Together, these results suggest that cell type, not neighboring neuron activity, is a better indicator of an interneuron's response during fictive locomotion. The ability to measure the phase preferences of many neurons with cell type and spatial information should be widely applicable for studying other rhythmic neural circuits.

Cercal sensory system and giant interneurons in Gryllodes sigillatus.

PubMed

Kanou, Masamichi; Nawae, Miyuki; Kuroishi, Hiroyuki

2006-04-01

The external morphologies of two cricket species, Gryllodes sigillatus and Gryllus bimaculatus, were investigated. Despite its small body length, G. sigillatus possessed longer cerci and longer cercal filiform hairs than G. bimaculatus. The estimated number of filiform hairs on a cercus was also larger in G. sigillatus than in G. bimaculatus. Wind-sensitive interneurons receiving sensory inputs from cercal filiform hairs and running in the ventral nerve cord (VNC) were investigated in G. sigillatus both morphologically and physiologically. By intracellular staining, these interneurons were proved to be morphologically homologous with previously identified giant interneurons (GIs 8-1, 9-1, 9-2, 9-3, 10-2, and 10-3) in G. bimaculatus and Acheta domesticus. In G. sigillatus, the intensity-response relationship (I-R curve) for each GI was investigated using a unidirectional air current stimulus. The stimulus was applied from 12 different directions, and an I-R curve was obtained for each stimulus direction. Each GI showed a characteristic I-R curve depending on stimulus direction. The directionality curve expressed in terms of threshold velocity showed that each GI had a distinctive directional characteristic. The functional properties of GIs in G. sigillatus, such as I-R curve, threshold velocity, and directional characteristics, were compared with those of homologous GIs in G. bimaculatus in Discussion.

Emergent gamma synchrony in all-to-all interneuronal networks.

PubMed

Ratnadurai-Giridharan, Shivakeshavan; Khargonekar, Pramod P; Talathi, Sachin S

2015-01-01

We investigate the emergence of in-phase synchronization in a heterogeneous network of coupled inhibitory interneurons in the presence of spike timing dependent plasticity (STDP). Using a simple network of two mutually coupled interneurons (2-MCI), we first study the effects of STDP on in-phase synchronization. We demonstrate that, with STDP, the 2-MCI network can evolve to either a state of stable 1:1 in-phase synchronization or exhibit multiple regimes of higher order synchronization states. We show that the emergence of synchronization induces a structural asymmetry in the 2-MCI network such that the synapses onto the high frequency firing neurons are potentiated, while those onto the low frequency firing neurons are de-potentiated, resulting in the directed flow of information from low frequency firing neurons to high frequency firing neurons. Finally, we demonstrate that the principal findings from our analysis of the 2-MCI network contribute to the emergence of robust synchronization in the Wang-Buzsaki network (Wang and Buzsáki, 1996) of all-to-all coupled inhibitory interneurons (100-MCI) for a significantly larger range of heterogeneity in the intrinsic firing rate of the neurons in the network. We conclude that STDP of inhibitory synapses provide a viable mechanism for robust neural synchronization.

Emergent gamma synchrony in all-to-all interneuronal networks

PubMed Central

Ratnadurai-Giridharan, Shivakeshavan; Khargonekar, Pramod P.; Talathi, Sachin S.

2015-01-01

We investigate the emergence of in-phase synchronization in a heterogeneous network of coupled inhibitory interneurons in the presence of spike timing dependent plasticity (STDP). Using a simple network of two mutually coupled interneurons (2-MCI), we first study the effects of STDP on in-phase synchronization. We demonstrate that, with STDP, the 2-MCI network can evolve to either a state of stable 1:1 in-phase synchronization or exhibit multiple regimes of higher order synchronization states. We show that the emergence of synchronization induces a structural asymmetry in the 2-MCI network such that the synapses onto the high frequency firing neurons are potentiated, while those onto the low frequency firing neurons are de-potentiated, resulting in the directed flow of information from low frequency firing neurons to high frequency firing neurons. Finally, we demonstrate that the principal findings from our analysis of the 2-MCI network contribute to the emergence of robust synchronization in the Wang-Buzsaki network (Wang and Buzsáki, 1996) of all-to-all coupled inhibitory interneurons (100-MCI) for a significantly larger range of heterogeneity in the intrinsic firing rate of the neurons in the network. We conclude that STDP of inhibitory synapses provide a viable mechanism for robust neural synchronization. PMID:26528174

Complementary interactions between command-like interneurons that function to activate and specify motor programs.

PubMed

Wu, Jin-Sheng; Wang, Nan; Siniscalchi, Michael J; Perkins, Matthew H; Zheng, Yu-Tong; Yu, Wei; Chen, Song-an; Jia, Ruo-nan; Gu, Jia-Wei; Qian, Yi-Qing; Ye, Yang; Vilim, Ferdinand S; Cropper, Elizabeth C; Weiss, Klaudiusz R; Jing, Jian

2014-05-07

Motor activity is often initiated by a population of command-like interneurons. Command-like interneurons that reliably drive programs have received the most attention, so little is known about how less reliable command-like interneurons may contribute to program generation. We study two electrically coupled interneurons, cerebral-buccal interneuron-2 (CBI-2) and CBI-11, which activate feeding motor programs in the mollusk Aplysia californica. Earlier work indicated that, in rested preparations, CBI-2, a powerful activator of programs, can trigger ingestive and egestive programs. CBI-2 reliably generated ingestive patterns only when it was repeatedly stimulated. The ability of CBI-2 to trigger motor activity has been attributed to the two program-promoting peptides it contains, FCAP and CP2. Here, we show that CBI-11 differs from CBI-2 in that it contains FCAP but not CP2. Furthermore, it is weak in its ability to drive programs. On its own, CBI-11 is therefore less effective as a program activator. When it is successful, however, CBI-11 is an effective specifier of motor activity; that is, it drives mostly ingestive programs. Importantly, we found that CBI-2 and CBI-11 complement each other's actions. First, prestimulation of CBI-2 enhanced the ability of CBI-11 to drive programs. This effect appears to be partly mediated by CP2. Second, coactivation of CBI-11 with CBI-2 makes CBI-2 programs immediately ingestive. This effect may be mediated by specific actions that CBI-11 exerts on pattern-generating interneurons. Therefore, different classes of command-like neurons in a motor network may make distinct, but potentially complementary, contributions as either activators or specifiers of motor activity.

Complementary Interactions between Command-Like Interneurons that Function to Activate and Specify Motor Programs

PubMed Central

Wu, Jin-Sheng; Wang, Nan; Siniscalchi, Michael J.; Perkins, Matthew H.; Zheng, Yu-Tong; Yu, Wei; Chen, Song-an; Jia, Ruo-nan; Gu, Jia-Wei; Qian, Yi-Qing; Ye, Yang; Vilim, Ferdinand S.; Cropper, Elizabeth C.; Weiss, Klaudiusz R.

2014-01-01

Motor activity is often initiated by a population of command-like interneurons. Command-like interneurons that reliably drive programs have received the most attention, so little is known about how less reliable command-like interneurons may contribute to program generation. We study two electrically coupled interneurons, cerebral-buccal interneuron-2 (CBI-2) and CBI-11, which activate feeding motor programs in the mollusk Aplysia californica. Earlier work indicated that, in rested preparations, CBI-2, a powerful activator of programs, can trigger ingestive and egestive programs. CBI-2 reliably generated ingestive patterns only when it was repeatedly stimulated. The ability of CBI-2 to trigger motor activity has been attributed to the two program-promoting peptides it contains, FCAP and CP2. Here, we show that CBI-11 differs from CBI-2 in that it contains FCAP but not CP2. Furthermore, it is weak in its ability to drive programs. On its own, CBI-11 is therefore less effective as a program activator. When it is successful, however, CBI-11 is an effective specifier of motor activity; that is, it drives mostly ingestive programs. Importantly, we found that CBI-2 and CBI-11 complement each other's actions. First, prestimulation of CBI-2 enhanced the ability of CBI-11 to drive programs. This effect appears to be partly mediated by CP2. Second, coactivation of CBI-11 with CBI-2 makes CBI-2 programs immediately ingestive. This effect may be mediated by specific actions that CBI-11 exerts on pattern-generating interneurons. Therefore, different classes of command-like neurons in a motor network may make distinct, but potentially complementary, contributions as either activators or specifiers of motor activity. PMID:24806677

APLP2 regulates neuronal stem cell differentiation during cortical development.

PubMed

Shariati, S Ali M; Lau, Pierre; Hassan, Bassem A; Müller, Ulrike; Dotti, Carlos G; De Strooper, Bart; Gärtner, Annette

2013-03-01

Expression of amyloid precursor protein (APP) and its two paralogues, APLP1 and APLP2 during brain development coincides with key cellular events such as neuronal differentiation and migration. However, genetic knockout and shRNA studies have led to contradictory conclusions about their role during embryonic brain development. To address this issue, we analysed in depth the role of APLP2 during neurogenesis by silencing APLP2 in vivo in an APP/APLP1 double knockout mouse background. We find that under these conditions cortical progenitors remain in their undifferentiated state much longer, displaying a higher number of mitotic cells. In addition, we show that neuron-specific APLP2 downregulation does not impact the speed or position of migrating excitatory cortical neurons. In summary, our data reveal that APLP2 is specifically required for proper cell cycle exit of neuronal progenitors, and thus has a distinct role in priming cortical progenitors for neuronal differentiation.

Inhibition of striatal cholinergic interneuron activity by the Kv7 opener retigabine and the nonsteroidal anti-inflammatory drug diclofenac.

PubMed

Paz, Rodrigo Manuel; Tubert, Cecilia; Stahl, Agostina; Díaz, Analía López; Etchenique, Roberto; Murer, Mario Gustavo; Rela, Lorena

2018-05-11

Striatal cholinergic interneurons provide modulation to striatal circuits involved in voluntary motor control and goal-directed behaviors through their autonomous tonic discharge and their firing "pause" responses to novel and rewarding environmental events. Striatal cholinergic interneuron hyperactivity was linked to the motor deficits associated with Parkinson's disease and the adverse effects of chronic antiparkinsonian therapy like l-DOPA-induced dyskinesia. Here we addressed whether Kv7 channels, which provide negative feedback to excitation in other neuron types, are involved in the control of striatal cholinergic interneuron tonic activity and response to excitatory inputs. We found that autonomous firing of striatal cholinergic interneurons is not regulated by Kv7 channels. In contrast, Kv7 channels limit the summation of excitatory postsynaptic potentials in cholinergic interneurons through a postsynaptic mechanism. Striatal cholinergic interneurons have a high reserve of Kv7 channels, as their opening using pharmacological tools completely silenced the tonic firing and markedly reduced their intrinsic excitability. A strong inhibition of striatal cholinergic interneurons was also observed in response to the anti-inflammatory drugs diclofenac and meclofenamic acid, however, this effect was independent of Kv7 channels. These data bring attention to new potential molecular targets and pharmacological tools to control striatal cholinergic interneuron activity in pathological conditions where they are believed to be hyperactive, including Parkinson's disease. Copyright © 2018 Elsevier Ltd. All rights reserved.

Malformations of cortical development: 3T magnetic resonance imaging features

PubMed Central

Battal, Bilal; Ince, Selami; Akgun, Veysel; Kocaoglu, Murat; Ozcan, Emrah; Tasar, Mustafa

2015-01-01

Malformation of cortical development (MCD) is a term representing an inhomogeneous group of central nervous system abnormalities, referring particularly to embriyological aspect as a consequence of any of the three developmental stages, i.e., cell proliferation, cell migration and cortical organization. These include cotical dysgenesis, microcephaly, polymicrogyria, schizencephaly, lissencephaly, hemimegalencephaly, heterotopia and focal cortical dysplasia. Since magnetic resonance imaging is the modality of choice that best identifies the structural anomalies of the brain cortex, we aimed to provide a mini review of MCD by using 3T magnetic resonance scanner images. PMID:26516429

Excitatory Effects of Parvalbumin-Expressing Interneurons Maintain Hippocampal Epileptiform Activity via Synchronous Afterdischarges

PubMed Central

Ellender, Tommas J.; Raimondo, Joseph V.; Irkle, Agnese; Lamsa, Karri P.

2014-01-01

Epileptic seizures are characterized by periods of hypersynchronous, hyperexcitability within brain networks. Most seizures involve two stages: an initial tonic phase, followed by a longer clonic phase that is characterized by rhythmic bouts of synchronized network activity called afterdischarges (ADs). Here we investigate the cellular and network mechanisms underlying hippocampal ADs in an effort to understand how they maintain seizure activity. Using in vitro hippocampal slice models from rats and mice, we performed electrophysiological recordings from CA3 pyramidal neurons to monitor network activity and changes in GABAergic signaling during epileptiform activity. First, we show that the highest synchrony occurs during clonic ADs, consistent with the idea that specific circuit dynamics underlie this phase of the epileptiform activity. We then show that ADs require intact GABAergic synaptic transmission, which becomes excitatory as a result of a transient collapse in the chloride (Cl−) reversal potential. The depolarizing effects of GABA are strongest at the soma of pyramidal neurons, which implicates somatic-targeting interneurons in AD activity. To test this, we used optogenetic techniques to selectively control the activity of somatic-targeting parvalbumin-expressing (PV+) interneurons. Channelrhodopsin-2-mediated activation of PV+ interneurons during the clonic phase generated excitatory GABAergic responses in pyramidal neurons, which were sufficient to elicit and entrain synchronous AD activity across the network. Finally, archaerhodopsin-mediated selective silencing of PV+ interneurons reduced the occurrence of ADs during the clonic phase. Therefore, we propose that activity-dependent Cl− accumulation subverts the actions of PV+ interneurons to perpetuate rather than terminate pathological network hyperexcitability during the clonic phase of seizures. PMID:25392490

Structural and functional evaluation of cortical motor areas in Amyotrophic Lateral Sclerosis.

PubMed

Cosottini, Mirco; Pesaresi, Ilaria; Piazza, Selina; Diciotti, Stefano; Cecchi, Paolo; Fabbri, Serena; Carlesi, Cecilia; Mascalchi, Mario; Siciliano, Gabriele

2012-03-01

cortical damage within the motor circuit of ALS patients. The functional changes in non-primary motor cortices pertaining to fronto-parietal circuit suggest an over-recruitment of a pre-existing physiological sensory-motor network. However, the concomitant fronto-parietal cortical atrophy arises the possibility that such a hyper-activation reflects cortical hyper-excitability due to loss of inhibitory inter-neurons. Copyright © 2011 Elsevier Inc. All rights reserved.

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.

Altered cortical beta-band oscillations reflect motor system degeneration in amyotrophic lateral sclerosis.

PubMed

Proudfoot, Malcolm; Rohenkohl, Gustavo; Quinn, Andrew; Colclough, Giles L; Wuu, Joanne; Talbot, Kevin; Woolrich, Mark W; Benatar, Michael; Nobre, Anna C; Turner, Martin R

2017-01-01

Continuous rhythmic neuronal oscillations underpin local and regional cortical communication. The impact of the motor system neurodegenerative syndrome amyotrophic lateral sclerosis (ALS) on the neuronal oscillations subserving movement might therefore serve as a sensitive marker of disease activity. Movement preparation and execution are consistently associated with modulations to neuronal oscillation beta (15-30 Hz) power. Cortical beta-band oscillations were measured using magnetoencephalography (MEG) during preparation for, execution, and completion of a visually cued, lateralized motor task that included movement inhibition trials. Eleven "classical" ALS patients, 9 with the primary lateral sclerosis (PLS) phenotype, and 12 asymptomatic carriers of ALS-associated gene mutations were compared with age-similar healthy control groups. Augmented beta desynchronization was observed in both contra- and ipsilateral motor cortices of ALS patients during motor preparation. Movement execution coincided with excess beta desynchronization in asymptomatic mutation carriers. Movement completion was followed by a slowed rebound of beta power in all symptomatic patients, further reflected in delayed hemispheric lateralization for beta rebound in the PLS group. This may correspond to the particular involvement of interhemispheric fibers of the corpus callosum previously demonstrated in diffusion tensor imaging studies. We conclude that the ALS spectrum is characterized by intensified cortical beta desynchronization followed by delayed rebound, concordant with a broader concept of cortical hyperexcitability, possibly through loss of inhibitory interneuronal influences. MEG may potentially detect cortical dysfunction prior to the development of overt symptoms, and thus be able to contribute to the assessment of future neuroprotective strategies. Hum Brain Mapp 38:237-254, 2017. © 2016 Wiley Periodicals, Inc. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals

Altered cortical beta‐band oscillations reflect motor system degeneration in amyotrophic lateral sclerosis

PubMed Central

Proudfoot, Malcolm; Rohenkohl, Gustavo; Quinn, Andrew; Colclough, Giles L.; Wuu, Joanne; Talbot, Kevin; Woolrich, Mark W.; Benatar, Michael

2016-01-01

Abstract Continuous rhythmic neuronal oscillations underpin local and regional cortical communication. The impact of the motor system neurodegenerative syndrome amyotrophic lateral sclerosis (ALS) on the neuronal oscillations subserving movement might therefore serve as a sensitive marker of disease activity. Movement preparation and execution are consistently associated with modulations to neuronal oscillation beta (15–30 Hz) power. Cortical beta‐band oscillations were measured using magnetoencephalography (MEG) during preparation for, execution, and completion of a visually cued, lateralized motor task that included movement inhibition trials. Eleven “classical” ALS patients, 9 with the primary lateral sclerosis (PLS) phenotype, and 12 asymptomatic carriers of ALS‐associated gene mutations were compared with age‐similar healthy control groups. Augmented beta desynchronization was observed in both contra‐ and ipsilateral motor cortices of ALS patients during motor preparation. Movement execution coincided with excess beta desynchronization in asymptomatic mutation carriers. Movement completion was followed by a slowed rebound of beta power in all symptomatic patients, further reflected in delayed hemispheric lateralization for beta rebound in the PLS group. This may correspond to the particular involvement of interhemispheric fibers of the corpus callosum previously demonstrated in diffusion tensor imaging studies. We conclude that the ALS spectrum is characterized by intensified cortical beta desynchronization followed by delayed rebound, concordant with a broader concept of cortical hyperexcitability, possibly through loss of inhibitory interneuronal influences. MEG may potentially detect cortical dysfunction prior to the development of overt symptoms, and thus be able to contribute to the assessment of future neuroprotective strategies. Hum Brain Mapp 38:237–254, 2017. © 2016 Wiley Periodicals, Inc. PMID:27623516

Somatic evoked high-frequency magnetic oscillations reflect activity of inhibitory interneurons in the human somatosensory cortex.

PubMed

Hashimoto, I; Mashiko, T; Imada, T

1996-05-01

High-frequency potential oscillations in the range of 300-900 Hz have recently been shown to concur with the primary response (N20) of the somatosensory cortex in awake humans. However, the physiological mechanisms of the high-frequency oscillations remained undetermined. We addressed the issue by analyzing magnetic fields during wakefulness and sleep over the left hemisphere to right median nerve stimulation with a wide bandpass (0.1-2000 Hz) recording with subsequent high-pass (> 300 Hz) and low-pass (< 300 Hz) filtering. With wide bandpass recordings, high-frequency magnetic oscillations with the main signal energy at 580-780 Hz were superimposed on the N20m during wakefulness. Isofield mapping at each peak of the high-pass filtered and isolated high-frequency oscillations showed a dipolar pattern and the estimated source for these peaks was the primary somatosensory cortex (area 3b) very close to that for the N20m peak. During sleep, the high-frequency oscillations showed dramatic diminution in amplitude while the N20m amplitude exhibited a moderate increment. This reciprocal relation between the high-frequency oscillations and the N20m during a wake-sleep cycle suggests that they represent different generator substrates. We speculate that the high-frequency oscillations represent a localized activity of the GABAergic inhibitory interneurons of layer 4, which have been shown in animal experiments to respond monosynaptically to thalamo-cortical input with a high-frequency (600-900 Hz) burst of short duration spikes. On the other hand, the underlying N20m represents activity of pyramidal neurons which receive monosynaptic excitatory input from the thalamus as well as a feed-forward inhibition from the interneurons.

Synaptic muscarinic response types in hippocampal CA1 interneurons depend on different levels of presynaptic activity and different muscarinic receptor subtypes

PubMed Central

Bell, L. Andrew; Bell, Karen A.; McQuiston, A. Rory

2013-01-01

Depolarizing, hyperpolarizing and biphasic muscarinic responses have been described in hippocampal inhibitory interneurons, but the receptor subtypes and activity patterns required to synaptically activate muscarinic responses in interneurons have not been completely characterized. Using optogenetics combined with whole cell patch clamp recordings in acute slices, we measured muscarinic responses produced by endogenously released acetylcholine (ACh) from cholinergic medial septum/diagonal bands of Broca inputs in hippocampal CA1. We found that depolarizing responses required more cholinergic terminal stimulation than hyperpolarizing ones. Furthermore, elevating extracellular ACh with the acetylcholinesterase inhibitor physostigmine had a larger effect on depolarizing versus hyperpolarizing responses. Another subpopulation of interneurons responded biphasically, and periodic release of ACh entrained some of these interneurons to rhythmically burst. M4 receptors mediated hyperpolarizing responses by activating inwardly rectifying K+ channels, whereas the depolarizing responses were inhibited by the nonselective muscarinic antagonist atropine but were unaffected by M1, M4 or M5 receptor modulators. In addition, activation of M4 receptors significantly altered biphasic interneuron firing patterns. Anatomically, interneuron soma location appeared predictive of muscarinic response types but response types did not correlate with interneuron morphological subclasses. Together these observations suggest that the hippocampal CA1 interneuron network will be differentially affected by cholinergic input activity levels. Low levels of cholinergic activity will preferentially suppress some interneurons via hyperpolarization and increased activity will recruit other interneurons to depolarize, possibly because of elevated extracellular ACh concentrations. These data provide important information for understanding how cholinergic therapies will affect hippocampal network function

Interneuronal mechanisms of hippocampal theta oscillations in a full-scale model of the rodent CA1 circuit

PubMed Central

Bezaire, Marianne J; Raikov, Ivan; Burk, Kelly; Vyas, Dhrumil; Soltesz, Ivan

2016-01-01

The hippocampal theta rhythm plays important roles in information processing; however, the mechanisms of its generation are not well understood. We developed a data-driven, supercomputer-based, full-scale (1:1) model of the rodent CA1 area and studied its interneurons during theta oscillations. Theta rhythm with phase-locked gamma oscillations and phase-preferential discharges of distinct interneuronal types spontaneously emerged from the isolated CA1 circuit without rhythmic inputs. Perturbation experiments identified parvalbumin-expressing interneurons and neurogliaform cells, as well as interneuronal diversity itself, as important factors in theta generation. These simulations reveal new insights into the spatiotemporal organization of the CA1 circuit during theta oscillations. DOI: http://dx.doi.org/10.7554/eLife.18566.001 PMID:28009257

Identification of Inhibitory Premotor Interneurons Activated at a Late Phase in a Motor Cycle during Drosophila Larval Locomotion

PubMed Central

Itakura, Yuki; Kohsaka, Hiroshi; Ohyama, Tomoko; Zlatic, Marta

2015-01-01

Rhythmic motor patterns underlying many types of locomotion are thought to be produced by central pattern generators (CPGs). Our knowledge of how CPG networks generate motor patterns in complex nervous systems remains incomplete, despite decades of work in a variety of model organisms. Substrate borne locomotion in Drosophila larvae is driven by waves of muscular contraction that propagate through multiple body segments. We use the motor circuitry underlying crawling in larval Drosophila as a model to try to understand how segmentally coordinated rhythmic motor patterns are generated. Whereas muscles, motoneurons and sensory neurons have been well investigated in this system, far less is known about the identities and function of interneurons. Our recent study identified a class of glutamatergic premotor interneurons, PMSIs (period-positive median segmental interneurons), that regulate the speed of locomotion. Here, we report on the identification of a distinct class of glutamatergic premotor interneurons called Glutamatergic Ventro-Lateral Interneurons (GVLIs). We used calcium imaging to search for interneurons that show rhythmic activity and identified GVLIs as interneurons showing wave-like activity during peristalsis. Paired GVLIs were present in each abdominal segment A1-A7 and locally extended an axon towards a dorsal neuropile region, where they formed GRASP-positive putative synaptic contacts with motoneurons. The interneurons expressed vesicular glutamate transporter (vGluT) and thus likely secrete glutamate, a neurotransmitter known to inhibit motoneurons. These anatomical results suggest that GVLIs are premotor interneurons that locally inhibit motoneurons in the same segment. Consistent with this, optogenetic activation of GVLIs with the red-shifted channelrhodopsin, CsChrimson ceased ongoing peristalsis in crawling larvae. Simultaneous calcium imaging of the activity of GVLIs and motoneurons showed that GVLIs’ wave-like activity lagged behind that of

Identification of Inhibitory Premotor Interneurons Activated at a Late Phase in a Motor Cycle during Drosophila Larval Locomotion.

PubMed

Itakura, Yuki; Kohsaka, Hiroshi; Ohyama, Tomoko; Zlatic, Marta; Pulver, Stefan R; Nose, Akinao

2015-01-01

Rhythmic motor patterns underlying many types of locomotion are thought to be produced by central pattern generators (CPGs). Our knowledge of how CPG networks generate motor patterns in complex nervous systems remains incomplete, despite decades of work in a variety of model organisms. Substrate borne locomotion in Drosophila larvae is driven by waves of muscular contraction that propagate through multiple body segments. We use the motor circuitry underlying crawling in larval Drosophila as a model to try to understand how segmentally coordinated rhythmic motor patterns are generated. Whereas muscles, motoneurons and sensory neurons have been well investigated in this system, far less is known about the identities and function of interneurons. Our recent study identified a class of glutamatergic premotor interneurons, PMSIs (period-positive median segmental interneurons), that regulate the speed of locomotion. Here, we report on the identification of a distinct class of glutamatergic premotor interneurons called Glutamatergic Ventro-Lateral Interneurons (GVLIs). We used calcium imaging to search for interneurons that show rhythmic activity and identified GVLIs as interneurons showing wave-like activity during peristalsis. Paired GVLIs were present in each abdominal segment A1-A7 and locally extended an axon towards a dorsal neuropile region, where they formed GRASP-positive putative synaptic contacts with motoneurons. The interneurons expressed vesicular glutamate transporter (vGluT) and thus likely secrete glutamate, a neurotransmitter known to inhibit motoneurons. These anatomical results suggest that GVLIs are premotor interneurons that locally inhibit motoneurons in the same segment. Consistent with this, optogenetic activation of GVLIs with the red-shifted channelrhodopsin, CsChrimson ceased ongoing peristalsis in crawling larvae. Simultaneous calcium imaging of the activity of GVLIs and motoneurons showed that GVLIs' wave-like activity lagged behind that of

GABAergic Local Interneurons Shape Female Fruit Fly Response to Mating Songs.

PubMed

Yamada, Daichi; Ishimoto, Hiroshi; Li, Xiaodong; Kohashi, Tsunehiko; Ishikawa, Yuki; Kamikouchi, Azusa

2018-05-02

Many animals use acoustic signals to attract a potential mating partner. In fruit flies ( Drosophila melanogaster ), the courtship pulse song has a species-specific interpulse interval (IPI) that activates mating. Although a series of auditory neurons in the fly brain exhibit different tuning patterns to IPIs, it is unclear how the response of each neuron is tuned. Here, we studied the neural circuitry regulating the activity of antennal mechanosensory and motor center (AMMC)-B1 neurons, key secondary auditory neurons in the excitatory neural pathway that relay song information. By performing Ca 2+ imaging in female flies, we found that the IPI selectivity observed in AMMC-B1 neurons differs from that of upstream auditory sensory neurons [Johnston's organ (JO)-B]. Selective knock-down of a GABA A receptor subunit in AMMC-B1 neurons increased their response to short IPIs, suggesting that GABA suppresses AMMC-B1 activity at these IPIs. Connection mapping identified two GABAergic local interneurons that synapse with AMMC-B1 and JO-B. Ca 2+ imaging combined with neuronal silencing revealed that these local interneurons, AMMC-LN and AMMC-B2, shape the response pattern of AMMC-B1 neurons at a 15 ms IPI. Neuronal silencing studies further suggested that both GABAergic local interneurons suppress the behavioral response to artificial pulse songs in flies, particularly those with a 15 ms IPI. Altogether, we identified a circuit containing two GABAergic local interneurons that affects the temporal tuning of AMMC-B1 neurons in the song relay pathway and the behavioral response to the courtship song. Our findings suggest that feedforward inhibitory pathways adjust the behavioral response to courtship pulse songs in female flies. SIGNIFICANCE STATEMENT To understand how the brain detects time intervals between sound elements, we studied the neural pathway that relays species-specific courtship song information in female Drosophila melanogaster We demonstrate that the signal

Long Pauses in Cerebellar Interneurons in Anesthetized Animals.

PubMed

Givon-Mayo, Ronit; Haar, Shlomi; Aminov, Yoav; Simons, Esther; Donchin, Opher

2017-04-01

Are long pauses in the firing of cerebellar interneurons (CINs) related to Purkinje cell (PC) pauses? If PC pauses affect the larger network, then we should find a close relationship between CIN pauses and those in PCs. We recorded activity of 241 cerebellar cortical neurons (206 CINs and 35 PCs) in three anesthetized cats. One fifth of the CINs and more than half of the PCs were identified as pausing. Pauses in CINs and PCs showed some differences: CIN mean pause length was shorter, and, after pauses, only CINs had sustained reduction in their firing rate (FR). Almost all pausing CINs fell into same cluster when we used different methods of clustering CINs by their spontaneous activity. The mean spontaneous firing rate of that cluster was approximately 53 Hz. We also examined cross-correlations in simultaneously recorded neurons. Of 39 cell pairs examined, 14 (35 %) had cross-correlations significantly different from those expected by chance. Almost half of the pairs with two CINs showed statistically significant negative correlations. In contrast, PC/CIN pairs did not often show significant effects in the cross-correlation (12/15 pairs). However, for both CIN/CIN and PC/CIN pairs, pauses in one unit tended to correspond to a reduction in the firing rate of the adjacent unit. In our view, our results support the possibility that previously reported PC bistability is part of a larger network response and not merely a biophysical property of PCs. Any functional role for PC bistability should probably be sought in the context of the broader network.

Environmental enrichment as a therapeutic avenue for anxiety in aged Wistar rats: Effect on cat odor exposition and GABAergic interneurons.

PubMed

Sampedro-Piquero, P; Castilla-Ortega, E; Zancada-Menendez, C; Santín, L J; Begega, A

2016-08-25

The use of more ethological animal models to study the neurobiology of anxiety has increased in recent years. We assessed the effect of an environmental enrichment (EE) protocol (24h/day over a period of two months) on anxiety-related behaviors when aged Wistar rats (21months old) were confronted with cat odor stimuli. Owing to the relationship between GABAergic interneurons and the anxiety-related neuronal network, we examined changes in the expression of Parvalbumin (PV) and 67kDa form of glutamic acid decarboxylase (GAD-67) immunoreactive cells in different brain regions involved in stress response. Behavioral results revealed that enriched rats traveled further and made more grooming behaviors during the habituation session. In the cat odor session, they traveled longer distances and they showed more active interaction with the odor stimuli and less time in freezing behavior. Zone analysis revealed that the enriched group spent more time in the intermediate zone according to the proximity of the predator odor. Regarding the neurobiological data, the EE increased the expression of PV-positive cells in some medial prefrontal regions (cingulate (Cg) and prelimbic (PL) cortices), whereas the GAD-67 expression in the basolateral amygdala was reduced in the enriched group. Our results suggest that EE is able to reduce anxiety-like behaviors in aged animals even when ethologically relevant stimuli are used. Moreover, GABAergic interneurons could be involved in mediating this resilient behavior. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

JIP3 regulates neuronal radial migration by mediating TrkB axonal anterograde transport in the developing cerebral cortex.

PubMed

Ma, Huixian; Yu, Hui; Li, Ting; Zhao, Yan; Hou, Ming; Chen, Zheyu; Wang, Yue; Sun, Tao

2017-04-15

Radial migration is essential for the precise lamination and the coordinated function of the cerebral cortex. However, the molecular mechanisms for neuronal radial migration are not clear. Here, we report that c-Jun NH2-terminal kinase (JNK)-interacting protein-3 (JIP3) is highly expressed in the brain of embryonic mice and essential for radial migration. Knocking down JIP3 by in utero electroporation specifically perturbs the radial migration of cortical neurons but has no effect on neurogenesis and neuronal differentiation. Furthermore, we illustrate that JIP3 knockdown delays but does not block the migration of cortical neurons by investigating the distribution of neurons with JIP3 knocked down in the embryo and postnatal mouse. Finally, we find that JIP3 regulates cortical neuronal migration by mediating TrkB axonal anterograde transport during brain development. These findings deepen our understanding of the regulation of neuronal development by JIP3 and provide us a novel view on the regulating mechanisms of neuronal radial migration. Copyright © 2017 Elsevier Inc. All rights reserved.

Integrative Mechanisms of Oriented Neuronal Migration in the Developing Brain

PubMed Central

Evsyukova, Irina; Plestant, Charlotte; Anton, E.S.

2014-01-01

The emergence of functional neuronal connectivity in the developing cerebral cortex depends on neuronal migration. This process enables appropriate positioning of neurons and the emergence of neuronal identity so that the correct patterns of functional synaptic connectivity between the right types and numbers of neurons can emerge. Delineating the complexities of neuronal migration is critical to our understanding of normal cerebral cortical formation and neurodevelopmental disorders resulting from neuronal migration defects. For the most part, the integrated cell biological basis of the complex behavior of oriented neuronal migration within the developing mammalian cerebral cortex remains an enigma. This review aims to analyze the integrative mechanisms that enable neurons to sense environmental guidance cues and translate them into oriented patterns of migration toward defined areas of the cerebral cortex. We discuss how signals emanating from different domains of neurons get integrated to control distinct aspects of migratory behavior and how different types of cortical neurons coordinate their migratory activities within the developing cerebral cortex to produce functionally critical laminar organization. PMID:23937349

Excitatory Local Interneurons Enhance Tuning of Sensory Information

PubMed Central

Assisi, Collins; Stopfer, Mark; Bazhenov, Maxim

2012-01-01

Neurons in the insect antennal lobe represent odors as spatiotemporal patterns of activity that unfold over multiple time scales. As these patterns unspool they decrease the overlap between odor representations and thereby increase the ability of the olfactory system to discriminate odors. Using a realistic model of the insect antennal lobe we examined two competing components of this process –lateral excitation from local excitatory interneurons, and slow inhibition from local inhibitory interneurons. We found that lateral excitation amplified differences between representations of similar odors by recruiting projection neurons that did not receive direct input from olfactory receptors. However, this increased sensitivity also amplified noisy variations in input and compromised the ability of the system to respond reliably to multiple presentations of the same odor. Slow inhibition curtailed the spread of projection neuron activity and increased response reliability. These competing influences must be finely balanced in order to decorrelate odor representations. PMID:22807661

Defective neuronal migration and inhibition of bipolar to multipolar transition of migrating neural cells by Mesoderm-Specific Transcript, Mest, in the developing mouse neocortex.

PubMed

Ji, Liting; Bishayee, Kausik; Sadra, Ali; Choi, Seunghyuk; Choi, Wooyul; Moon, Sungho; Jho, Eek-Hoon; Huh, Sung-Oh

2017-07-04

Brain developmental disorders such as lissencephaly can result from faulty neuronal migration and differentiation during the formation of the mammalian neocortex. The cerebral cortex is a modular structure, where developmentally, newborn neurons are generated as a neuro-epithelial sheet and subsequently differentiate, migrate and organize into their final positions in the cerebral cortical plate via a process involving both tangential and radial migration. The specific role of Mest, an imprinted gene, in neuronal migration has not been previously studied. In this work, we reduced expression of Mest with in utero electroporation of neuronal progenitors in the developing embryonic mouse neocortex. Reduction of Mest levels by shRNA significantly reduced the number of neurons migrating to the cortical plate. Also, Mest-knockdown disrupted the transition of bipolar neurons into multipolar neurons migrating out of the sub-ventricular zone region. The migrating neurons also adopted a more tangential migration pattern upon knockdown of the Mest message, losing their potential to attach to radial glia cells, required for radial migration. The differentiation and migration properties of neurons via Wnt-Akt signaling were affected by Mest changes. In addition, miR-335, encoded in a Mest gene intron, was identified as being responsible for blocking the default tangential migration of the neurons. Our results suggest that Mest and its intron product, miR-335, play important roles in neuronal migration with Mest regulating the morphological transition of primary neurons required in the formation of the mammalian neocortex. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

ApoER2 Controls Not Only Neuronal Migration in the Intermediate Zone But Also Termination of Migration in the Developing Cerebral Cortex.

PubMed

Hirota, Yuki; Kubo, Ken-Ichiro; Fujino, Takahiro; Yamamoto, Tokuo T; Nakajima, Kazunori

2018-01-01

Neuronal migration contributes to the establishment of mammalian brain. The extracellular protein Reelin sends signals to various downstream molecules by binding to its receptors, the apolipoprotein E receptor 2 (ApoER2) and very low-density lipoprotein receptor and exerts essential roles in the neuronal migration and formation of the layered neocortex. However, the cellular and molecular functions of Reelin signaling in the cortical development are not yet fully understood. Here, to gain insight into the role of Reelin signaling during cortical development, we examined the migratory behavior of Apoer2-deficient neurons in the developing brain. Stage-specific labeling of newborn neurons revealed that the neurons ectopically invaded the marginal zone (MZ) and that neuronal migration of both early- and late-born neurons was disrupted in the intermediate zone (IZ) in the Apoer2 KO mice. Rescue experiments showed that ApoER2 functions both in cell-autonomous and noncell-autonomous manners, that Rap1, integrin, and Akt are involved in the termination of migration beneath the MZ, and that Akt also controls neuronal migration in the IZ downstream of ApoER2. These data indicate that ApoER2 controls multiple processes in neuronal migration, including the early stage of radial migration and termination of migration beneath the MZ in the developing neocortex. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Role of ionotropic glutamate receptors in LTP in rat hippocampal CA1 oriens-lacunosum moleculare interneurons

PubMed Central

Oren, Iris; Nissen, Wiebke; Kullmann, Dimitri M.; Somogyi, Peter; Lamsa, Karri P.

2009-01-01

Some interneurons of the hippocampus exhibit NMDA receptor-independent long-term potentiation (LTP) that is induced by presynaptic glutamate release when the postsynaptic membrane potential is hyperpolarized. This ‘anti-Hebbian’ form of LTP is prevented by postsynaptic depolarization or by blocking AMPA and kainate receptors. Although both AMPA and kainate receptors are expressed in hippocampal interneurons, their relative roles in anti-Hebbian LTP are not known. Because interneuron diversity potentially conceals simple rules underlying different forms of plasticity, we focus on glutamatergic synapses onto a subset of interneurons with dendrites in stratum oriens and a main ascending axon that projects to stratum lacunosum-moleculare, the O-LM cells. We show that anti-Hebbian LTP in O-LM interneurons has consistent induction and expression properties, and is prevented by selective inhibition of AMPA receptors. The majority of the ionotropic glutamatergic synaptic current in these cells is mediated by inwardly rectifying Ca2+ -permeable AMPA receptors. Although GluR5-containing kainate receptors contribute to synaptic currents at high stimulus frequency, they are not required for LTP induction. Glutamatergic synapses on O-LM cells thus behave in a homogeneous manner, and exhibit LTP dependent on Ca2+-permeable AMPA receptors. PMID:19176803

Parvalbumin and neuropeptide Y expressing hippocampal GABA-ergic inhibitory interneuron numbers decline in a model of Gulf War illness.

PubMed

Megahed, Tarick; Hattiangady, Bharathi; Shuai, Bing; Shetty, Ashok K

2014-01-01

Cognitive dysfunction is amongst the most conspicuous symptoms in Gulf War illness (GWI). Combined exposure to the nerve gas antidote pyridostigmine bromide (PB), pesticides and stress during the Persian Gulf War-1 (PGW-1) are presumed to be among the major causes of GWI. Indeed, our recent studies in rat models have shown that exposure to GWI-related (GWIR) chemicals and mild stress for 4 weeks engenders cognitive impairments accompanied with several detrimental changes in the hippocampus. In this study, we tested whether reduced numbers of hippocampal gamma-amino butyric acid (GABA)-ergic interneurons are among the pathological changes induced by GWIR-chemicals and stress. Animals were exposed to low doses of GWIR-chemicals and mild stress for 4 weeks. Three months after this exposure, subpopulations of GABA-ergic interneurons expressing the calcium binding protein parvalbumin (PV), the neuropeptide Y (NPY) and somatostatin (SS) in the hippocampus were stereologically quantified. Animals exposed to GWIR-chemicals and stress for 4 weeks displayed reduced numbers of PV-expressing GABA-ergic interneurons in the dentate gyrus and NPY-expressing interneurons in the CA1 and CA3 subfields. However, no changes in SS+ interneuron population were observed in the hippocampus. Furthermore, GABA-ergic interneuron deficiency in these animals was associated with greatly diminished hippocampus neurogenesis. Because PV+ and NPY+ interneurons play roles in maintaining normal cognitive function and neurogenesis, and controlling the activity of excitatory neurons in the hippocampus, reduced numbers of these interneurons may be one of the major causes of cognitive dysfunction and reduced neurogenesis observed in GWI. Hence, strategies that improve inhibitory neurotransmission in the hippocampus may prove beneficial for reversing cognitive dysfunction in GWI.

Evolution of a new sense for wind in flying phasmids? Afferents and interneurons

NASA Astrophysics Data System (ADS)

Hustert, Reinhold; Klug, Rebecca

2009-12-01

The evolution of winged stick insects (phasmids) from secondarily wingless ancestors was proposed in recent studies. We explored the cuticle of flying phasmids for wind sensors that could be involved in their flight control, comparable to those known for locusts. Surprisingly, wind-sensitive hairs (wsH) occur on the palps of mouthparts and on the antennae of the winged phasmid Sipyloidea sipylus which can fly in tethered position only when air currents blow over the mouthparts. The present study describes the morphology and major functional properties of these “new” wsH with soft and bulging hair bases which are different from the beaker-like hair bases of the wsH on the cerci of phasmids and the wsH described in other insects. The most sensitive wsH of antennae and palps respond with phasic-tonic afferents to air currents exceeding 0.2 ms-1. The fields of wsH on one side of the animal respond mainly to ventral, lateral, and frontal wind on the ipsilateral side of the head. Afferent inputs from the wsH converge but also diverge to a group of specific interneurons at their branches in the suboesophageal ganglion and can send their integrated input from wsH fields of the palps and antennae to the thoracic central nervous system. Response types of individual wsH-interneurons are either phasic or phasic-tonic to air puffs or constant air currents and also, the receptive fields of individual interneurons differ. We conclude that the “new” wsH system and its interneurons mainly serve to maintain flight activity in airborne phasmids and also, the “new” wsH must have emerged together with the integrating interneurons during the evolution from wingless to the recent winged forms of phasmids.

An in silico agent-based model demonstrates Reelin function in directing lamination of neurons during cortical development.

PubMed

Caffrey, James R; Hughes, Barry D; Britto, Joanne M; Landman, Kerry A

2014-01-01

The characteristic six-layered appearance of the neocortex arises from the correct positioning of pyramidal neurons during development and alterations in this process can cause intellectual disabilities and developmental delay. Malformations in cortical development arise when neurons either fail to migrate properly from the germinal zones or fail to cease migration in the correct laminar position within the cortical plate. The Reelin signalling pathway is vital for correct neuronal positioning as loss of Reelin leads to a partially inverted cortex. The precise biological function of Reelin remains controversial and debate surrounds its role as a chemoattractant or stop signal for migrating neurons. To investigate this further we developed an in silico agent-based model of cortical layer formation. Using this model we tested four biologically plausible hypotheses for neuron motility and four biologically plausible hypotheses for the loss of neuron motility (conversion from migration). A matrix of 16 combinations of motility and conversion rules was applied against the known structure of mouse cortical layers in the wild-type cortex, the Reelin-null mutant, the Dab1-null mutant and a conditional Dab1 mutant. Using this approach, many combinations of motility and conversion mechanisms can be rejected. For example, the model does not support Reelin acting as a repelling or as a stopping signal. In contrast, the study lends very strong support to the notion that the glycoprotein Reelin acts as a chemoattractant for neurons. Furthermore, the most viable proposition for the conversion mechanism is one in which conversion is affected by a motile neuron sensing in the near vicinity neurons that have already converted. Therefore, this model helps elucidate the function of Reelin during neuronal migration and cortical development.

Meninges control tangential migration of hem-derived Cajal-Retzius cells via CXCL12/CXCR4 signaling.

PubMed

Borrell, Víctor; Marín, Oscar

2006-10-01

Cajal-Retzius cells are critical in the development of the cerebral cortex, but little is known about the mechanisms controlling their development. Three focal sources of Cajal-Retzius cells have been identified in mice-the cortical hem, the ventral pallium and the septum-from where they migrate tangentially to populate the cortical surface. Using a variety of tissue culture assays and in vivo manipulations, we demonstrate that the tangential migration of cortical hem-derived Cajal-Retzius cells is controlled by the meninges. We show that the meningeal membranes are a necessary and sufficient substrate for the tangential migration of Cajal-Retzius cells. We also show that the chemokine CXCL12 secreted by the meninges enhances the dispersion of Cajal-Retzius cells along the cortical surface, while retaining them within the marginal zone in a CXCR4-dependent manner. Thus, the meningeal membranes are fundamental in the development of Cajal-Retzius cells and, hence, in the normal development of the cerebral cortex.

Perineuronal nets labeled by monoclonal antibody VC1.1 ensheath interneurons expressing parvalbumin and calbindin in the rat amygdala

PubMed Central

McDonald, Alexander J.; Hamilton, Patricia G.; Barnstable, Colin J.

2018-01-01

Perineuronal nets (PNNs) are specialized condensations of extracellular matrix that ensheath particular neuronal subpopulations in the brain and spinal cord. PNNs regulate synaptic plasticity, including the encoding of fear memories by the amygdala. The present immunohistochemical investigation studied PNN structure and distribution, as well as the neurochemistry of their ensheathed neurons, in the rat amygdala using monoclonal antibody VC1.1, which recognizes a glucuronic acid 3-sulfate glycan associated with PNNs in the cerebral cortex. VC1.1+ PNNs surrounded the cell bodies and dendrites of a subset of nonpyramidal neurons in cortex-like portions of the amygdala (basolateral amygdalar complex, cortical nuclei, nucleus of the lateral olfactory tract, and amygdalohippocampal region). There was also significant neuropilar VC1.1 immunoreactivity whose density varied in different amygdalar nuclei. Cell counts in the basolateral nucleus revealed that virtually all neurons ensheathed by VC1.1+ PNNs were parvalbumin-positive (PV+) interneurons, and these VC1.1+/PV+ cells constituted 60% of all PV+ interneurons, including all of the larger PV+ neurons. Approximately 70% of VC1.1+ neurons were calbindin-positive (CB+), and these VC1.1+/CB+ cells constituted about 40% of all CB+ neurons. Colocalization of VC1.1 with Vicia villosa agglutinin (VVA) binding, which stains terminal N-acetylgalactosamines, revealed that VC1.1+ PNNs were largely a subset of VVA+ PNNs. This investigation provides baseline data regarding PNNs in the rat which should be useful for future studies of their function in this species. PMID:29094304

Adult Olfactory Bulb Interneuron Phenotypes Identified by Targeting Embryonic and Postnatal Neural Progenitors

PubMed Central

Figueres-Oñate, Maria; López-Mascaraque, Laura

2016-01-01

Neurons are generated during embryonic development and in adulthood, although adult neurogenesis is restricted to two main brain regions, the hippocampus and olfactory bulb. The subventricular zone (SVZ) of the lateral ventricles generates neural stem/progenitor cells that continually provide the olfactory bulb (OB) with new granule or periglomerular neurons, cells that arrive from the SVZ via the rostral migratory stream. The continued neurogenesis and the adequate integration of these newly generated interneurons is essential to maintain homeostasis in the olfactory bulb, where the differentiation of these cells into specific neural cell types is strongly influenced by temporal cues. Therefore, identifying the critical features that control the generation of adult OB interneurons at either pre- or post-natal stages is important to understand the dynamic contribution of neural stem cells. Here, we used in utero and neonatal SVZ electroporation along with a transposase-mediated stable integration plasmid, in order to track interneurons and glial lineages in the OB. These plasmids are valuable tools to study the development of OB interneurons from embryonic and post-natal SVZ progenitors. Accordingly, we examined the location and identity of the adult progeny of embryonic and post-natally transfected progenitors by examining neurochemical markers in the adult OB. These data reveal the different cell types in the olfactory bulb that are generated in function of age and different electroporation conditions. PMID:27242400

Functional characterization of dI6 interneurons in the neonatal mouse spinal cord.

PubMed

Dyck, Jason; Lanuza, Guillermo M; Gosgnach, Simon

2012-06-01

Our understanding of the neural control of locomotion has been greatly enhanced by the ability to identify and manipulate genetically defined populations of interneurons that comprise the locomotor central pattern generator (CPG). To date, the dI6 interneurons are one of the few populations that settle in the ventral region of the postnatal spinal cord that have not been investigated. In the present study, we utilized a novel transgenic mouse line to electrophysiologically characterize dI6 interneurons located close to the central canal and study their function during fictive locomotion. The majority of dI6 cells investigated were found to be rhythmically active during fictive locomotion and could be divided into two electrophysiologically distinct populations of interneurons. The first population fired rhythmic trains of action potentials that were loosely coupled to ventral root output and contained several intrinsic membrane properties of rhythm-generating neurons, raising the possibility that these cells may be involved in the generation of rhythmic activity in the locomotor CPG. The second population fired rhythmic trains of action potentials that were tightly coupled to ventral root output and lacked intrinsic oscillatory mechanisms, indicating that these neurons may be driven by a rhythm-generating network. Together these results indicate that dI6 neurons comprise an important component of the locomotor CPG that participate in multiple facets of motor behavior.

Functional characterization of dI6 interneurons in the neonatal mouse spinal cord

PubMed Central

Dyck, Jason; Lanuza, Guillermo M.

2012-01-01

Our understanding of the neural control of locomotion has been greatly enhanced by the ability to identify and manipulate genetically defined populations of interneurons that comprise the locomotor central pattern generator (CPG). To date, the dI6 interneurons are one of the few populations that settle in the ventral region of the postnatal spinal cord that have not been investigated. In the present study, we utilized a novel transgenic mouse line to electrophysiologically characterize dI6 interneurons located close to the central canal and study their function during fictive locomotion. The majority of dI6 cells investigated were found to be rhythmically active during fictive locomotion and could be divided into two electrophysiologically distinct populations of interneurons. The first population fired rhythmic trains of action potentials that were loosely coupled to ventral root output and contained several intrinsic membrane properties of rhythm-generating neurons, raising the possibility that these cells may be involved in the generation of rhythmic activity in the locomotor CPG. The second population fired rhythmic trains of action potentials that were tightly coupled to ventral root output and lacked intrinsic oscillatory mechanisms, indicating that these neurons may be driven by a rhythm-generating network. Together these results indicate that dI6 neurons comprise an important component of the locomotor CPG that participate in multiple facets of motor behavior. PMID:22442567

Decrease of a Current Mediated by Kv1.3 Channels Causes Striatal Cholinergic Interneuron Hyperexcitability in Experimental Parkinsonism.

PubMed

Tubert, Cecilia; Taravini, Irene R E; Flores-Barrera, Eden; Sánchez, Gonzalo M; Prost, María Alejandra; Avale, María Elena; Tseng, Kuei Y; Rela, Lorena; Murer, Mario Gustavo

2016-09-06

The mechanism underlying a hypercholinergic state in Parkinson's disease (PD) remains uncertain. Here, we show that disruption of the Kv1 channel-mediated function causes hyperexcitability of striatal cholinergic interneurons in a mouse model of PD. Specifically, our data reveal that Kv1 channels containing Kv1.3 subunits contribute significantly to the orphan potassium current known as IsAHP in striatal cholinergic interneurons. Typically, this Kv1 current provides negative feedback to depolarization that limits burst firing and slows the tonic activity of cholinergic interneurons. However, such inhibitory control of cholinergic interneuron excitability by Kv1.3-mediated current is markedly diminished in the parkinsonian striatum, suggesting that targeting Kv1.3 subunits and their regulatory pathways may have therapeutic potential in PD therapy. These studies reveal unexpected roles of Kv1.3 subunit-containing channels in the regulation of firing patterns of striatal cholinergic interneurons, which were thought to be largely dependent on KCa channels. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

The hybrid modulatory/pattern generating N1L interneuron in the buccal feeding system of Lymnaea is cholinergic.

PubMed

Vehovszky, A; Elliott, C J

1995-01-01

This study examines neurotransmission between identified buccal interneurons in the feeding system of the snail Lymnaea stagnalis. We compare the pharmacology of the individual synaptic connections from a hybrid modulatory/pattern generating interneuron (N1L) to a pattern generating interneuron (N1M) with that from a modulatory interneuron (SO) to the same follower cell (N1M). The pharmacological properties of the N1L to N1M and the SO to N1M connections closely resemble each other. Both interneurons produce fast cholinergic EPSPs as judged by the blocking effects of cholinergic antagonists hexamethonium, d-tubocurarine and the cholinergic neurotoxin AF-64A. A slower, more complex but non-cholinergic component of the synaptic response is also present after stimulating either the presynaptic N1L or SO interneurons. This second component of the postsynaptic response is not dopaminergic, on the basis of its persistence in the presence of dopaminergic antagonists ergometrine and fluphenazine and the dopaminergic neurotoxin MPP+. We conclude that, although there has been an evolutionary divergence in function, the modulatory SO and the hybrid modulatory/pattern generating N1L are pharmacologically similar. Neither of them contributes directly to dopaminergic modulation of the feeding activity. These neurons also resemble the N1M protraction phase pattern generating neurons which are cholinergic (Elliott and Kemenes, 1992).

[Regulation of cortical cytoskeleton dynamics during migration of free-living amoebae].

PubMed

Kłopocka, Wanda; Redowicz, Maria Jolanta; Wasik, Anna

2009-01-01

Amoeba proteus and smaller by an order of magnitude (and evolutionary younger) Acanthamoeba castellanii have been for many years model cells for studies of amoeboidal (crawling) type of movement, characteristic also for some of metazoan cells such as fibroblasts, granulocytes and macrophages. Amoeboidal migration is indispensable of organization and dynamics of actin-based cytoskeleton. While there is a number of data on molecular mechanisms of motility of A. castellanii, there is very little known about bases of migration of A. proteus. Noteworthy, a large A. proteus (length approximately 600 microm) have been from over a century an object for studies on biology and physiology of cellular migration. This review describes the current knowledge on molecular aspects of force generation required for migration of these two amoebae and attempts to compare the functioning and regulation of actin cytoskeleton in these free-living unicellular species.

Interactions between Inhibitory Interneurons and Excitatory Associational Circuitry in Determining Spatio-Temporal Dynamics of Hippocampal Dentate Granule Cells: A Large-Scale Computational Study

PubMed Central

Hendrickson, Phillip J.; Yu, Gene J.; Song, Dong; Berger, Theodore W.

2015-01-01

This paper reports on findings from a million-cell granule cell model of the rat dentate gyrus that was used to explore the contributions of local interneuronal and associational circuits to network-level activity. The model contains experimentally derived morphological parameters for granule cells, which each contain approximately 200 compartments, and biophysical parameters for granule cells, basket cells, and mossy cells that were based both on electrophysiological data and previously published models. Synaptic input to cells in the model consisted of glutamatergic AMPA-like EPSPs and GABAergic-like IPSPs from excitatory and inhibitory neurons, respectively. The main source of input to the model was from layer II entorhinal cortical neurons. Network connectivity was constrained by the topography of the system, and was derived from axonal transport studies, which provided details about the spatial spread of axonal terminal fields, as well as how subregions of the medial and lateral entorhinal cortices project to subregions of the dentate gyrus. Results of this study show that strong feedback inhibition from the basket cell population can cause high-frequency rhythmicity in granule cells, while the strength of feedforward inhibition serves to scale the total amount of granule cell activity. Results furthermore show that the topography of local interneuronal circuits can have just as strong an impact on the development of spatio-temporal clusters in the granule cell population as the perforant path topography does, both sharpening existing clusters and introducing new ones with a greater spatial extent. Finally, results show that the interactions between the inhibitory and associational loops can cause high frequency oscillations that are modulated by a low-frequency oscillatory signal. These results serve to further illustrate the importance of topographical constraints on a global signal processing feature of a neural network, while also illustrating how rich

Differentiation of V2a interneurons from human pluripotent stem cells

PubMed Central

Butts, Jessica C.; McCreedy, Dylan A.; Martinez-Vargas, Jorge Alexis; Mendoza-Camacho, Frederico N.; Hookway, Tracy A.; Gifford, Casey A.; Taneja, Praveen; Noble-Haeusslein, Linda; McDevitt, Todd C.

2017-01-01

The spinal cord consists of multiple neuronal cell types that are critical to motor control and arise from distinct progenitor domains in the developing neural tube. Excitatory V2a interneurons in particular are an integral component of central pattern generators that control respiration and locomotion; however, the lack of a robust source of human V2a interneurons limits the ability to molecularly profile these cells and examine their therapeutic potential to treat spinal cord injury (SCI). Here, we report the directed differentiation of CHX10+ V2a interneurons from human pluripotent stem cells (hPSCs). Signaling pathways (retinoic acid, sonic hedgehog, and Notch) that pattern the neural tube were sequentially perturbed to identify an optimized combination of small molecules that yielded ∼25% CHX10+ cells in four hPSC lines. Differentiated cultures expressed much higher levels of V2a phenotypic markers (CHX10 and SOX14) than other neural lineage markers. Over time, CHX10+ cells expressed neuronal markers [neurofilament, NeuN, and vesicular glutamate transporter 2 (VGlut2)], and cultures exhibited increased action potential frequency. Single-cell RNAseq analysis confirmed CHX10+ cells within the differentiated population, which consisted primarily of neurons with some glial and neural progenitor cells. At 2 wk after transplantation into the spinal cord of mice, hPSC-derived V2a cultures survived at the site of injection, coexpressed NeuN and VGlut2, extended neurites >5 mm, and formed putative synapses with host neurons. These results provide a description of V2a interneurons differentiated from hPSCs that may be used to model central nervous system development and serve as a potential cell therapy for SCI. PMID:28438991

Parvalbumin Interneurons of Central Amygdala Regulate the Negative Affective States and the Expression of Corticotrophin-Releasing Hormone During Morphine Withdrawal

PubMed Central

Wang, Li; Shen, Minjie; Jiang, Changyou

2016-01-01

Background: The central nucleus of the amygdala (CeA) is a crucial component of the neuronal circuitry mediating aversive emotion. Its role in the negative affective states during drug withdrawal includes changes in opioidergic, GABAergic, and corticotropin-releasing factor neurotransmission. However, the modulation of the neurobiological interconnectivity in the CeA and its effects in the negative reinforcement of drug dependents are poorly understood. Method: We performed electrophysiological recordings to assess the membrane excitability of parvalbumin (PV)+ interneurons in the CeA during chronic morphine withdrawal. We tested the morphine withdrawal–induced negative affective states, such as the aversive (assessed by conditioned place aversion), anxiety (assessed by elevated plus maze), and anhedonic-like (assessed by saccharin preference test) behaviors, as well as the mRNA level of corticotropin-releasing hormone (CRH) via optogenetic inhibition or activation of PV+ interneurons in the CeA. Result: Chronic morphine withdrawal increased the firing rate of CeA PV+ interneurons. Optogenetic inhibition of the activity of CeA PV+ interneurons attenuated the morphine withdrawal–induced negative affective states, such as the aversive, anxiety, and anhedonic-like behaviors, while direct activation of CeA PV+ interneurons could trigger those negative affective-like behaviors. Optogenetic inhibition of the CeA PV+ interneurons during the morphine withdrawal significantly attenuated the elevated CRH mRNA level in the CeA. Conclusion: The activity of PV+ interneurons in the CeA was up-regulated during chronic morphine withdrawal. The activation of PV+ interneurons during morphine withdrawal was crucial for the induction of the negative emotion and the up-regulation of CRH mRNA levels in the CeA. PMID:27385383

Mechanical Coordination of Single-Cell and Collective-Cell Amoeboid Migration

NASA Astrophysics Data System (ADS)

Del Alamo, Juan Carlos

Amoeboid migration consists of the sequential repetition of pseudopod extensions and retractions driven by actin polymerization and actomyosin contraction, and requires cells to apply mechanical forces on their surroundings. We measure the three-dimensional forces exerted by chemotaxing Dictyostelium cells, and examine wild-type cells as well as mutants with defects in contractility, F-actin polymerization, internal F-actin crosslinking, and cortical integrity. We find that cells pull on their substrate adhesions using two distinct, yet interconnected mechanisms: axial actomyosin contractility and cortical tension. The 3D pulling forces generated by both mechanisms are internally balanced by an increase in cytoplasmic pressure that allows cells to push on their substrate, and we show that these pushing forces are relevant for cell invasion and migration in three-dimensional environments. We observe that cells migrate mainly by forming two stationary adhesion sites at the front and back of the cell, over which the cell body moves forward in a step-wise fashion. During this process, the traction forces at each adhesion site are switched off and subsequently their direction is reversed. The cell migration speed is found to be proportional to the rate at which cells are able regulate these forces to produce the cell shape changes needed for locomotion, which is increased when axial contractility overcomes the stabilizing effect of cortical tension. This spatiotemporal coordination is conserved in streams of multiple migratory cells connected head to tail, which also migrate by exerting traction forces on stationary sites. Furthermore, we observe that trailing cells reuse the adhesion sites of the leading cells. Finally, we provide evidence that the above modes of migration may be conserved in a range of other amoeboid-type moving cells such as neutrophils.

Girdin Is an Intrinsic Regulator of Neuroblast Chain Migration in the Rostral Migratory Stream of the Postnatal Brain

PubMed Central

Wang, Yun; Kaneko, Naoko; Asai, Naoya; Enomoto, Atsushi; Isotani-Sakakibara, Mayu; Kato, Takuya; Asai, Masato; Murakumo, Yoshiki; Ota, Haruko; Hikita, Takao; Namba, Takashi; Kuroda, Keisuke; Kaibuchi, Kozo; Ming, Guo-li; Song, Hongjun; Sawamoto, Kazunobu; Takahashi, Masahide

2017-01-01

In postnatally developing and adult brains, interneurons of the olfactory bulb (OB) are continuously generated at the subventricular zone of the forebrain. The newborn neuroblasts migrate tangentially to the OB through a well defined pathway, the rostral migratory stream (RMS), where the neuroblasts undergo collective migration termed “chain migration.” The cell-intrinsic regulatory mechanism of neuroblast chain migration, however, has not been uncovered. Here we show that mice lacking the actin-binding Akt substrate Girdin (a protein that interacts with Disrupted-In-Schizophrenia 1 to regulate neurogenesis in the dentate gyrus) have profound defects in neuroblast chain migration along the RMS. Analysis of two gene knock-in mice harboring Girdin mutants identified unique amino acid residues in Girdin’s C-terminal domain that are responsible for the regulation of neuroblast chain migration but revealed no apparent requirement of Girdin phosphorylation by Akt. Electron microscopic analyses demonstrated the involvement of Girdin in neuroblast cell–cell interactions. These findings suggest that Girdin is an important intrinsic factor that specifically governs neuroblast chain migration along the RMS. PMID:21632933

Barrels XXX meeting report: Barrels in Baltimore.

PubMed

Shin, Hyeyoung; Bitzidou, Malamati; Palaguachi, Fernando; Brumberg, Joshua C

2018-03-01

The Barrels meeting annually brings together researchers focused on the rodent whisker to cortical barrel system prior to the Society for Neuroscience meeting. The 2017 meeting focused on the classification of cortical interneurons, the role interneurons have in shaping brain dynamics, and finally on the circuitry underlying oral sensations. The meeting highlighted the latest advancements in this rapidly advancing field.

Excitation-transcription coupling in parvalbumin-positive interneurons employs a novel CaM Kinase-dependent pathway distinct from excitatory neurons

PubMed Central

Cohen, Samuel M.; Ma, Huan; Kuchibhotla, Kishore V.; Watson, Brendon O.; Buzsáki, György; Froemke, Robert C.; Tsien, Richard W.

2016-01-01

Properly functional CNS circuits depend on inhibitory interneurons that in turn rely upon activity-dependent gene expression for morphological development, connectivity and excitatory-inhibitory coordination. Despite its importance, excitation-transcription coupling in inhibitory interneurons is poorly understood. Here, we report that PV+ interneurons employ a novel CaMK-dependent pathway to trigger CREB phosphorylation and gene expression. As in excitatory neurons, voltage-gated Ca2+ influx through CaV1 channels triggers CaM nuclear translocation via local Ca2+ signaling. However, PV+ interneurons are distinct in that nuclear signaling is mediated by γCaMKI, not γCaMKII. CREB phosphorylation also proceeds with slow, sigmoid kinetics, rate-limited by paucity of CaMKIV, protecting against saturation of phospho-CREB in the face of higher firing rates and bigger Ca2+ transients. Our findings support the generality of CaM shuttling to drive nuclear CaMK activity, and are relevant to disease pathophysiology, insofar as dysfunction of PV+ interneurons and molecules underpinning their excitation-transcription coupling both relate to neuropsychiatric disease. PMID:27041500

Expression of gastrin-releasing peptide by excitatory interneurons in the mouse superficial dorsal horn.

PubMed

Gutierrez-Mecinas, Maria; Watanabe, Masahiko; Todd, Andrew J

2014-12-11

Gastrin-releasing peptide (GRP) and its receptor have been shown to play an important role in the sensation of itch. However, although GRP immunoreactivity has been detected in the spinal dorsal horn, there is debate about whether this originates from primary afferents or local excitatory interneurons. We therefore examined the relation of GRP immunoreactivity to that seen with antibodies that label primary afferent or excitatory interneuron terminals. We tested the specificity of the GRP antibody by preincubating with peptides with which it could potentially cross-react. We also examined tissue from a mouse line in which enhanced green fluorescent protein (EGFP) is expressed under control of the GRP promoter. GRP immunoreactivity was seen in both primary afferent and non-primary glutamatergic axon terminals in the superficial dorsal horn. However, immunostaining was blocked by pre-incubation of the antibody with substance P, which is present at high levels in many nociceptive primary afferents. EGFP+ cells in the GRP-EGFP mouse did not express Pax2, and their axons contained the vesicular glutamate transporter 2 (VGLUT2), indicating that they are excitatory interneurons. In most cases, their axons were also GRP-immunoreactive. Multiple-labelling immunocytochemical studies indicated that these cells did not express either of the preprotachykinin peptides, and that they generally lacked protein kinase Cγ, which is expressed by a subset of the excitatory interneurons in this region. These results show that GRP is expressed by a distinct population of excitatory interneurons in laminae I-II that are likely to be involved in the itch pathway. They also suggest that the GRP immunoreactivity seen in primary afferents in previous studies may have resulted from cross-reaction of the GRP antibody with substance P or the closely related peptide neurokinin A.

Patterned sensory nerve stimulation enhances the reactivity of spinal Ia inhibitory interneurons.

PubMed

Kubota, Shinji; Hirano, Masato; Morishita, Takuya; Uehara, Kazumasa; Funase, Kozo

2015-03-25

Patterned sensory nerve stimulation has been shown to induce plastic changes in the reciprocal Ia inhibitory circuit. However, the mechanisms underlying these changes have not yet been elucidated in detail. The aim of the present study was to determine whether the reactivity of Ia inhibitory interneurons could be altered by patterned sensory nerve stimulation. The degree of reciprocal Ia inhibition, the conditioning effects of transcranial magnetic stimulation (TMS) on the soleus (SOL) muscle H-reflex, and the ratio of the maximum H-reflex amplitude versus maximum M-wave (H(max)/M(max)) were examined in 10 healthy individuals. Patterned electrical nerve stimulation was applied to the common peroneal nerve every 1 s (100 Hz-5 train) at the motor threshold intensity of tibialis anterior muscle to induce activity changes in the reciprocal Ia inhibitory circuit. Reciprocal Ia inhibition, the TMS-conditioned H-reflex amplitude, and H(max)/M(max) were recorded before, immediately after, and 15 min after the electrical stimulation. The patterned electrical nerve stimulation significantly increased the degree of reciprocal Ia inhibition and decreased the amplitude of the TMS-conditioned H-reflex in the short-latency inhibition phase, which was presumably mediated by Ia inhibitory interneurons. However, it had no effect on H(max)/M(max). Our results indicated that patterned sensory nerve stimulation could modulate the activity of Ia inhibitory interneurons, and this change may have been caused by the synaptic modification of Ia inhibitory interneuron terminals. These results may lead to a clearer understanding of the spinal cord synaptic plasticity produced by repetitive sensory inputs. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Visual Receptive Field Heterogeneity and Functional Connectivity of Adjacent Neurons in Primate Frontoparietal Association Cortices.

PubMed

Viswanathan, Pooja; Nieder, Andreas

2017-09-13

The basic organization principles of the primary visual cortex (V1) are commonly assumed to also hold in the association cortex such that neurons within a cortical column share functional connectivity patterns and represent the same region of the visual field. We mapped the visual receptive fields (RFs) of neurons recorded at the same electrode in the ventral intraparietal area (VIP) and the lateral prefrontal cortex (PFC) of rhesus monkeys. We report that the spatial characteristics of visual RFs between adjacent neurons differed considerably, with increasing heterogeneity from VIP to PFC. In addition to RF incongruences, we found differential functional connectivity between putative inhibitory interneurons and pyramidal cells in PFC and VIP. These findings suggest that local RF topography vanishes with hierarchical distance from visual cortical input and argue for increasingly modified functional microcircuits in noncanonical association cortices that contrast V1. SIGNIFICANCE STATEMENT Our visual field is thought to be represented faithfully by the early visual brain areas; all the information from a certain region of the visual field is conveyed to neurons situated close together within a functionally defined cortical column. We examined this principle in the association areas, PFC, and ventral intraparietal area of rhesus monkeys and found that adjacent neurons represent markedly different areas of the visual field. This is the first demonstration of such noncanonical organization of these brain areas. Copyright © 2017 the authors 0270-6474/17/378919-10$15.00/0.

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

Amelioration of improper differentiation of somatostatin-positive interneurons by triiodothyronine in a growth-retarded hypothyroid mouse strain.

PubMed

Uchida, Katsuya; Taguchi, Yusuke; Sato, Chika; Miyazaki, Hidetaka; Kobayashi, Kenichi; Kobayashi, Tetsuya; Itoi, Keiichi

2014-01-24

Thyroid hormone (TH) plays an important role in brain development, and TH deficiency during pregnancy or early postnatal periods leads to neurological disorders such as cretinism. Hypothyroidism reduces the number of parvalbumin (PV)-positive interneurons in the neocortex and hippocampus. Here we used a mouse strain (growth-retarded; grt) that shows growth retardation and hypothyroidism to examine whether somatostatin (Sst)-positive interneurons that are generated from the same pool of neural progenitor cells as PV-positive cells are also altered by TH deficiency. The number of PV-positive interneurons was significantly decreased in the neocortex and hippocampus of grt mice as compared with normal control mice. In contrast to the decrease in the number of PV neurons, the number of Sst-positive interneurons in grt mice was increased in the stratum oriens of the hippocampus and the hilus of the dentate gyrus, although their number was unchanged in the neocortex. These changes were reversed by triiodothyronine administration from postnatal day (PD) 0 to 20. TH supplementation that was initiated after PD21 did not, however, affect the number of PV- or Sst-positive cells. These results suggest that during the first three postnatal weeks, TH may be critical for the generation of subpopulations of interneurons. Copyright © 2013 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Long-term plasticity in identified hippocampal GABAergic interneurons in the CA1 area in vivo.

PubMed

Lau, Petrina Yau-Pok; Katona, Linda; Saghy, Peter; Newton, Kathryn; Somogyi, Peter; Lamsa, Karri P

2017-05-01

Long-term plasticity is well documented in synapses between glutamatergic principal cells in the cortex both in vitro and in vivo. Long-term potentiation (LTP) and -depression (LTD) have also been reported in glutamatergic connections to hippocampal GABAergic interneurons expressing parvalbumin (PV+) or nitric oxide synthase (NOS+) in brain slices, but plasticity in these cells has not been tested in vivo. We investigated synaptically-evoked suprathreshold excitation of identified hippocampal neurons in the CA1 area of urethane-anaesthetized rats. Neurons were recorded extracellularly with glass microelectrodes, and labelled with neurobiotin for anatomical analyses. Single-shock electrical stimulation of afferents from the contralateral CA1 elicited postsynaptic action potentials with monosynaptic features showing short delay (9.95 ± 0.41 ms) and small jitter in 13 neurons through the commissural pathway. Theta-burst stimulation (TBS) generated LTP of the synaptically-evoked spike probability in pyramidal cells, and in a bistratified cell and two unidentified fast-spiking interneurons. On the contrary, PV+ basket cells and NOS+ ivy cells exhibited either LTD or LTP. An identified axo-axonic cell failed to show long-term change in its response to stimulation. Discharge of the cells did not explain whether LTP or LTD was generated. For the fast-spiking interneurons, as a group, no correlation was found between plasticity and local field potential oscillations (1-3 or 3-6 Hz components) recorded immediately prior to TBS. The results demonstrate activity-induced long-term plasticity in synaptic excitation of hippocampal PV+ and NOS+ interneurons in vivo. Physiological and pathological activity patterns in vivo may generate similar plasticity in these interneurons.

Striatal fast-spiking interneurons selectively modulate circuit output and are required for habitual behavior

PubMed Central

O'Hare, Justin K; Li, Haofang; Kim, Namsoo; Gaidis, Erin; Ade, Kristen; Beck, Jeff; Yin, Henry

2017-01-01

Habit formation is a behavioral adaptation that automates routine actions. Habitual behavior correlates with broad reconfigurations of dorsolateral striatal (DLS) circuit properties that increase gain and shift pathway timing. The mechanism(s) for these circuit adaptations are unknown and could be responsible for habitual behavior. Here we find that a single class of interneuron, fast-spiking interneurons (FSIs), modulates all of these habit-predictive properties. Consistent with a role in habits, FSIs are more excitable in habitual mice compared to goal-directed and acute chemogenetic inhibition of FSIs in DLS prevents the expression of habitual lever pressing. In vivo recordings further reveal a previously unappreciated selective modulation of SPNs based on their firing patterns; FSIs inhibit most SPNs but paradoxically promote the activity of a subset displaying high fractions of gamma-frequency spiking. These results establish a microcircuit mechanism for habits and provide a new example of how interneurons mediate experience-dependent behavior. PMID:28871960

Subunit-dependent postsynaptic expression of kainate receptors on hippocampal interneurons in area CA1

PubMed Central

Wondolowski, Joyce; Frerking, Matthew

2009-01-01

Kainate receptors (KARs) contribute to postsynaptic excitation in only a select subset of neurons. To define the parameters that specify the postsynaptic expression of KARs, we examined the contribution of KARs to EPSCs on hippocampal interneurons in area CA1. Interneurons in stratum radiatum/lacunosum-moleculare (SR/SLM) express KARs both with and without the GluR5 subunit, but KAR-mediated EPSCs are generated mainly, if not entirely, by GluR5-containing KARs. Extrasynaptic glutamate spillover profoundly recruits AMPARs with little effect on KARs, indicating that KARs are targeted at the synapse more precisely than AMPARs. However, spontaneous EPSCs with a conventional AMPAR component did not have a resolvable contribution of KARs, suggesting that the KARs that contribute to the evoked EPSCs are at a distinct set of synapses. GluR5-containing KARs on interneurons in stratum oriens do not contribute substantially to the EPSC. We conclude that KARs are localized to synapses by cell type-, synapse-, and subunit-selective mechanisms. PMID:19144856

Identification of Parvalbumin Interneurons as Cellular Substrate of Fear Memory Persistence.

PubMed

Çaliskan, Gürsel; Müller, Iris; Semtner, Marcus; Winkelmann, Aline; Raza, Ahsan S; Hollnagel, Jan O; Rösler, Anton; Heinemann, Uwe; Stork, Oliver; Meier, Jochen C

2016-05-01

Parvalbumin-positive (PV) basket cells provide perisomatic inhibition in the cortex and hippocampus and control generation of memory-related network activity patterns, such as sharp wave ripples (SPW-R). Deterioration of this class of fast-spiking interneurons has been observed in neuropsychiatric disorders and evidence from animal models suggests their involvement in the acquisition and extinction of fear memories. Here, we used mice with neuron type-targeted expression of the presynaptic gain-of-function glycine receptor RNA variant GlyR α3L(185L)to genetically enhance the network activity of PV interneurons. These mice showed reduced extinction of contextual fear memory but normal auditory cued fear memory. They furthermore displayed increase of SPW-R activity in area CA3 and CA1 and facilitated propagation of this particular network activity pattern, as determined in ventral hippocampal slice preparations. Individual freezing levels during extinction and SPW-R propagation were correlated across genotypes. The same was true for parvalbumin immunoreactivity in the ventral hippocampus, which was generally augmented in the GlyR mutant mice and correlated with individual freezing levels. Together, these results identify PV interneurons as critical cellular substrate of fear memory persistence and associated SPW-R activity in the hippocampus. Our findings may be relevant for the identification and characterization of physiological correlates for posttraumatic stress and anxiety disorders. © The Author 2016. Published by Oxford University Press.

Identification of Parvalbumin Interneurons as Cellular Substrate of Fear Memory Persistence

PubMed Central

Çalışkan, Gürsel; Müller, Iris; Semtner, Marcus; Winkelmann, Aline; Raza, Ahsan S.; Hollnagel, Jan O.; Rösler, Anton; Heinemann, Uwe; Stork, Oliver; Meier, Jochen C.

2016-01-01

Parvalbumin-positive (PV) basket cells provide perisomatic inhibition in the cortex and hippocampus and control generation of memory-related network activity patterns, such as sharp wave ripples (SPW-R). Deterioration of this class of fast-spiking interneurons has been observed in neuropsychiatric disorders and evidence from animal models suggests their involvement in the acquisition and extinction of fear memories. Here, we used mice with neuron type-targeted expression of the presynaptic gain-of-function glycine receptor RNA variant GlyR α3L185L to genetically enhance the network activity of PV interneurons. These mice showed reduced extinction of contextual fear memory but normal auditory cued fear memory. They furthermore displayed increase of SPW-R activity in area CA3 and CA1 and facilitated propagation of this particular network activity pattern, as determined in ventral hippocampal slice preparations. Individual freezing levels during extinction and SPW-R propagation were correlated across genotypes. The same was true for parvalbumin immunoreactivity in the ventral hippocampus, which was generally augmented in the GlyR mutant mice and correlated with individual freezing levels. Together, these results identify PV interneurons as critical cellular substrate of fear memory persistence and associated SPW-R activity in the hippocampus. Our findings may be relevant for the identification and characterization of physiological correlates for posttraumatic stress and anxiety disorders. PMID:26908632

Monosynaptic EPSPs elicited by single interneurones and spindle afferents in trigeminal motoneurones of anaesthetized rats.

PubMed Central

Grimwood, P D; Appenteng, K; Curtis, J C

1992-01-01

1. Our aim has been to quantify the monosynaptic connections of trigeminal interneurones and spindle afferents onto jaw-elevator motoneurones as a step towards identifying common features in organization of monosynaptic inputs onto motoneurones. We have used the intracellular variant of the spike-triggered averaging method to examine the connections of single identified trigeminal interneurones and jaw-elevator muscle spindle afferents onto single jaw-elevator motoneurones. The interneurones examined lay in the region immediately caudal to the trigeminal motor nucleus. The experiments were performed on rats anaesthetized with pentobarbitone, paralysed and artificially ventilated. 2. Ten EPSPs and eight IPSPs were obtained from examining the connections of seventeen interneurones to thirty-six motoneurones, suggesting a functional connectivity of 50% for individual interneurones onto elevator motoneurones. Fourteen EPSPs were obtained from examining the connections of thirteen spindle afferents onto twenty-seven motoneurones, giving a functional connectivity of 52% for individual spindle afferents onto elevator motoneurones. The amplitudes of the EPSPs elicited by interneurones ranged from 7-48 microV (mean = 17, S.D. = 12.5, n = 10) and from 7 to 289 microV (mean = 64, S.D. = 76.0, n = 14) for the spindle-mediated EPSPs; the difference in the two means was not significant (P = 0.07). 3. However, the amplitude of averaged responses obtained by signal averaging methods are dependent on the assumption that the postsynaptic response occurs following every impulse in the presynaptic neurone. We therefore estimated the percentage of sweeps which contained EPSPs triggered by the presynaptic neurone under study. In essence the method used consisted of visual inspection of the individual sweeps comprising an average in order to assess the occurrence of EPSPs within six separate time windows, each of duration +/- 0.3 ms. Five windows were placed at randomly selected times on

Large variability in synaptic N-methyl-D-aspartate receptor density on interneurons and a comparison with pyramidal-cell spines in the rat hippocampus.

PubMed

Nyíri, G; Stephenson, F A; Freund, T F; Somogyi, P

2003-01-01

Pyramidal cells receive input from several types of GABA-releasing interneurons and innervate them reciprocally. Glutamatergic activation of interneurons involves both alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) type glutamate receptors expressed in type I synapses, mostly on their dendritic shafts. On average, the synaptic AMPA receptor content is several times higher on interneurons than in the spines of pyramidal cells. To compare the NMDA receptor content of synapses, we used a quantitative postembedding immunogold technique on serial electron microscopic sections, and analysed the synapses on interneuron dendrites and pyramidal cell spines in the CA1 area. Because all NMDA receptors contain the obligatory NR1 subunit, receptor localisation was carried out using antibodies recognising all splice variants of the NR1 subunit. Four populations of synapse were examined: i). on spines of pyramidal cells in stratum (str.) radiatum and str. oriens; ii). on parvalbumin-positive interneuronal dendritic shafts in str. radiatum; iii). on randomly found dendritic shafts in str. oriens and iv). on somatostatin-positive interneuronal dendritic shafts and somata in str. oriens. On average, the size of the synapses on spines was about half of those on interneurons. The four populations of synapse significantly differed in labelling for the NR1 subunit. The median density of NR1 subunit labelling was highest on pyramidal cell spines. It was lowest in the synapses on parvalbumin-positive dendrites in str. radiatum, where more than half of these synapses were immunonegative. In str. oriens, synapses on interneurons had a high variability of receptor content; some dendrites were similar to those in str. radiatum, including the proximal synapses of somatostatin-positive cells, whereas others had immunoreactivity for the NR1 subunit similar to or higher than synapses on pyramidal cell spines. These results show that synaptic NMDA

Cortical and subcortical innervation of band heterotopia after developmental thyroid hormone insufficiency

EPA Science Inventory

The characteristic laminated cytoarchitecture of the neocortex emerges from the orderly proliferation and migration of neurons during corticogenesis. Not surprisingly, developmental disorders affecting the laminar positioning of cortical neurons can have dramatic affects on cogni...

Apolipoprotein E4 Causes Age- and Sex-Dependent Impairments of Hilar GABAergic Interneurons and Learning and Memory Deficits in Mice

PubMed Central

Leung, Laura; Andrews-Zwilling, Yaisa; Yoon, Seo Yeon; Jain, Sachi; Ring, Karen; Dai, Jessica; Wang, Max Mu; Tong, Leslie; Walker, David; Huang, Yadong

2012-01-01

Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease (AD). ApoE4 has sex-dependent effects, whereby the risk of developing AD is higher in apoE4-expressing females than males. However, the mechanism underlying the sex difference, in relation to apoE4, is unknown. Previous findings indicate that apoE4 causes age-dependent impairments of hilar GABAergic interneurons in female mice, leading to learning and memory deficits. Here, we investigate whether the detrimental effects of apoE4 on hilar GABAergic interneurons are sex-dependent using apoE knock-in (KI) mice across different ages. We found that in female apoE-KI mice, there was an age-dependent depletion of hilar GABAergic interneurons, whereby GAD67- or somatostatin-positive–but not NPY- or parvalbumin-positive–interneuron loss was exacerbated by apoE4. Loss of these neuronal populations was correlated with the severity of spatial learning deficits at 16 months of age in female apoE4-KI mice; however, this effect was not observed in female apoE3-KI mice. In contrast, we found an increase in the numbers of hilar GABAergic interneurons with advancing age in male apoE-KI mice, regardless of apoE genotype. Moreover, male apoE-KI mice showed a consistent ratio of hilar inhibitory GABAergic interneurons to excitatory mossy cells approximating 1.5 that is independent of apoE genotype and age, whereas female apoE-KI mice exhibited an age-dependent decrease in this ratio, which was exacerbated by apoE4. Interestingly, there are no apoE genotype effects on GABAergic interneurons in the CA1 and CA3 subregions of the hippocampus as well as the entorhinal and auditory cortexes. These findings suggest that the sex-dependent effects of apoE4 on developing AD is in part attributable to inherent sex-based differences in the numbers of hilar GABAergic interneurons, which is further modulated by apoE genotype. PMID:23300939

Shunting inhibition improves robustness of gamma oscillations in hippocampal interneuron networks by homogenizing firing rates.

PubMed

Vida, Imre; Bartos, Marlene; Jonas, Peter

2006-01-05

Networks of GABAergic neurons are key elements in the generation of gamma oscillations in the brain. Computational studies suggested that the emergence of coherent oscillations requires hyperpolarizing inhibition. Here, we show that GABA(A) receptor-mediated inhibition in mature interneurons of the hippocampal dentate gyrus is shunting rather than hyperpolarizing. Unexpectedly, when shunting inhibition is incorporated into a structured interneuron network model with fast and strong synapses, coherent oscillations emerge. In comparison to hyperpolarizing inhibition, networks with shunting inhibition show several advantages. First, oscillations are generated with smaller tonic excitatory drive. Second, network frequencies are tuned to the gamma band. Finally, robustness against heterogeneity in the excitatory drive is markedly improved. In single interneurons, shunting inhibition shortens the interspike interval for low levels of drive but prolongs it for high levels, leading to homogenization of neuronal firing rates. Thus, shunting inhibition may confer increased robustness to gamma oscillations in the brain.

A resilient formin-derived cortical actin meshwork in the rear drives actomyosin-based motility in 2D confinement

PubMed Central

Ramalingam, Nagendran; Franke, Christof; Jaschinski, Evelin; Winterhoff, Moritz; Lu, Yao; Brühmann, Stefan; Junemann, Alexander; Meier, Helena; Noegel, Angelika A.; Weber, Igor; Zhao, Hongxia; Merkel, Rudolf; Schleicher, Michael; Faix, Jan

2015-01-01

Cell migration is driven by the establishment of disparity between the cortical properties of the softer front and the more rigid rear allowing front extension and actomyosin-based rear contraction. However, how the cortical actin meshwork in the rear is generated remains elusive. Here we identify the mDia1-like formin A (ForA) from Dictyostelium discoideum that generates a subset of filaments as the basis of a resilient cortical actin sheath in the rear. Mechanical resistance of this actin compartment is accomplished by actin crosslinkers and IQGAP-related proteins, and is mandatory to withstand the increased contractile forces in response to mechanical stress by impeding unproductive blebbing in the rear, allowing efficient cell migration in two-dimensional-confined environments. Consistently, ForA supresses the formation of lateral protrusions, rapidly relocalizes to new prospective ends in repolarizing cells and is required for cortical integrity. Finally, we show that ForA utilizes the phosphoinositide gradients in polarized cells for subcellular targeting. PMID:26415699

VAV-1 acts in a single interneuron to inhibit motor circuit activity in Caenorhabditis elegans.

PubMed

Fry, Amanda L; Laboy, Jocelyn T; Norman, Kenneth R

2014-11-21

The complex molecular and cellular mechanisms underlying neuronal control of animal movement are not well understood. Locomotion of Caenorhabditis elegans is mediated by a neuronal circuit that produces coordinated sinusoidal movement. Here we utilize this simple, yet elegant, behaviour to show that VAV-1, a conserved guanine nucleotide exchange factor for Rho-family GTPases, negatively regulates motor circuit activity and the rate of locomotion. While vav-1 is expressed in a small subset of neurons, we find that VAV-1 function is required in a single interneuron, ALA, to regulate motor neuron circuit activity. Furthermore, we show by genetic and optogenetic manipulation of ALA that VAV-1 is required for the excitation and activation of this neuron. We find that ALA signalling inhibits command interneuron activity by abrogating excitatory signalling in the command interneurons, which is responsible for promoting motor neuron circuit activity. Together, our data describe a novel neuromodulatory role for VAV-1-dependent signalling in the regulation of motor circuit activity and locomotion.

The Caenorhabditis elegans interneuron ALA is (also) a high-threshold mechanosensor

PubMed Central

2013-01-01

Background To survive dynamic environments, it is essential for all animals to appropriately modulate their behavior in response to various stimulus intensities. For instance, the nematode Caenorhabditis elegans suppresses the rate of egg-laying in response to intense mechanical stimuli, in a manner dependent on the mechanosensory neurons FLP and PVD. We have found that the unilaterally placed single interneuron ALA acted as a high-threshold mechanosensor, and that it was required for this protective behavioral response. Results ALA was required for the inhibition of egg-laying in response to a strong (picking-like) mechanical stimulus, characteristic of routine handling of the animals. Moreover, ALA did not respond physiologically to less intense touch stimuli, but exhibited distinct physiological responses to anterior and posterior picking-like touch, suggesting that it could distinguish between spatially separated stimuli. These responses required neither neurotransmitter nor neuropeptide release from potential upstream neurons. In contrast, the long, bilaterally symmetric processes of ALA itself were required for producing its physiological responses; when they were severed, responses to stimuli administered between the cut and the cell body were unaffected, while responses to stimuli administered posterior to the cut were abolished. Conclusion C. elegans neurons are typically classified into three major groups: sensory neurons with specialized sensory dendrites, interneurons, and motoneurons with neuromuscular junctions. Our findings suggest that ALA can autonomously sense intense touch and is thus a dual-function neuron, i.e., an interneuron as well as a novel high-threshold mechanosensor. PMID:24341457

The Caenorhabditis elegans interneuron ALA is (also) a high-threshold mechanosensor.

PubMed

Sanders, Jarred; Nagy, Stanislav; Fetterman, Graham; Wright, Charles; Treinin, Millet; Biron, David

2013-12-17

To survive dynamic environments, it is essential for all animals to appropriately modulate their behavior in response to various stimulus intensities. For instance, the nematode Caenorhabditis elegans suppresses the rate of egg-laying in response to intense mechanical stimuli, in a manner dependent on the mechanosensory neurons FLP and PVD. We have found that the unilaterally placed single interneuron ALA acted as a high-threshold mechanosensor, and that it was required for this protective behavioral response. ALA was required for the inhibition of egg-laying in response to a strong (picking-like) mechanical stimulus, characteristic of routine handling of the animals. Moreover, ALA did not respond physiologically to less intense touch stimuli, but exhibited distinct physiological responses to anterior and posterior picking-like touch, suggesting that it could distinguish between spatially separated stimuli. These responses required neither neurotransmitter nor neuropeptide release from potential upstream neurons. In contrast, the long, bilaterally symmetric processes of ALA itself were required for producing its physiological responses; when they were severed, responses to stimuli administered between the cut and the cell body were unaffected, while responses to stimuli administered posterior to the cut were abolished. C. elegans neurons are typically classified into three major groups: sensory neurons with specialized sensory dendrites, interneurons, and motoneurons with neuromuscular junctions. Our findings suggest that ALA can autonomously sense intense touch and is thus a dual-function neuron, i.e., an interneuron as well as a novel high-threshold mechanosensor.

CDYL Deficiency Disrupts Neuronal Migration and Increases Susceptibility to Epilepsy.

PubMed

Qin, Rui; Cao, Shuai; Lyu, Tianjie; Qi, Cai; Zhang, Weiguang; Wang, Yun

2017-01-10

During brain development, the correct migration of newborn neurons is one of the determinants of circuit formation, and neuronal migration defects may lead to neurological and psychiatric disorders. The molecular mechanisms underlying neuronal migration and related disorders are poorly understood. Here, we report that Chromodomain Y-like (CDYL) is critical for neuronal migration in mice. Knocking down CDYL caused neuronal migration defects and disrupted both mobility and multipolar-to-bipolar transition of migrating neurons. We find that CDYL regulates neuronal migration by transcriptionally repressing RhoA. In addition, CDYL deficiency increased the excitability of cortical pyramidal neurons and the susceptibility of mice to convulsant-induced seizures. These results demonstrate that CDYL is a regulator of neuronal migration and shed light on the pathogenesis of seizure-related neurodevelopmental disorders. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

A supercritical density of fast Na+ channels ensures rapid propagation of action potentials in GABAergic interneuron axons

PubMed Central

Hu, Hua; Jonas, Peter

2014-01-01

Fast-spiking, parvalbumin-expressing GABAergic interneurons/basket cells (BCs) play a key role in feedforward and feedback inhibition, gamma oscillations, and complex information processing. For these functions, fast propagation of action potentials (APs) from the soma to the presynaptic terminals is important. However, the functional properties of interneuron axons remain elusive. Here, we examined interneuron axons by confocally targeted subcellular patch-clamp recording in rat hippocampal slices. APs were initiated in the proximal axon ~20 μm from the soma, and propagated to the distal axon with high reliability and speed. Subcellular mapping revealed a stepwise increase of Na+ conductance density from the soma to the proximal axon, followed by a further gradual increase in the distal axon. Active cable modeling and experiments with partial channel block indicated that low axonal Na+ conductance density was sufficient for reliability, but high Na+ density was necessary for both speed of propagation and fast-spiking AP phenotype. Our results suggest that a supercritical density of Na+ channels compensates for the morphological properties of interneuron axons (small segmental diameter, extensive branching, and high bouton density), ensuring fast AP propagation and high-frequency repetitive firing. PMID:24657965

Regulation of cerebral cortex development by Rho GTPases: insights from in vivo studies

PubMed Central

Azzarelli, Roberta; Kerloch, Thomas; Pacary, Emilie

2015-01-01

The cerebral cortex is the site of higher human cognitive and motor functions. Histologically, it is organized into six horizontal layers, each containing unique populations of molecularly and functionally distinct excitatory projection neurons and inhibitory interneurons. The stereotyped cellular distribution of cortical neurons is crucial for the formation of functional neural circuits and it is predominantly established during embryonic development. Cortical neuron development is a multiphasic process characterized by sequential steps of neural progenitor proliferation, cell cycle exit, neuroblast migration and neuronal differentiation. This series of events requires an extensive and dynamic remodeling of the cell cytoskeleton at each step of the process. As major regulators of the cytoskeleton, the family of small Rho GTPases has been shown to play essential functions in cerebral cortex development. Here we review in vivo findings that support the contribution of Rho GTPases to cortical projection neuron development and we address their involvement in the etiology of cerebral cortex malformations. PMID:25610373

Bayesian Computation Emerges in Generic Cortical Microcircuits through Spike-Timing-Dependent Plasticity

PubMed Central

Nessler, Bernhard; Pfeiffer, Michael; Buesing, Lars; Maass, Wolfgang

2013-01-01

The principles by which networks of neurons compute, and how spike-timing dependent plasticity (STDP) of synaptic weights generates and maintains their computational function, are unknown. Preceding work has shown that soft winner-take-all (WTA) circuits, where pyramidal neurons inhibit each other via interneurons, are a common motif of cortical microcircuits. We show through theoretical analysis and computer simulations that Bayesian computation is induced in these network motifs through STDP in combination with activity-dependent changes in the excitability of neurons. The fundamental components of this emergent Bayesian computation are priors that result from adaptation of neuronal excitability and implicit generative models for hidden causes that are created in the synaptic weights through STDP. In fact, a surprising result is that STDP is able to approximate a powerful principle for fitting such implicit generative models to high-dimensional spike inputs: Expectation Maximization. Our results suggest that the experimentally observed spontaneous activity and trial-to-trial variability of cortical neurons are essential features of their information processing capability, since their functional role is to represent probability distributions rather than static neural codes. Furthermore it suggests networks of Bayesian computation modules as a new model for distributed information processing in the cortex. PMID:23633941

Cortical Structure Alterations and Social Behavior Impairment in p50-Deficient Mice.

PubMed

Bonini, Sara Anna; Mastinu, Andrea; Maccarinelli, Giuseppina; Mitola, Stefania; Premoli, Marika; La Rosa, Luca Rosario; Ferrari-Toninelli, Giulia; Grilli, Mariagrazia; Memo, Maurizio

2016-06-01

Alterations in genes that regulate neurodevelopment can lead to cortical malformations, resulting in malfunction during postnatal life. The NF-κB pathway has a key role during neurodevelopment by regulating the maintenance of the neural progenitor cell pool and inhibiting neuronal differentiation. In this study, we evaluated whether mice lacking the NF-κB p50 subunit (KO) present alterations in cortical structure and associated behavioral impairment. We found that, compared with wild type (WT), KO mice at postnatal day 2 present an increase in radial glial cells, an increase in Reelin protein expression levels, in addition to an increase of specific layer thickness. Moreover, adult KO mice display abnormal columnar organization in the somatosensory cortex, a specific decrease in somatostatin- and parvalbumin-expressing interneurons, altered neurite orientation, and a decrease in Synapsin I protein levels. Concerning behavior, KO mice, in addition to an increase in locomotor and exploratory activity, display impairment in social behaviors, with a reduction in social interaction. Finally, we found that risperidone treatment decreased hyperactivity of KO mice, but had no effect on defective social interaction. Altogether, these data add complexity to a growing body of data, suggesting a link between dysregulation of the NF-κB pathway and neurodevelopmental disorders pathogenesis. © The Author 2016. Published by Oxford University Press.

BDNF-Val66Met-Polymorphism Impact on Cortical Plasticity in Schizophrenia Patients: A Proof-of-Concept Study

PubMed Central

Nitsche, Michael A.; Wobrock, Thomas; Bunse, Tilmann; Rein, Bettina; Herrmann, Maximiliane; Schmitt, Andrea; Nieratschker, Vanessa; Witt, Stephanie H.; Rietschel, Marcella; Falkai, Peter; Hasan, Alkomiet

2015-01-01

intracortical interneuron-networks, cortical plasticity, and the BDNF-Val66Met-polymorphism. Further replication and validation need to be dedicated to this question to confirm this relationship. PMID:25612896

Rhythmically Active Enkephalin-Expressing GABAergic Cells in the CA1 Area of the Hippocampus Project to the Subiculum and Preferentially Innervate Interneurons

PubMed Central

Fuentealba, Pablo; Tomioka, Ryohei; Dalezios, Yannis; Márton, László F.; Studer, Michele; Rockland, Kathleen; Klausberger, Thomas; Somogyi, Peter

2015-01-01

Enkephalins (ENKs) are endogenous opioids that regulate synaptic excitability of GABAergic networks in the cerebral cortex. Using retrograde tracer injections in the subiculum, we identified a hippocampal population of ENK-expressing projection neurons. In situ hybridization for GAD shows that ENK-expressing cells are a small GABAergic subpopulation. Furthermore, by extracellular recording and juxtacellular labeling in vivo, we identified an ENK-expressing cell in stratum radiatum of the CA1 area by its complete axodendritic arborization and characteristic spike timing during network oscillations. The somatodendritic membrane was immunopositive for mGluR1α, and there was both a rich local axon in CA1 and subicular-projecting branches. The boutons showed cell-type- and layer-specific innervation, i.e., interneurons were the main targets in the alveus, both interneurons and pyramidal cell dendrites were innervated in the other layers, and interneurons were exclusive targets in the subiculum. Parvalbumin-, but not somatostatin-, calbindin-, or cholecystokinin-expressing interneurons were preferred synaptic targets. During network activity, the juxtacellularly labeled ENK-expressing cell was phase modulated throughout theta oscillations, but silenced during sharp-wave/ripple episodes. After these episodes the interneuron exhibited rebound activity of high-frequency spike bursts, presumably causing peptide release. The ENK-expressing interneurons innervating parvalbumin-positive interneurons might contribute to the organization of the sharp-wave/ripple episodes by decreased firing during and rebound activity after the ripple episodes, as well as to the coordination of activity between the CA1 and subicular areas during network oscillations. PMID:18829959

A Single Bolus of Docosahexaenoic Acid Promotes Neuroplastic Changes in the Innervation of Spinal Cord Interneurons and Motor Neurons and Improves Functional Recovery after Spinal Cord Injury.

PubMed

Liu, Zhuo-Hao; Yip, Ping K; Adams, Louise; Davies, Meirion; Lee, Jae Won; Michael, Gregory J; Priestley, John V; Michael-Titus, Adina T

2015-09-16

Docosahexaenoic acid (DHA) is an ω-3 polyunsaturated fatty acid that is essential in brain development and has structural and signaling roles. Acute DHA administration is neuroprotective and promotes functional recovery in animal models of adult spinal cord injury (SCI). However, the mechanisms underlying this recovery have not been fully characterized. Here we investigated the effects of an acute intravenous bolus of DHA delivered after SCI and characterized DHA-induced neuroplasticity within the adult injured spinal cord. We found robust sprouting of uninjured corticospinal and serotonergic fibers in a rat cervical hemisection SCI model. A mouse pyramidotomy model was used to confirm that this robust sprouting was not species or injury model specific. Furthermore, we demonstrated that corticospinal fibers sprouting to the denervated side of the cord following pyramidotomy contact V2a interneurons. We also demonstrated increased serotonin fibers and synaptophysin in direct contact with motor neurons. DHA also increased synaptophysin in rat cortical cell cultures. A reduction in phosphatase and tensin homolog (PTEN) has been shown to be involved in axonal regeneration and synaptic plasticity. We showed that DHA significantly upregulates miR-21 and downregulates PTEN in corticospinal neurons. Downregulation of PTEN and upregulation of phosphorylated AKT by DHA were also seen in primary cortical neuron cultures and were accompanied by increased neurite outgrowth. In summary, acute DHA induces anatomical and synaptic plasticity in adult injured spinal cord. This study shows that DHA has therapeutic potential in cervical SCI and provides evidence that DHA could exert its beneficial effects in SCI via enhancement of neuroplasticity. In this study, we show that an acute intravenous injection of docosahexaenoic acid (DHA) 30 min after spinal cord injury induces neuroplasticity. We found robust sprouting of uninjured corticospinal and serotonergic fibers in a rat

Responses of Withdrawal Interneurons to Serotonin Applications in Naïve and Learned Snails Are Different

PubMed Central

Bogodvid, Tatiana K.; Andrianov, Vyatcheslav V.; Deryabina, Irina B.; Muranova, Lyudmila N.; Silantyeva, Dinara I.; Vinarskaya, Aliya; Balaban, Pavel M.; Gainutdinov, Khalil L.

2017-01-01

Long-term changes in membrane potential after associative training were described previously in identified premotor interneurons for withdrawal of the terrestrial snail Helix. Serotonin was shown to be a major transmitter involved in triggering the long-term changes in mollusks. In the present study we compared the changes in electrophysiological characteristics of identifiable premotor interneurons for withdrawal in response to bath applications of serotonin (5-HT) or serotonin precursor 5-hydroxytryptophan (5-HTP) in preparations from naïve, neurotoxin-injected or associatively trained snails. It was found that 5-HT or 5-HTP applications caused a significant decrease of membrane potential in premotor interneurons of naïve snails, associatively trained snails and snails with impaired serotonergic system by injection of a selective neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) 1 week before the experiments. Applications of 5-HT or 5-HTP did not cause significant changes in the action potential (AP) threshold potential of these neurons in naïve snails. Conversely, applications of 5-HT or 5-HTP to the premotor interneurons of previously trained or 5,7-DHT-injected snails caused a significant increase in the firing threshold potential in spite of a depolarizing shift of the resting membrane potential. Results demonstrate that responsiveness of premotor interneurons to extracellularly applied 5-HT or 5-HTP changes for days after the associative training or serotonin depletion. Similarity of the effects in trained and 5,7-DHT-injected animals may be due to massive release of serotonin elicited by 5,7-DHT injection. Our results suggest that serotonin release due to aversive conditionining or elicited by the neurotoxin administration triggers similar changes in resting membrane potential and AP threshold in response to bath applications of 5-HT or its precursor 5-HTP. PMID:29311833

Unitary IPSPs evoked by interneurons at the stratum radiatum-stratum lacunosum-moleculare border in the CA1 area of the rat hippocampus in vitro

PubMed Central

Vida, Imre; Halasy, Katalin; Szinyei, Csaba; Somogyi, Peter; Buhl, Eberhard H

1998-01-01

Hippocampal non-principal neurons at the stratum radiatum-stratum lacunosum-moleculare border (R-LM interneurons) of the CA1 area may constitute several cell classes and have been implicated in the generation of GABAergic unitary IPSPs. Using biocytin-filled electrodes we recorded R-LM interneurons intracellularly in vitro and determined their postsynaptic effects in concomitantly recorded pyramidal cells. Light microscopic analysis revealed four populations of R-LM interneurons with distinct axons: (1) basket cells (n= 4) with axons predominantly ramifying in the pyramidal cell layer; (2) Schaffer collateral/commissural pathway-associated interneurons (n= 10) stratifying in stratum radiatum and, to a lesser extent, stratum oriens; (3) perforant pathway-associated interneurons (n= 6) innervating the perforant path termination zone in stratum lacunosum-moleculare of the CA1 area as well as equivalent portions of the dentate gyrus and subiculum; and (4) neurogliaform interneurons (n= 2) characterized by their dense, compact axonal and dendritic arbour. Random electron microscopic sampling of synaptic targets revealed a preponderance of pyramidal neurons as postsynaptic elements. Basket cells had a synaptic target preference for somata and proximal dendrites, whereas the remainder of R-LM interneurons innervated dendritic shafts and spines. The axon of dendrite-targeting cells formed up to six putative contacts with individual postsynaptic pyramidal cells. Anatomically recovered R-LM interneurons (n= 22) had a mean resting membrane potential of -56.7 ± 3.6 mV, a membrane time constant of 12.9 ± 7.7 ms and an input resistance of 86.4 ± 29.2 MΩ. Depolarizing current pulses generally elicited overshooting action potentials (70.8 ± 6.9 mV) which had a mean duration, when measured at half-amplitude, of 0.7 ± 0.1 ms. In response to prolonged (> 200 ms) depolarizing current pulses all R-LM interneurons displayed (a varying degree of) spike frequency adaptation. Basket

Apolipoprotein E4 causes age- and Tau-dependent impairment of GABAergic interneurons, leading to learning and memory deficits in mice.

PubMed

Andrews-Zwilling, Yaisa; Bien-Ly, Nga; Xu, Qin; Li, Gang; Bernardo, Aubrey; Yoon, Seo Yeon; Zwilling, Daniel; Yan, Tonya Xue; Chen, Ligong; Huang, Yadong

2010-10-13

Apolipoprotein E4 (apoE4) is the major genetic risk factor for Alzheimer's disease. However, the underlying mechanisms are unclear. We found that female apoE4 knock-in (KI) mice had an age-dependent decrease in hilar GABAergic interneurons that correlated with the extent of learning and memory deficits, as determined in the Morris water maze, in aged mice. Treating apoE4-KI mice with daily peritoneal injections of the GABA(A) receptor potentiator pentobarbital at 20 mg/kg for 4 weeks rescued the learning and memory deficits. In neurotoxic apoE4 fragment transgenic mice, hilar GABAergic interneuron loss was even more pronounced and also correlated with the extent of learning and memory deficits. Neurodegeneration and tauopathy occurred earliest in hilar interneurons in apoE4 fragment transgenic mice; eliminating endogenous Tau prevented hilar GABAergic interneuron loss and the learning and memory deficits. The GABA(A) receptor antagonist picrotoxin abolished this rescue, while pentobarbital rescued learning deficits in the presence of endogenous Tau. Thus, apoE4 causes age- and Tau-dependent impairment of hilar GABAergic interneurons, leading to learning and memory deficits in mice. Consequently, reducing Tau and enhancing GABA signaling are potential strategies to treat or prevent apoE4-related Alzheimer's disease.

Temporal lobe dual pathology in malignant migrating partial seizures in infancy.

PubMed

Coppola, Giangennaro; Operto, Francesca Felicia; Auricchio, Gianfranca; D'Amico, Alessandra; Fortunato, Delia; Pascotto, Antonio

2007-06-01

A child had the characteristic clinical and EEG pattern of migrating partial seizures in infancy with left temporal lobe atrophy, hippocampal sclerosis and cortical-subcortical blurring. Seizures were drug-resistant, with recurring episodes of status epilepticus. The child developed microcephaly with arrest of psychomotor development. Focal brain lesions, in the context of migrating partial seizures, have not been previously reported.[Published with video sequences].

Active action potential propagation but not initiation in thalamic interneuron dendrites

PubMed Central

Casale, Amanda E.; McCormick, David A.

2012-01-01

Inhibitory interneurons of the dorsal lateral geniculate nucleus of the thalamus modulate the activity of thalamocortical cells in response to excitatory input through the release of inhibitory neurotransmitter from both axons and dendrites. The exact mechanisms by which release can occur from dendrites are, however, not well understood. Recent experiments using calcium imaging have suggested that Na/K based action potentials can evoke calcium transients in dendrites via local active conductances, making the back-propagating action potential a candidate for dendritic neurotransmitter release. In this study, we employed high temporal and spatial resolution voltage-sensitive dye imaging to assess the characteristics of dendritic voltage deflections in response to Na/K action potentials in interneurons of the mouse dorsal lateral geniculate nucleus. We found that trains or single action potentials elicited by somatic current injection or local synaptic stimulation led to action potentials that rapidly and actively back-propagated throughout the entire dendritic arbor and into the fine filiform dendritic appendages known to release GABAergic vesicles. Action potentials always appeared first in the soma or proximal dendrite in response to somatic current injection or local synaptic stimulation, and the rapid back-propagation into the dendritic arbor depended upon voltage-gated sodium and TEA-sensitive potassium channels. Our results indicate that thalamic interneuron dendrites integrate synaptic inputs that initiate action potentials, most likely in the axon initial segment, that then back-propagate with high-fidelity into the dendrites, resulting in a nearly synchronous release of GABA from both axonal and dendritic compartments. PMID:22171033

Collagen XIX Is Expressed by Interneurons and Contributes to the Formation of Hippocampal Synapses

PubMed Central

Su, Jianmin; Gorse, Karen; Ramirez, Francesco; Fox, Michael A.

2010-01-01

Extracellular matrix (ECM) molecules contribute to the formation and maintenance of synapses in the mammalian nervous system. We previously discovered a family of nonfibrillar collagens that organize synaptic differentiation at the neuromuscular junction (NMJ). Although many NMJ-organizing cues contribute to central nervous system (CNS) synaptogenesis, whether similar roles for collagens exist at central synapses remained unclear. In the present study we discovered that col19a1, the gene encoding nonfibrillar collagen XIX, is expressed by subsets of hippocampal neurons. Colocalization with the interneuron-specific enzyme glutamate decarboxylase 67 (Gad67), but not other cell-type-specific markers, suggests that hippocampal expression of col19a1 is restricted to interneurons. However, not all hippocampal interneurons express col19a1 mRNA; subsets of neuropeptide Y (NPY)-, somatostatin (Som)-, and calbindin (Calb)-immunoreactive interneurons express col19a1, but those containing parvalbumin (Parv) or calretinin (Calr) do not. To assess whether collagen XIX is required for the normal formation of hippocampal synapses, we examined synaptic morphology and composition in targeted mouse mutants lacking collagen XIX. We show here that subsets of synaptotagmin 2 (Syt2)-containing hippocampal nerve terminals appear malformed in the absence of collagen XIX. The presence of Syt2 in inhibitory hippocampal synapses, the altered distribution of Gad67 in collagen XIX-deficient subiculum, and abnormal levels of gephyrin in collagen XIX-deficient hippocampal extracts all suggest inhibitory synapses are affected by the loss of collagen XIX. Together, these data not only reveal that collagen XIX is expressed by central neurons, but show for the first time that a nonfibrillar collagen is necessary for the formation of hippocampal synapses. PMID:19937713

The evolution of cortical development: the synapsid-diapsid divergence.

PubMed

Goffinet, Andre M

2017-11-15

The cerebral cortex covers the rostral part of the brain and, in higher mammals and particularly humans, plays a key role in cognition and consciousness. It is populated with neuronal cell bodies distributed in radially organized layers. Understanding the common and lineage-specific molecular mechanisms that orchestrate cortical development and evolution are key issues in neurobiology. During evolution, the cortex appeared in stem amniotes and evolved divergently in two main branches of the phylogenetic tree: the synapsids (which led to present day mammals) and the diapsids (reptiles and birds). Comparative studies in organisms that belong to those two branches have identified some common principles of cortical development and organization that are possibly inherited from stem amniotes and regulated by similar molecular mechanisms. These comparisons have also highlighted certain essential features of mammalian cortices that are absent or different in diapsids and that probably evolved after the synapsid-diapsid divergence. Chief among these is the size and multi-laminar organization of the mammalian cortex, and the propensity to increase its area by folding. Here, I review recent data on cortical neurogenesis, neuronal migration and cortical layer formation and folding in this evolutionary perspective, and highlight important unanswered questions for future investigation. © 2017. Published by The Company of Biologists Ltd.

Sleep and Movement Differentiates Actions of Two Types of Somatostatin-Expressing GABAergic Interneuron in Rat Hippocampus

PubMed Central

Katona, Linda; Lapray, Damien; Viney, Tim J.; Oulhaj, Abderrahim; Borhegyi, Zsolt; Micklem, Benjamin R.; Klausberger, Thomas; Somogyi, Peter

2014-01-01

Summary Neuropeptides acting on pre- and postsynaptic receptors are coreleased with GABA by interneurons including bistratified and O-LM cells, both expressing somatostatin but innervating segregated dendritic domains of pyramidal cells. Neuropeptide release requires high-frequency action potentials, but the firing patterns of most peptide/GABA-releasing interneurons during behavior are unknown. We show that behavioral and network states differentiate the activities of bistratified and O-LM cells in freely moving rats. Bistratified cells fire at higher rates during sleep than O-LM cells and, unlike O-LM cells, strongly increase spiking during sharp wave-associated ripples (SWRs). In contrast, O-LM interneurons decrease firing during sleep relative to awake states and are mostly inhibited during SWRs. During movement, both cell types fire cooperatively at the troughs of theta oscillations but with different frequencies. Somatostatin and GABA are differentially released to distinct dendritic zones of CA1 pyramidal cells during sleep and wakefulness to coordinate segregated glutamatergic inputs from entorhinal cortex and CA3. PMID:24794095

Neuronal migration, apoptosis and bipolar disorder.

PubMed

Uribe, Ezequiel; Wix, Richard

2012-01-01

Bipolar disorder, like the majority of psychiatric disorders, is considered a neurodevelopment disease of neurodevelopment. There is an increased rate of neuronal birth and death during this development period. In the particular case of the processes that determine neuronal death, it is known that those neurons that establish connections have to be removed from the central nervous system. There is a deficit of GABAergic interneurons in the cerebral cortex in bipolar disorder, accompanied by overexpression of proapoptic genes. There is also an alteration in the expression of molecules that mediate in the migration of these neurons and their inclusion in functional synapsis during the foetal stage. The role of these molecules in the neuronal death pathways by apoptosis will be reviewed here in an attempt to establish biological hypotheses of the genesis of bipolar disorder. Copyright © 2011 SEP y SEPB. Published by Elsevier Espana. All rights reserved.

The Changing Roles of Neurons in the Cortical Subplate

PubMed Central

Friedlander, Michael J.; Torres-Reveron, Juan

2009-01-01

Neurons may serve different functions over the course of an organism's life. Recent evidence suggests that cortical subplate (SP) neurons including those that reside in the white matter may perform longitudinal multi-tasking at different stages of development. These cells play a key role in early cortical development in coordinating thalamocortical reciprocal innervation. At later stages of development, they become integrated within the cortical microcircuitry. This type of longitudinal multi-tasking can enhance the capacity for information processing by populations of cells serving different functions over the lifespan. Subplate cells are initially derived when cells from the ventricular zone underlying the cortex migrate to the cortical preplate that is subsequently split by the differentiating neurons of the cortical plate with some neurons locating in the marginal zone and others settling below in the SP. While the cortical plate neurons form most of the cortical layers (layers 2–6), the marginal zone neurons form layer 1 and the SP neurons become interstitial cells of the white matter as well as forming a compact sublayer along the bottom of layer 6. After serving as transient innervation targets for thalamocortical axons, most of these cells die and layer 4 neurons become innervated by thalamic axons. However, 10–20% survives, remaining into adulthood along the bottom of layer 6 and as a scattered population of interstitial neurons in the white matter. Surviving SP cells' axons project throughout the overlying laminae, reaching layer 1 and issuing axon collaterals within white matter and in lower layer 6. This suggests that they participate in local synaptic networks, as well. Moreover, they receive excitatory and inhibitory synaptic inputs, potentially monitoring outputs from axon collaterals of cortical efferents, from cortical afferents and/or from each other. We explore our understanding of the functional connectivity of these cells at different

Mapping cortical mesoscopic networks of single spiking cortical or sub-cortical neurons

PubMed Central

Xiao, Dongsheng; Vanni, Matthieu P; Mitelut, Catalin C; Chan, Allen W; LeDue, Jeffrey M; Xie, Yicheng; Chen, Andrew CN; Swindale, Nicholas V; Murphy, Timothy H

2017-01-01

Understanding the basis of brain function requires knowledge of cortical operations over wide-spatial scales, but also within the context of single neurons. In vivo, wide-field GCaMP imaging and sub-cortical/cortical cellular electrophysiology were used in mice to investigate relationships between spontaneous single neuron spiking and mesoscopic cortical activity. We make use of a rich set of cortical activity motifs that are present in spontaneous activity in anesthetized and awake animals. A mesoscale spike-triggered averaging procedure allowed the identification of motifs that are preferentially linked to individual spiking neurons by employing genetically targeted indicators of neuronal activity. Thalamic neurons predicted and reported specific cycles of wide-scale cortical inhibition/excitation. In contrast, spike-triggered maps derived from single cortical neurons yielded spatio-temporal maps expected for regional cortical consensus function. This approach can define network relationships between any point source of neuronal spiking and mesoscale cortical maps. DOI: http://dx.doi.org/10.7554/eLife.19976.001 PMID:28160463

KCa3.1 Modulates Neuroblast Migration Along the Rostral Migratory Stream (RMS) In Vivo

PubMed Central

Turner, Kathryn L.; Sontheimer, Harald

2014-01-01

From the subventricular zone (SVZ), neuronal precursor cells (NPCs), called neuroblasts, migrate through the rostral migratory stream (RMS) to become interneurons in the olfactory bulb (OB). Ion channels regulate neuronal migration during development, yet their role in migration through the adult RMS is unknown. To address this question, we utilized Nestin-CreERT2/R26R-YFP mice to fluorescently label neuroblasts in the adult. Patch-clamp recordings from neuroblasts reveal K+ currents that are sensitive to intracellular Ca2+ levels and blocked by clotrimazole and TRAM-34, inhibitors of intermediate conductance Ca2+-activated K+ (KCa3.1) channels. Immunolabeling and electrophysiology show KCa3.1 expression restricted to neuroblasts in the SVZ and RMS, but absent in OB neurons. Time-lapse confocal microscopy in situ showed inhibiting KCa3.1 prolonged the stationary phase of neuroblasts' saltatory migration, reducing migration speed by over 50%. Both migration and KCa3.1 currents could also be inhibited by blocking Ca2+ influx via transient receptor potential (TRP) channels, which, together with positive immunostaining for transient receptor potential canonical 1 (TRPC1), suggest that TRP channels are an important Ca2+ source modulating KCa3.1 activity. Finally, injecting TRAM-34 into Nestin-CreERT2/R26R-YFP mice significantly reduced the number of neuroblasts that reached the OB, suggesting an important role for KCa3.1 in vivo. These studies describe a previously unrecognized protein in migration of adult NPCs. PMID:23585521

Antipsychotics promote GABAergic interneuron genesis in the adult rat brain: Role of heat-shock protein production.

PubMed

Kaneta, Hiroo; Ukai, Wataru; Tsujino, Hanako; Furuse, Kengo; Kigawa, Yoshiyasu; Tayama, Masaya; Ishii, Takao; Hashimoto, Eri; Kawanishi, Chiaki

2017-09-01

Current antipsychotics reduce positive symptoms and reverse negative symptoms in conjunction with cognitive behavioral issues with the goal of restoring impaired occupational and social functioning. However, limited information is available on their influence on gliogenesis or their neurogenic properties in adult schizophrenia brains, particularly on GABAergic interneuron production. In the present study, we used young adult subventricular zone (SVZ)-derived progenitor cells expressing proteoglycan NG2 cultures to examine the oligodendrocyte and GABAergic interneuron genesis effects of several kinds of antipsychotics on changes in differentiation function induced by exposure to the NMDA receptor antagonist MK-801. We herein demonstrated that antipsychotics promoted or restored changes in the oligodendrocyte/GABAergic interneuron differentiation functions of NG2(+) cells induced by the exposure to MK-801, which was considered to be one of the drug-induced schizophrenia model. We also demonstrated that antipsychotics restored heat-shock protein (HSP) production in NG2(+) cells with differentiation impairment. The antipsychotics olanzapine, aripiprazole, and blonanserin, but not haloperidol increased HSP90 levels, which were reduced by the exposure to MK-801. Our results showed that antipsychotics, particularly those recently synthesized, exerted similar GABAergic interneuron genesis effects on NG2(+) neuronal/glial progenitor cells in the adult rat brain by increasing cellular HSP production, and also suggest that HSP90 may play a crucial role in the pathophysiology of schizophrenia and is a key target for next drug development. Copyright © 2017 Elsevier Ltd. All rights reserved.

Serotonin inhibits low-threshold spike interneurons in the striatum

PubMed Central

Cains, Sarah; Blomeley, Craig P; Bracci, Enrico

2012-01-01

Low-threshold spike interneurons (LTSIs) are important elements of the striatal architecture and the only known source of nitric oxide in this nucleus, but their rarity has so far prevented systematic studies. Here, we used transgenic mice in which green fluorescent protein is expressed under control of the neuropeptide Y (NPY) promoter and striatal NPY-expressing LTSIs can be easily identified, to investigate the effects of serotonin on these neurons. In sharp contrast with its excitatory action on other striatal interneurons, serotonin (30 μm) strongly inhibited LTSIs, reducing or abolishing their spontaneous firing activity and causing membrane hyperpolarisations. These hyperpolarisations persisted in the presence of tetrodotoxin, were mimicked by 5-HT2C receptor agonists and reversed by 5-HT2C antagonists. Voltage-clamp slow-ramp experiments showed that serotonin caused a strong increase in an outward current activated by depolarisations that was blocked by the specific M current blocker XE 991. In current-clamp experiments, XE 991 per se caused membrane depolarisations in LTSIs and subsequent application of serotonin (in the presence of XE 991) failed to affect these neurons. We concluded that serotonin strongly inhibits striatal LTSIs acting through postsynaptic 5-HT2C receptors and increasing an M type current. PMID:22495583

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.

A Computational Model of How Cholinergic Interneurons Protect Striatal-Dependent Learning

ERIC Educational Resources Information Center

Ashby, F. Gregory; Crossley, Matthew J.

2011-01-01

An essential component of skill acquisition is learning the environmental conditions in which that skill is relevant. This article proposes and tests a neurobiologically detailed theory of how such learning is mediated. The theory assumes that a key component of this learning is provided by the cholinergic interneurons in the striatum known as…

Continuous and intermittent transcranial magnetic theta burst stimulation modify tactile learning performance and cortical protein expression in the rat differently.

PubMed

Mix, Annika; Benali, Alia; Eysel, Ulf T; Funke, Klaus

2010-11-01

Repetitive transcranial magnetic stimulation (rTMS) can modulate cortical excitability in a stimulus-frequency-dependent manner. Two kinds of theta burst stimulation (TBS) [intermittent TBS (iTBS) and continuous TBS (cTBS)] modulate human cortical excitability differently, with iTBS increasing it and cTBS decreasing it. In rats, we recently showed that this is accompanied by changes in the cortical expression of proteins related to the activity of inhibitory neurons. Expression levels of the calcium-binding protein parvalbumin (PV) and of the 67-kDa isoform of glutamic acid decarboxylase (GAD67) were strongly reduced following iTBS, but not cTBS, whereas both increased expression of the 65-kDa isoform of glutamic acid decarboxylase. In the present study, to investigate possible functional consequences, we applied iTBS and cTBS to rats learning a tactile discrimination task. Conscious rats received either verum or sham rTMS prior to the task. Finally, to investigate how rTMS and learning effects interact, protein expression was determined for cortical areas directly involved in the task and for those either not, or indirectly, involved. We found that iTBS, but not cTBS, improved learning and strongly reduced cortical PV and GAD67 expression. However, the combination of learning and iTBS prevented this effect in those cortical areas involved in the task, but not in unrelated areas. We conclude that the improved learning found following iTBS is a result of the interaction of two effects, possibly in a homeostatic manner: a general weakening of inhibition mediated by the fast-spiking interneurons, and re-established activity in those neurons specifically involved in the learning task, leading to enhanced contrast between learning-induced and background activity. © 2010 The Authors. European Journal of Neuroscience © 2010 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Gating, modulation and subunit composition of voltage-gated K+ channels in dendritic inhibitory interneurones of rat hippocampus

PubMed Central

Lien, Cheng-Chang; Martina, Marco; Schultz, Jobst H; Ehmke, Heimo; Jonas, Peter

2002-01-01

GABAergic interneurones are diverse in their morphological and functional properties. Perisomatic inhibitory cells show fast spiking during sustained current injection, whereas dendritic inhibitory cells fire action potentials with lower frequency. We examined functional and molecular properties of K+ channels in interneurones with horizontal dendrites in stratum oriens-alveus (OA) of the hippocampal CA1 region, which mainly comprise somatostatin-positive dendritic inhibitory cells. Voltage-gated K+ currents in nucleated patches isolated from OA interneurones consisted of three major components: a fast delayed rectifier K+ current component that was highly sensitive to external 4-aminopyridine (4-AP) and tetraethylammonium (TEA) (half-maximal inhibitory concentrations < 0.1 mm for both blockers), a slow delayed rectifier K+ current component that was sensitive to high concentrations of TEA, but insensitive to 4-AP, and a rapidly inactivating A-type K+ current component that was blocked by high concentrations of 4-AP, but resistant to TEA. The relative contributions of these components to the macroscopic K+ current were estimated as 57 ± 5, 25 ± 6, and 19 ± 2 %, respectively. Dendrotoxin, a selective blocker of Kv1 channels had only minimal effects on K+ currents in nucleated patches. Coapplication of the membrane-permeant cAMP analogue 8-(4-chlorophenylthio)-adenosine 3′:5′-cyclic monophosphate (cpt-cAMP) and the phosphodiesterase blocker isobutyl-methylxanthine (IBMX) resulted in a selective inhibition of the fast delayed rectifier K+ current component. This inhibition was absent in the presence of the protein kinase A (PKA) inhibitor H-89, implying the involvement of PKA-mediated phosphorylation. Single-cell reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed a high abundance of Kv3.2 mRNA in OA interneurones, whereas the expression level of Kv3.1 mRNA was markedly lower. Similarly, RT-PCR analysis showed a high abundance of Kv4.3 m

Cholinergic Interneurons Underlie Spontaneous Dopamine Release in Nucleus Accumbens

PubMed Central

2017-01-01

The release of dopamine from terminals in the NAc is regulated by a number of factors, including voltage-gated ion channels, D2-autoreceptors, and nAChRs. Cholinergic interneurons (CINs) drive dopamine release through activation of nAChRs on dopamine terminals. Using cyclic voltammetry in mouse brain slices, nAChR-dependent spontaneous dopamine transients and the mechanisms underlying the origin were examined in the NAc. Spontaneous events were infrequent (0.3 per minute), but the rate and amplitude were increased after blocking Kv channels with 4-aminopyridine. Although the firing frequency of CINs was increased by blocking glutamate reuptake with TBOA and the Sk blocker apamin, only 4-aminopyridine increased the frequency of dopamine transients. In contrast, inhibition of CIN firing with the μ/δ selective opioid [Met5]enkephalin (1 μm) decreased spontaneous dopamine transients. Cocaine increased the rate and amplitude of dopamine transients, suggesting that the activity of the dopamine transporter limits the detection of these events. In the presence of cocaine, the rate of spontaneous dopamine transients was further increased after blocking D2-autoreceptors. Blockade of muscarinic receptors had no effect on evoked dopamine release, suggesting that feedback inhibition of acetylcholine release was not involved. Thus, although spontaneous dopamine transients are reliant on nAChRs, the frequency was not strictly governed by the activity of CINs. The increase in frequency of spontaneous dopamine transients induced by cocaine was not due to an increase in cholinergic tone and is likely a product of an increase in detection resulting from decreased dopamine reuptake. SIGNIFICANCE STATEMENT The actions of dopamine in the NAc are thought to be responsible for endogenous reward and the reinforcing properties of drugs of abuse, such as psychostimulants. The present work examines the mechanisms underlying nAChR-induced spontaneous dopamine release. This study

Serotonin homeostasis and serotonin receptors as actors of cortical construction: special attention to the 5-HT3A and 5-HT6 receptor subtypes

PubMed Central

Vitalis, Tania; Ansorge, Mark S.; Dayer, Alexandre G.

2013-01-01

Cortical circuits control higher-order cognitive processes and their function is highly dependent on their structure that emerges during development. The construction of cortical circuits involves the coordinated interplay between different types of cellular processes such as proliferation, migration, and differentiation of neural and glial cell subtypes. Among the multiple factors that regulate the assembly of cortical circuits, 5-HT is an important developmental signal that impacts on a broad diversity of cellular processes. 5-HT is detected at the onset of embryonic telencephalic formation and a variety of serotonergic receptors are dynamically expressed in the embryonic developing cortex in a region and cell-type specific manner. Among these receptors, the ionotropic 5-HT3A receptor and the metabotropic 5-HT6 receptor have recently been identified as novel serotonergic targets regulating different aspects of cortical construction including neuronal migration and dendritic differentiation. In this review, we focus on the developmental impact of serotonergic systems on the construction of cortical circuits and discuss their potential role in programming risk for human psychiatric disorders. PMID:23801939

Interneuron- and GABAA receptor-specific inhibitory synaptic plasticity in cerebellar Purkinje cells

NASA Astrophysics Data System (ADS)

He, Qionger; Duguid, Ian; Clark, Beverley; Panzanelli, Patrizia; Patel, Bijal; Thomas, Philip; Fritschy, Jean-Marc; Smart, Trevor G.

2015-07-01

Inhibitory synaptic plasticity is important for shaping both neuronal excitability and network activity. Here we investigate the input and GABAA receptor subunit specificity of inhibitory synaptic plasticity by studying cerebellar interneuron-Purkinje cell (PC) synapses. Depolarizing PCs initiated a long-lasting increase in GABA-mediated synaptic currents. By stimulating individual interneurons, this plasticity was observed at somatodendritic basket cell synapses, but not at distal dendritic stellate cell synapses. Basket cell synapses predominantly express β2-subunit-containing GABAA receptors; deletion of the β2-subunit ablates this plasticity, demonstrating its reliance on GABAA receptor subunit composition. The increase in synaptic currents is dependent upon an increase in newly synthesized cell surface synaptic GABAA receptors and is abolished by preventing CaMKII phosphorylation of GABAA receptors. Our results reveal a novel GABAA receptor subunit- and input-specific form of inhibitory synaptic plasticity that regulates the temporal firing pattern of the principal output cells of the cerebellum.

Coordination of locomotor and cardiorespiratory networks of Lymnaea stagnalis by a pair of identified interneurones.

PubMed

Syed, N I; Winlow, W

1991-07-01

1. The morphology and electrophysiology of a newly identified bilateral pair of interneurones in the central nervous system of the pulmonate pond snail Lymnaea stagnalis is described. 2. These interneurones, identified as left and right pedal dorsal 11 (L/RPeD11), are electrically coupled to each other as well as to a large number of foot and body wall motoneurones, forming a fast-acting neural network which coordinates the activities of foot and body wall muscles. 3. The left and right sides of the body wall of Lymnaea are innervated by left and right cerebral A cluster neurones. Although these motoneurones have only ipsilateral projections, they are indirectly electrically coupled to their contralateral homologues via their connections with L/RPeD11. Similarly, the activities of left and right pedal G cluster neurones, which are known to be involved in locomotion, are also coordinated by L/RPeD11. 4. Selective ablation of both neurones PeD11 results in the loss of coordination between the bilateral cerebral A clusters. 5. Interneurones L/RPeD11 are multifunctional. In addition to coordinating motoneuronal activity, they make chemical excitatory connections with heart motoneurones. They also synapse upon respiratory motoneurones, hyperpolarizing those involved in pneumostome opening (expiration) and depolarizing those involved in pneumostome closure (inspiration). 6. An identified respiratory interneurone involved in pneumostome closure (visceral dorsal 4) inhibits L/RPeD11 together with all their electrically coupled follower cells. 7. Both L/RPeD11 have strong excitatory effects on another pair of electrically coupled neurones, visceral dorsal 1 and right parietal dorsal 2, which have previously been shown to be sensitive to changes in the partial pressure of environmental oxygen (PO2). 8. Although L/RPeD11 participate in whole-body withdrawal responses, electrical stimulation applied directly to these neurones was not sufficient to induce this behaviour.

Slow synaptic transmission mediated by TRPV1 channels in CA3 interneurons of the hippocampus.

PubMed

Eguchi, Noriomi; Hishimoto, Akitoyo; Sora, Ichiro; Mori, Masahiro

2016-03-11

Metabotropic glutamate receptors (mGluRs) modulate various neuronal functions in the central nervous system. Many studies reported that mGluRs have linkages to neuronal disorders such as schizophrenia and autism related disorders, indicating that mGluRs are involved in critical functions of the neuronal circuits. To study this possibility further, we recorded mGluR-induced synaptic responses in the interneurons of the CA3 stratum radiatum using rat hippocampal organotypic slice cultures. Electrical stimulation in the CA3 pyramidal cell layer evoked a slow inward current in the interneurons at a holding potential of -70mV in the presence of antagonists for AMPA/kainate receptors, NMDA receptors, GABAA receptors and GABAB receptors. The slow inward current was blocked in the absence of extracellular calcium, suggesting that this was a synaptic response. The slow excitatory postsynaptic current (EPSC) reversed near 0mV, reflecting an increase in a non-selective cationic conductance. The slow EPSC is mediated by group I mGluRs, as it was blocked by AP3, a group I mGluR antagonist. Neither a calcium chelator BAPTA nor a phospholipase C (PLC) inhibitor U73122 affected the slow EPSC. La(3+), a general TRP channel blocker or capsazepine, a selective TRPV1 channel antagonist significantly suppressed the slow EPSC. DHPG, a selective group I mGluRs agonist induced an inward current, which was suppressed by capsazepine. These results indicate that in the interneurons of the hippocampal CA3 stratum radiatum group I mGluRs activate TRPV1 channels independently of PLC and intracellular Ca(2+), resulting in the slow EPSC in the interneurons. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Graphene Oxide Dysregulates Neuroligin/NLG-1-Mediated Molecular Signaling in Interneurons in Caenorhabditis elegans

NASA Astrophysics Data System (ADS)

Chen, He; Li, Huirong; Wang, Dayong

2017-01-01

Graphene oxide (GO) can be potentially used in many medical and industrial fields. Using assay system of Caenorhabditis elegans, we identified the NLG-1/Neuroligin-mediated neuronal signaling dysregulated by GO exposure. In nematodes, GO exposure significantly decreased the expression of NLG-1, a postsynaptic cell adhesion protein. Loss-of-function mutation of nlg-1 gene resulted in a susceptible property of nematodes to GO toxicity. Rescue experiments suggested that NLG-1 could act in AIY interneurons to regulate the response to GO exposure. In the AIY interneurons, PKC-1, a serine/threonine protein kinase C (PKC) protein, was identified as the downstream target for NLG-1 in the regulation of response to GO exposure. LIN-45, a Raf protein in ERK signaling pathway, was further identified as the downstream target for PKC-1 in the regulation of response to GO exposure. Therefore, GO may dysregulate NLG-1-mediated molecular signaling in the interneurons, and a neuronal signaling cascade of NLG-1-PKC-1-LIN-45 was raised to be required for the control of response to GO exposure. More importantly, intestinal RNAi knockdown of daf-16 gene encoding a FOXO transcriptional factor in insulin signaling pathway suppressed the resistant property of nematodes overexpressing NLG-1 to GO toxicity, suggesting the possible link between neuronal NLG-1 signaling and intestinal insulin signaling in the regulation of response to GO exposure.

GABAergic Projections from the Medial Septum Selectively Inhibit Interneurons in the Medial Entorhinal Cortex

PubMed Central

Gonzalez-Sulser, Alfredo; Parthier, Daniel; Candela, Antonio; McClure, Christina; Pastoll, Hugh; Garden, Derek; Sürmeli, Gülşen

2014-01-01

The medial septum (MS) is required for theta rhythmic oscillations and grid cell firing in the medial entorhinal cortex (MEC). While GABAergic, glutamatergic, and cholinergic neurons project from the MS to the MEC, their synaptic targets are unknown. To investigate whether MS neurons innervate specific layers and cell types in the MEC, we expressed channelrhodopsin-2 in mouse MS neurons and used patch-clamp recording in brain slices to determine the response to light activation of identified cells in the MEC. Following activation of MS axons, we observed fast monosynaptic GABAergic IPSPs in the majority (>60%) of fast-spiking (FS) and low-threshold-spiking (LTS) interneurons in all layers of the MEC, but in only 1.5% of nonstellate principal cells (NSPCs) and in no stellate cells. We also observed fast glutamatergic responses to MS activation in a minority (<5%) of NSPCs, FS, and LTS interneurons. During stimulation of MS inputs at theta frequency (10 Hz), the amplitude of GABAergic IPSPs was maintained, and spike output from LTS and FS interneurons was entrained at low (25–60 Hz) and high (60–180 Hz) gamma frequencies, respectively. By demonstrating cell type-specific targeting of the GABAergic projection from the MS to the MEC, our results support the idea that the MS controls theta frequency activity in the MEC through coordination of inhibitory circuits. PMID:25505326

Short-Term Exposure to Enriched Environment in Adult Rats Restores MK-801-Induced Cognitive Deficits and GABAergic Interneuron Immunoreactivity Loss.

PubMed

Murueta-Goyena, Ane; Ortuzar, Naiara; Gargiulo, Pascual Ángel; Lafuente, José Vicente; Bengoetxea, Harkaitz

2018-01-01

Perinatal injections of N-methyl-D-aspartate (NMDA) receptor antagonist in rodents emulate some cognitive impairments and neurochemical alterations, such as decreased GABAergic (gamma aminobutyric acid) interneuron immunoreactivity, also found in schizophrenia. These features are pervasive, and developing neuroprotective or neurorestorative strategies is of special interest. In this work, we aimed to investigate if a short exposure to enriched environment (EE) in early adulthood (P55-P73) was an effective strategy to improve cognitive dysfunction and to restore interneuron expression in medial prefrontal cortex (mPFC) and hippocampus (HPC). For that purpose, we administered MK-801 intraperitoneally to Long Evans rats from postnatal days 10 to 20. Twenty-four hours after the last injection, MK-801 produced a transient decrease in spontaneous motor activity and exploration, but those abnormalities were absent at P24 and P55. The open field test on P73 manifested that EE reduced anxiety-like behavior. In addition, MK-801-treated rats showed cognitive impairment in novel object recognition test that was reversed by EE. We quantified different interneuron populations based on their calcium-binding protein expression (parvalbumin, calretinin, and calbindin), glutamic acid decarboxylase 67, and neuronal nuclei-positive cells by means of unbiased stereology and found that EE enhanced interneuron immunoreactivity up to normal values in MK-801-treated rats. Our results demonstrate that a timely intervention with EE is a powerful tool to reverse long-lasting changes in cognition and neurochemical markers of interneurons in an animal model of schizophrenia.

Causal Evidence for the Role of Specific GABAergic Interneuron Types in Entorhinal Recruitment of Dentate Granule Cells

PubMed Central

Lee, Cheng-Ta; Kao, Min-Hua; Hou, Wen-Hsien; Wei, Yu-Ting; Chen, Chin-Lin; Lien, Cheng-Chang

2016-01-01

The dentate gyrus (DG) is the primary gate of the hippocampus and controls information flow from the cortex to the hippocampus proper. To maintain normal function, granule cells (GCs), the principal neurons in the DG, receive fine-tuned inhibition from local-circuit GABAergic inhibitory interneurons (INs). Abnormalities of GABAergic circuits in the DG are associated with several brain disorders, including epilepsy, autism, schizophrenia, and Alzheimer disease. Therefore, understanding the network mechanisms of inhibitory control of GCs is of functional and pathophysiological importance. GABAergic inhibitory INs are heterogeneous, but it is unclear how individual subtypes contribute to GC activity. Using cell-type-specific optogenetic perturbation, we investigated whether and how two major IN populations defined by parvalbumin (PV) and somatostatin (SST) expression, regulate GC input transformations. We showed that PV-expressing (PV+) INs, and not SST-expressing (SST+) INs, primarily suppress GC responses to single cortical stimulation. In addition, these two IN classes differentially regulate GC responses to θ and γ frequency inputs from the cortex. Notably, PV+ INs specifically control the onset of the spike series, whereas SST+ INs preferentially regulate the later spikes in the series. Together, PV+ and SST+ GABAergic INs engage differentially in GC input-output transformations in response to various activity patterns. PMID:27830729

Induction of Anti-Hebbian LTP in CA1 Stratum Oriens Interneurons: Interactions between Group I Metabotropic Glutamate Receptors and M1 Muscarinic Receptors

PubMed Central

Savary, Etienne; Kullmann, Dimitri M.; Miles, Richard

2015-01-01

An anti-Hebbian form of LTP is observed at excitatory synapses made with some hippocampal interneurons. LTP induction is facilitated when postsynaptic interneurons are hyperpolarized, presumably because Ca2+ entry through Ca2+-permeable glutamate receptors is enhanced. The contribution of modulatory transmitters to anti-Hebbian LTP induction remains to be established. Activation of group I metabotropic receptors (mGluRs) is required for anti-Hebbian LTP induction in interneurons with cell bodies in the CA1 stratum oriens. This region receives a strong cholinergic innervation from the septum, and muscarinic acetylcholine receptors (mAChRs) share some signaling pathways and cooperate with mGluRs in the control of neuronal excitability. We therefore examined possible interactions between group I mGluRs and mAChRs in anti-Hebbian LTP at synapses which excite oriens interneurons in rat brain slices. We found that blockade of either group I mGluRs or M1 mAChRs prevented the induction of anti-Hebbian LTP by pairing presynaptic activity with postsynaptic hyperpolarization. Blocking either receptor also suppressed long-term effects of activation of the other G-protein coupled receptor on interneuron membrane potential. However, no crossed blockade was detected for mGluR or mAchR effects on interneuron after-burst potentials or on the frequency of miniature EPSPs. Paired recordings between pyramidal neurons and oriens interneurons were obtained to determine whether LTP could be induced without concurrent stimulation of cholinergic axons. Exogenous activation of mAChRs led to LTP, with changes in EPSP amplitude distributions consistent with a presynaptic locus of expression. LTP, however, required noninvasive presynaptic and postsynaptic recordings. SIGNIFICANCE STATEMENT In the hippocampus, a form of NMDA receptor-independent long-term potentiation (LTP) occurs at excitatory synapses made on some inhibitory neurons. This is preferentially induced when postsynaptic

Posterior Thalamic Nucleus Modulation of Tactile Stimuli Processing in Rat Motor and Primary Somatosensory Cortices

PubMed Central

Casas-Torremocha, Diana; Clascá, Francisco; Núñez, Ángel

2017-01-01

Rodents move rhythmically their facial whiskers and compute differences between signals predicted and those resulting from the movement to infer information about objects near their head. These computations are carried out by a large network of forebrain structures that includes the thalamus and the primary somatosensory (S1BF) and motor (M1wk) cortices. Spatially and temporally precise mechanorreceptive whisker information reaches the S1BF cortex via the ventroposterior medial thalamic nucleus (VPM). Other whisker-related information may reach both M1wk and S1BF via the axons from the posterior thalamic nucleus (Po). However, Po axons may convey, in addition to direct sensory signals, the dynamic output of computations between whisker signals and descending motor commands. It has been proposed that this input may be relevant for adjusting cortical responses to predicted vs. unpredicted whisker signals, but the effects of Po input on M1wk and S1BF function have not been directly tested or compared in vivo. Here, using electrophysiology, optogenetics and pharmacological tools, we compared in adult rats M1wk and S1BF in vivo responses in the whisker areas of the motor and primary somatosensory cortices to passive multi-whisker deflection, their dependence on Po activity, and their changes after a brief intense activation of Po axons. We report that the latencies of the first component of tactile-evoked local field potentials in M1wk and S1BF are similar. The evoked potentials decrease markedly in M1wk, but not in S1BF, by injection in Po of the GABAA agonist muscimol. A brief high-frequency electrical stimulation of Po decreases the responsivity of M1wk and S1BF cells to subsequent whisker stimulation. This effect is prevented by the local application of omega-agatoxin, suggesting that it may in part depend on GABA release by fast-spiking parvalbumin (PV)-expressing cortical interneurons. Local optogenetic activation of Po synapses in different cortical layers also

Histamine H3 Receptors Decrease Dopamine Release in the Ventral Striatum by Reducing the Activity of Striatal Cholinergic Interneurons.

PubMed

Varaschin, Rafael Koerich; Osterstock, Guillaume; Ducrot, Charles; Leino, Sakari; Bourque, Marie-Josée; Prado, Marco A M; Prado, Vania Ferreira; Salminen, Outi; Rannanpää Née Nuutinen, Saara; Trudeau, Louis-Eric

2018-04-15

Histamine H 3 receptors are widely distributed G i -coupled receptors whose activation reduces neuronal activity and inhibits release of numerous neurotransmitters. Although these receptors are abundantly expressed in the striatum, their modulatory role on activity-dependent dopamine release is not well understood. Here, we observed that histamine H 3 receptor activation indirectly diminishes dopamine overflow in the ventral striatum by reducing cholinergic interneuron activity. Acute brain slices from C57BL/6 or channelrhodopsin-2-transfected DAT-cre mice were obtained, and dopamine transients evoked either electrically or optogenetically were measured by fast-scan cyclic voltammetry. The H 3 agonist α-methylhistamine significantly reduced electrically- evoked dopamine overflow, an effect blocked by the nicotinic acetylcholine receptor antagonist dihydro-β-erythroidine, suggesting involvement of cholinergic interneurons. None of the drug treatments targeting H 3 receptors affected optogenetically evoked dopamine overflow, indicating that direct H 3 -modulation of dopaminergic axons is unlikely. Next, we used qPCR and confirmed the expression of histamine H 3 receptor mRNA in cholinergic interneurons, both in ventral and dorsal striatum. Activation of H 3 receptors by α-methylhistamine reduced spontaneous firing of cholinergic interneurons in the ventral, but not in the dorsal striatum. Resting membrane potential and number of spontaneous action potentials in ventral-striatal cholinergic interneurons were significantly reduced by α-methylhistamine. Acetylcholine release from isolated striatal synaptosomes, however, was not altered by α-methylhistamine. Together, these results indicate that histamine H 3 receptors are important modulators of dopamine release, specifically in the ventral striatum, and that they do so by decreasing the firing rate of cholinergic neurons and, consequently, reducing cholinergic tone on dopaminergic axons. Copyright © 2018 IBRO

KChIP1 modulation of Kv4.3-mediated A-type K(+) currents and repetitive firing in hippocampal interneurons.

PubMed

Bourdeau, M L; Laplante, I; Laurent, C E; Lacaille, J-C

2011-03-10

Neuronal A-type K(+) channels regulate action potential waveform, back-propagation and firing frequency. In hippocampal CA1 interneurons located at the stratum lacunosum-moleculare/radiatum junction (LM/RAD), Kv4.3 mediates A-type K(+) currents and a Kv4 β-subunit of the Kv channel interacting protein (KChIP) family, KChIP1, appears specifically expressed in these cells. However, the functional role of this accessory subunit in A-type K(+) currents and interneuron excitability remains largely unknown. Thus, first we studied KChIP1 and Kv4.3 channel interactions in human embryonic kidney 293 (HEK293) cells and determined that KChIP1 coexpression modulated the biophysical properties of Kv4.3 A-type currents (faster recovery from inactivation, leftward shift of activation curve, faster rise time and slower decay) and this modulation was selectively prevented by KChIP1 short interfering RNA (siRNA) knockdown. Next, we evaluated the effects of KChIP1 down-regulation by siRNA on A-type K(+) currents in LM/RAD interneurons in slice cultures. Recovery from inactivation of A-type K(+) currents was slower after KChIP1 down-regulation but other properties were unchanged. In addition, down-regulation of KChIP1 levels did not affect action potential waveform and firing, but increased firing frequency during suprathreshold depolarizations, indicating that KChIP1 regulates interneuron excitability. The effects of KChIP1 down-regulation were cell-specific since CA1 pyramidal cells that do not express KChIP1 were unaffected. Overall, our findings suggest that KChIP1 interacts with Kv4.3 in LM/RAD interneurons, enabling faster recovery from inactivation of A-type currents and thus promoting stronger inhibitory control of firing during sustained activity. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

Reelin is essential for neuronal migration but not for radial glial elongation in neonatal ferret cortex.

PubMed

Schaefer, Alisa; Poluch, Sylvie; Juliano, Sharon

2008-04-01

Numerous functions related to neuronal migration are linked to the glycoprotein reelin. Reelin also elongates radial glia, which are disrupted in mutant reeler mice. Our lab developed a model of cortical dysplasia in ferrets that shares features with the reeler mouse, including impaired migration of neurons into the cerebral cortex and disrupted radial glia. Explants of normal ferret cortex in coculture with dysplastic ferret cortex restore the deficits in this model. To determine if reelin is integral to the repair, we used explants of P0 mouse cortex either of the wild type (WT) or heterozygous (het) for the reelin gene, as well as P0 reeler cortex (not containing reelin), in coculture with organotypic cultures of dysplastic ferret cortex. This arrangement revealed that all types of mouse cortical explants (WT, het, reeler) elongated radial glia in ferret cortical dysplasia, indicating that reelin is not required for proper radial glial morphology. Migration of cells into ferret neocortex, however, did not improve with explants of reeler cortex, but was almost normal after pairing with WT or het explants. We also placed an exogenous source of reelin in ferret cultures at the pial surface to reveal that migrating cells move toward the reelin source in dysplastic cortex; radial glia in these cultures were also improved toward normal. Our results demonstrate that the normotopic position of reelin is important for proper neuronal positioning, and that reelin is capable of elongating radial glial cells but is not the only radialization factor.

A 3-synapse positive feedback loop regulates the excitability of an interneuron critical for sensitization in the leech.

PubMed

Crisp, Kevin M; Muller, Kenneth J

2006-03-29

Sensitization of reflexive shortening in the leech has been linked to serotonin (5-HT)-induced changes in the excitability of a single interneuron, the S cell. This neuron is necessary for sensitization and complete dishabituation of reflexive shortening, during which it contributes to the sensory-motor reflex. The S cell does not contain 5-HT, which is released primarily from the Retzius (R) cells, whose firing enhances S-cell excitability. Here, we show that the S cell excites the R cells, mainly via a fast disynaptic pathway in which the first synapse is the electrical junction between the S cell and the coupling interneurons, and the second synapse is a glutamatergic synapse of the coupling interneurons onto the R cells. The S cell-triggered excitatory postsynaptic potential in the R cell diminishes and nearly disappears in elevated concentrations of divalent cations because the coupling interneurons become inexcitable under these conditions. Serotonin released from the R cells feeds back on the S cell and increases its excitability by activating a 5-HT7-like receptor; 5-methoxytryptamine (5-MeOT; 10 microM) mimics the effects of 5-HT on S cell excitability, and effects of both 5-HT and 5-MeOT are blocked by pimozide (10 microM) and SB-269970 [(R)-3-(2-(2-(4-methylpiperidin-1-yl)-ethyl)pyrrolidine-1-sulfonyl)phenol] (5 microM). This feedback loop may be critical for the full expression of sensitization of reflexive shortening.

A 3-SYNAPSE POSITIVE FEEDBACK LOOP REGULATES THE EXCITABILITY OF AN INTERNEURON CRITICAL FOR SENSITIZATION IN THE LEECH

PubMed Central

Crisp, Kevin M.; Muller, Kenneth J.

2007-01-01

Sensitization of reflexive shortening in the leech has been linked to serotonin (5-HT)-induced changes in the excitability of a single interneuron, the S cell. This neuron is necessary for sensitization and complete dishabituation of reflexive shortening, during which it contributes to the sensory-motor reflex. The S cell does not contain 5-HT, which is released primarily from the Retzius (R) cells, whose firing enhances S-cell excitability. Here we show that the S cell excites the R cells, mainly via a fast disynaptic pathway in which the first synapse is the electrical junction between the S cell and the coupling interneurons, and the second synapse is a glutamatergic synapse of the coupling interneurons onto the R cells. The S cell-triggered excitatory postsynaptic potential in the R cell diminishes and nearly disappears in elevated concentrations of divalent cations because the coupling interneurons become inexcitable under these conditions. Serotonin released from the R cells feeds back upon the S cell and increases its excitability by activating a 5-HT7-like receptor; 5-methoxytryptamine (5-MeOT; 10 μM) mimics the effects of 5-HT on S cell excitability, and effects of both 5-HT and 5-MeOT are blocked by pimozide (10 μM) and SB-269970 (5 μM). This feedback loop may be critical for the full expression of sensitization of reflexive shortening. PMID:16571760

Epilepsy following cortical injury: Cellular and molecular mechanisms as targets for potential prophylaxis

PubMed Central

Prince, David A.; Parada, Isabel; Scalise, Karina; Graber, Kevin; Shen, Fran

2009-01-01

Summary The sequelae of traumatic brain injury, including posttraumatic epilepsy, represent a major societal problem. Significant resources are required to develop a better understanding of the underlying pathophysiologic mechanisms as targets for potential prophylactic therapies. Posttraumatic epilepsy undoubtedly involves numerous pathogenic factors that develop more or less in parallel. We have highlighted two potential “prime movers”: disinhibition and development of new functional excitatory connectivity, which occur in a number of animal models and some forms of epilepsy in humans. Previous experiments have shown that tetrodotoxin (TTX) applied to injured cortex during a critical period early after lesion placement can prevent epileptogenesis in the partial cortical (“undercut”) model of posttraumatic epilepsy. Here we show that such treatment markedly attenuates histologic indices of axonal and terminal sprouting and presumably associated aberrant excitatory connectivity. A second finding in the undercut model is a decrease in spontaneous inhibitory events. Current experiments show that this is accompanied by regressive alterations in fast-spiking γ-aminobutyric acid (GABA)ergic interneurons, including shrinkage of dendrites, marked decreases in axonal length, structural changes in inhibitory boutons, and loss of inhibitory synapses on pyramidal cells. Other data support the hypothesis that these anatomic abnormalities may result from loss of trophic support normally provided to interneurons by brain-derived neurotrophic factor (BDNF). Approaches that prevent these two pathophysiologic mechanisms may offer avenues for prophylaxis for posttraumatic epilepsy. However, major issues such as the role of these processes in functional recovery from injury and the timing of the critical period(s) for application of potential therapies in humans are critical and need to be resolved. PMID:19187292

The sox gene Dichaete is expressed in local interneurons and functions in development of the Drosophila adult olfactory circuit.

PubMed

Melnattur, Krishna V; Berdnik, Daniela; Rusan, Zeid; Ferreira, Christopher J; Nambu, John R

2013-02-01

In insects, the primary sites of integration for olfactory sensory input are the glomeruli in the antennal lobes. Here, axons of olfactory receptor neurons synapse with dendrites of the projection neurons that relay olfactory input to higher brain centers, such as the mushroom bodies and lateral horn. Interactions between olfactory receptor neurons and projection neurons are modulated by excitatory and inhibitory input from a group of local interneurons. While significant insight has been gleaned into the differentiation of olfactory receptor and projection neurons, much less is known about the development and function of the local interneurons. We have found that Dichaete, a conserved Sox HMG box gene, is strongly expressed in a cluster of LAAL cells located adjacent to each antennal lobe in the adult brain. Within these clusters, Dichaete protein expression is detected in both cholinergic and GABAergic local interneurons. In contrast, Dichaete expression is not detected in mature or developing projection neurons, or developing olfactory receptor neurons. Analysis of novel viable Dichaete mutant alleles revealed misrouting of specific projection neuron dendrites and axons, and alterations in glomeruli organization. These results suggest noncell autonomous functions of Dichaete in projection neuron differentiation as well as a potential role for Dichaete-expressing local interneurons in development of the adult olfactory circuitry. Copyright © 2012 Wiley Periodicals, Inc.

Overexpression of Dyrk1A, a Down Syndrome Candidate, Decreases Excitability and Impairs Gamma Oscillations in the Prefrontal Cortex.

PubMed

Ruiz-Mejias, Marcel; Martinez de Lagran, Maria; Mattia, Maurizio; Castano-Prat, Patricia; Perez-Mendez, Lorena; Ciria-Suarez, Laura; Gener, Thomas; Sancristobal, Belen; García-Ojalvo, Jordi; Gruart, Agnès; Delgado-García, José M; Sanchez-Vives, Maria V; Dierssen, Mara

2016-03-30

The dual-specificity tyrosine phosphorylation-regulated kinase DYRK1A is a serine/threonine kinase involved in neuronal differentiation and synaptic plasticity and a major candidate of Down syndrome brain alterations and cognitive deficits. DYRK1A is strongly expressed in the cerebral cortex, and its overexpression leads to defective cortical pyramidal cell morphology, synaptic plasticity deficits, and altered excitation/inhibition balance. These previous observations, however, do not allow predicting how the behavior of the prefrontal cortex (PFC) network and the resulting properties of its emergent activity are affected. Here, we integrate functional, anatomical, and computational data describing the prefrontal network alterations in transgenic mice overexpressingDyrk1A(TgDyrk1A). Usingin vivoextracellular recordings, we show decreased firing rate and gamma frequency power in the prefrontal network of anesthetized and awakeTgDyrk1Amice. Immunohistochemical analysis identified a selective reduction of vesicular GABA transporter punctae on parvalbumin positive neurons, without changes in the number of cortical GABAergic neurons in the PFC ofTgDyrk1Amice, which suggests that selective disinhibition of parvalbumin interneurons would result in an overinhibited functional network. Using a conductance-based computational model, we quantitatively demonstrate that this alteration could explain the observed functional deficits including decreased gamma power and firing rate. Our results suggest that dysfunction of cortical fast-spiking interneurons might be central to the pathophysiology of Down syndrome. DYRK1Ais a major candidate gene in Down syndrome. Its overexpression results into altered cognitive abilities, explained by defective cortical microarchitecture and excitation/inhibition imbalance. An open question is how these deficits impact the functionality of the prefrontal cortex network. Combining functional, anatomical, and computational approaches, we identified

A laminar cortical model of stereopsis and 3D surface perception: closure and da Vinci stereopsis.

PubMed

Cao, Yongqiang; Grossberg, Stephen

2005-01-01

A laminar cortical model of stereopsis and 3D surface perception is developed and simulated. The model describes how monocular and binocular oriented filtering interact with later stages of 3D boundary formation and surface filling-in in the LGN and cortical areas V1, V2, and V4. It proposes how interactions between layers 4, 3B, and 2/3 in V1 and V2 contribute to stereopsis, and how binocular and monocular information combine to form 3D boundary and surface representations. The model includes two main new developments: (1) It clarifies how surface-to-boundary feedback from V2 thin stripes to pale stripes helps to explain data about stereopsis. This feedback has previously been used to explain data about 3D figure-ground perception. (2) It proposes that the binocular false match problem is subsumed under the Gestalt grouping problem. In particular, the disparity filter, which helps to solve the correspondence problem by eliminating false matches, is realized using inhibitory interneurons as part of the perceptual grouping process by horizontal connections in layer 2/3 of cortical area V2. The enhanced model explains all the psychophysical data previously simulated by Grossberg and Howe (2003), such as contrast variations of dichoptic masking and the correspondence problem, the effect of interocular contrast differences on stereoacuity, Panum's limiting case, the Venetian blind illusion, stereopsis with polarity-reversed stereograms, and da Vinci stereopsis. It also explains psychophysical data about perceptual closure and variations of da Vinci stereopsis that previous models cannot yet explain.

An inhibitory gate for state transition in cortex

PubMed Central

Zucca, Stefano; D’Urso, Giulia; Pasquale, Valentina; Vecchia, Dania; Pica, Giuseppe; Bovetti, Serena; Moretti, Claudio; Varani, Stefano; Molano-Mazón, Manuel; Chiappalone, Michela; Panzeri, Stefano; Fellin, Tommaso

2017-01-01

Large scale transitions between active (up) and silent (down) states during quiet wakefulness or NREM sleep regulate fundamental cortical functions and are known to involve both excitatory and inhibitory cells. However, if and how inhibition regulates these activity transitions is unclear. Using fluorescence-targeted electrophysiological recording and cell-specific optogenetic manipulation in both anesthetized and non-anesthetized mice, we found that two major classes of interneurons, the parvalbumin and the somatostatin positive cells, tightly control both up-to-down and down-to-up state transitions. Inhibitory regulation of state transition was observed under both natural and optogenetically-evoked conditions. Moreover, perturbative optogenetic experiments revealed that the inhibitory control of state transition was interneuron-type specific. Finally, local manipulation of small ensembles of interneurons affected cortical populations millimetres away from the modulated region. Together, these results demonstrate that inhibition potently gates transitions between cortical activity states, and reveal the cellular mechanisms by which local inhibitory microcircuits regulate state transitions at the mesoscale. DOI: http://dx.doi.org/10.7554/eLife.26177.001 PMID:28509666

Developmental changes in somatostatin-positive interneurons in a freeze-lesion model of epilepsy.

PubMed

Patrick, Saundra L; Connors, Barry W; Landisman, Carole E

2006-08-01

Somatostatin-expressing (SS) cells are inhibitory interneurons critical to the regulation of excitability in the cerebral cortex. It has been suggested in several animal models of epilepsy that the activity of these neurons reduces the occurrence and strength of epileptiform activity. The physiological properties of SS cells further support these hypotheses. Freeze lesions of neonatal rats serve as a model of human polymicrogyria, which is often characterized by severe seizures. Here we investigate the effects of neonatal freeze lesions on SS-expressing neurons by measuring their densities in control and lesioned hemispheres at two ages. We found that in late juveniles (P30-P32), SS-expressing neurons were depleted by 20% in areas adjacent to the freeze lesion, but at an earlier developmental age (P14-15), there was no significant loss. Since the deficit in SS-expressing neurons occurs well after the onset of epileptiform activity (P12-P18), we conclude that the death of these interneurons does not initiate hyperexcitability in this model.

Loss of Either Rac1 or Rac3 GTPase Differentially Affects the Behavior of Mutant Mice and the Development of Functional GABAergic Networks

PubMed Central

Pennucci, Roberta; Talpo, Francesca; Astro, Veronica; Montinaro, Valentina; Morè, Lorenzo; Cursi, Marco; Castoldi, Valerio; Chiaretti, Sara; Bianchi, Veronica; Marenna, Silvia; Cambiaghi, Marco; Tonoli, Diletta; Leocani, Letizia; Biella, Gerardo; D'Adamo, Patrizia; de Curtis, Ivan

2016-01-01

Rac GTPases regulate the development of cortical/hippocampal GABAergic interneurons by affecting the early development and migration of GABAergic precursors. We have addressed the function of Rac1 and Rac3 proteins during the late maturation of hippocampal interneurons. We observed specific phenotypic differences between conditional Rac1 and full Rac3 knockout mice. Rac1 deletion caused greater generalized hyperactivity and cognitive impairment compared with Rac3 deletion. This phenotype matched with a more evident functional impairment of the inhibitory circuits in Rac1 mutants, showing higher excitability and reduced spontaneous inhibitory currents in the CA hippocampal pyramidal neurons. Morphological analysis confirmed a differential modification of the inhibitory circuits: deletion of either Rac caused a similar reduction of parvalbumin-positive inhibitory terminals in the pyramidal layer. Intriguingly, cannabinoid receptor-1-positive terminals were strongly increased only in the CA1 of Rac1-depleted mice. This increase may underlie the stronger electrophysiological defects in this mutant. Accordingly, incubation with an antagonist for cannabinoid receptors partially rescued the reduction of spontaneous inhibitory currents in the pyramidal cells of Rac1 mutants. Our results show that Rac1 and Rac3 have independent roles in the formation of GABAergic circuits, as highlighted by the differential effects of their deletion on the late maturation of specific populations of interneurons. PMID:26582364

Gap junctions between interneurons are required for normal spatial coding in the hippocampus and short-term spatial memory

PubMed Central

Allen, Kevin; Fuchs, Elke C.; Jaschonek, Hannah; Bannerman, David M.; Monyer, Hannah

2011-01-01

Gap junctions containing connexin-36 (Cx36) electrically couple interneurons in many brain regions and synchronize their activity. We used Cx36 knockout mice (Cx36−/−) to study the importance of electrical coupling between interneurons for spatial coding in the hippocampus and for different forms of hippocampus-dependent spatial memory. Recordings in behaving mice revealed that the spatial selectivity of hippocampal pyramidal neurons was reduced and less stable in Cx36−/− mice. Altered network activity was reflected in slower theta oscillations in the mutants. Temporal coding, assessed by determining the presence and characteristics of theta phase precession, had different dynamics in Cx36−/− mice compared to controls. At the behavioral level, Cx36−/− mice displayed impaired short-term spatial memory but normal spatial reference memory. These results highlight the functional role of electrically coupled interneurons for spatial coding and cognition. Moreover, they suggest that the precise spatial selectivity of place cells is not essential for normal performance on spatial tasks assessing associative long-term memory. PMID:21525295

Depression of Excitatory Synapses onto Parvalbumin Interneurons in the Medial Prefrontal Cortex in Susceptibility to Stress

PubMed Central

Delevich, Kristen

2015-01-01

In response to extreme stress, individuals either show resilience or succumb to despair. The prefrontal cortex (PFC) is required for coping with stress, and PFC dysfunction has been implicated in stress-related mental disorders, including depression. Nevertheless, the mechanisms by which the PFC participates in stress responses remain unclear. Here, we investigate the role of parvalbumin (PV) interneurons in the medial PFC (mPFC) in shaping behavioral responses to stress induced by the learned helplessness procedure, in which animals are subjected to an unpredictable and inescapable stressor. PV interneurons in the mPFC were probed and manipulated in knock-in mice expressing the Cre recombinase under the endogenous parvalbumin promoter. Notably, we found that excitatory synaptic transmission onto these neurons was decreased in mice showing helplessness, a behavioral state that is thought to resemble features of human depression. Furthermore, selective suppression of PV interneurons in the mPFC using hM4Di, a DREADD (designer receptor exclusively activated by designer drug), promoted helplessness, indicating that activation of these neurons during stress promotes the establishment of resilient behavior. Our results reveal a cellular mechanism of mPFC dysfunction that may contribute to the emergence of maladaptive behavioral responses in the face of adverse life events. PMID:25698754

In Vitro, Ex Vivo and In Vivo Techniques to Study Neuronal Migration in the Developing Cerebral Cortex

PubMed Central

Azzarelli, Roberta; Oleari, Roberto; Lettieri, Antonella; Andre', Valentina; Cariboni, Anna

2017-01-01

Neuronal migration is a fundamental biological process that underlies proper brain development and neuronal circuit formation. In the developing cerebral cortex, distinct neuronal populations, producing excitatory, inhibitory and modulatory neurotransmitters, are generated in different germinative areas and migrate along various routes to reach their final positions within the cortex. Different technical approaches and experimental models have been adopted to study the mechanisms regulating neuronal migration in the cortex. In this review, we will discuss the most common in vitro, ex vivo and in vivo techniques to visualize and study cortical neuronal migration. PMID:28448448

Thresholds of cortical activation of muscle spindles and α motoneurones of the baboon's hand

PubMed Central

Koeze, T. H.; Phillips, C. G.; Sheridan, J. D.

1968-01-01

1. Much current thinking about voluntary movement assumes that the segmental γ loops can function as a servomechanism operated by the brain. However, the α motoneurones of the baboon's hand receive a powerful monosynaptic (CM) projection from the precentral gyrus. If servo-driving from the same cortical area is to be possible, it must project independently to the fusimotor neurones and have sufficient power to increase the afferent signalling from the muscle spindles. The cortical thresholds for contraction of m. extensor digitorum communis and for acceleration of the discharges of its muscle spindles have therefore been compared. 2. Significant results in this context require that the spindles studied be coupled in parallel with the responding extrafusal muscle fibres. Many spindles were not unloaded by the submaximal contractions evoked by cortical stimulation, although all so tested were unloaded by maximal motor nerve twitches. Reasons are given for thinking that such apparent lack of parallel coupling is an artifact of complex intramuscular anatomy and limitation of shortening by `isometric' myography. 3. A brief burst of corticospinal volleys at 500/sec, which is specially effective in exciting α motoneurones over the CM projection, failed to excite spindle afferents at or below the threshold for a cortical `twitch'. 4. In a few epileptiform discharges, bursts of spindle acceleration occurred independently of the clonic contractions. A relatively direct and independent cortico-fusimotor (CF) projection may therefore exist. 5. Prolonged near-threshold stimulation at 50-100/sec, which allows time for temporal summation in the less direct projections (e.g. cortico-interneuronal, cortico-rubro-spinal) and does not cause frequency-potentiation at CM synapses, gives abundant evidence of independent α and fusimotor projections, whose actions hardly outlast the stimulation period. 6. Although independent CF projections would permit servo-driving in natural

Computational Modeling of Distinct Neocortical Oscillations Driven by Cell-Type Selective Optogenetic Drive: Separable Resonant Circuits Controlled by Low-Threshold Spiking and Fast-Spiking Interneurons

PubMed Central

Vierling-Claassen, Dorea; Cardin, Jessica A.; Moore, Christopher I.; Jones, Stephanie R.

2010-01-01

Selective optogenetic drive of fast-spiking (FS) interneurons (INs) leads to enhanced local field potential (LFP) power across the traditional “gamma” frequency band (20–80 Hz; Cardin et al., 2009). In contrast, drive to regular-spiking (RS) pyramidal cells enhances power at lower frequencies, with a peak at 8 Hz. The first result is consistent with previous computational studies emphasizing the role of FS and the time constant of GABAA synaptic inhibition in gamma rhythmicity. However, the same theoretical models do not typically predict low-frequency LFP enhancement with RS drive. To develop hypotheses as to how the same network can support these contrasting behaviors, we constructed a biophysically principled network model of primary somatosensory neocortex containing FS, RS, and low-threshold spiking (LTS) INs. Cells were modeled with detailed cell anatomy and physiology, multiple dendritic compartments, and included active somatic and dendritic ionic currents. Consistent with prior studies, the model demonstrated gamma resonance during FS drive, dependent on the time constant of GABAA inhibition induced by synchronous FS activity. Lower-frequency enhancement during RS drive was replicated only on inclusion of an inhibitory LTS population, whose activation was critically dependent on RS synchrony and evoked longer-lasting inhibition. Our results predict that differential recruitment of FS and LTS inhibitory populations is essential to the observed cortical dynamics and may provide a means for amplifying the natural expression of distinct oscillations in normal cortical processing. PMID:21152338

How did the chicken cross the road? With her striatal cholinergic interneurons, of course

PubMed Central

Schoenbaum, Geoffrey; Stalnaker, Thomas A; Niv, Yael

2013-01-01

Recognizing when the world changes is fundamental for normal learning. Here, Bradfield and colleagues show that cholinergic interneurons in dorsomedial striatum are critical to the process whereby new states of the world are appropriately registered and retrieved during associative learning. PMID:23849192

Contribution of NMDA receptor hypofunction in prefrontal and cortical excitatory neurons to schizophrenia-like phenotypes.

PubMed

Rompala, Gregory R; Zsiros, Veronika; Zhang, Shuqin; Kolata, Stefan M; Nakazawa, Kazu

2013-01-01

Pharmacological and genetic studies support a role for NMDA receptor (NMDAR) hypofunction in the etiology of schizophrenia. We have previously demonstrated that NMDAR obligatory subunit 1 (GluN1) deletion in corticolimbic interneurons during early postnatal development is sufficient to confer schizophrenia-like phenotypes in mice. However, the consequence of NMDAR hypofunction in cortical excitatory neurons is not well delineated. Here, we characterize a conditional knockout mouse strain (CtxGluN1 KO mice), in which postnatal GluN1 deletion is largely confined to the excitatory neurons in layer II/III of the medial prefrontal cortex and sensory cortices, as evidenced by the lack of GluN1 mRNA expression in in situ hybridization immunocytochemistry as well as the lack of NMDA currents with in vitro recordings. Mutants were impaired in prepulse inhibition of the auditory startle reflex as well as object-based short-term memory. However, they did not exhibit impairments in additional hallmarks of schizophrenia-like phenotypes (e.g. spatial working memory, social behavior, saccharine preference, novelty and amphetamine-induced hyperlocomotion, and anxiety-related behavior). Furthermore, upon administration of the NMDA receptor antagonist, MK-801, there were no differences in locomotor activity versus controls. The mutant mice also showed negligible levels of reactive oxygen species production following chronic social isolation, and recording of miniature-EPSC/IPSCs from layer II/III excitatory neurons in medial prefrontal cortex suggested no alteration in GABAergic activity. All together, the mutant mice displayed cognitive deficits in the absence of additional behavioral or cellular phenotypes reflecting schizophrenia pathophysiology. Thus, NMDAR hypofunction in prefrontal and cortical excitatory neurons may recapitulate only a cognitive aspect of human schizophrenia symptoms.

Confinement and low adhesion induce fast amoeboid migration of slow mesenchymal cells.

PubMed

Liu, Yan-Jun; Le Berre, Maël; Lautenschlaeger, Franziska; Maiuri, Paolo; Callan-Jones, Andrew; Heuzé, Mélina; Takaki, Tohru; Voituriez, Raphaël; Piel, Matthieu

2015-02-12

The mesenchymal-amoeboid transition (MAT) was proposed as a mechanism for cancer cells to adapt their migration mode to their environment. While the molecular pathways involved in this transition are well documented, the role of the microenvironment in the MAT is still poorly understood. Here, we investigated how confinement and adhesion affect this transition. We report that, in the absence of focal adhesions and under conditions of confinement, mesenchymal cells can spontaneously switch to a fast amoeboid migration phenotype. We identified two main types of fast migration--one involving a local protrusion and a second involving a myosin-II-dependent mechanical instability of the cell cortex that leads to a global cortical flow. Interestingly, transformed cells are more prone to adopt this fast migration mode. Finally, we propose a generic model that explains migration transitions and predicts a phase diagram of migration phenotypes based on three main control parameters: confinement, adhesion, and contractility. Copyright © 2015 Elsevier Inc. All rights reserved.

V1 and v2b interneurons secure the alternating flexor-extensor motor activity mice require for limbed locomotion.

PubMed

Zhang, Jingming; Lanuza, Guillermo M; Britz, Olivier; Wang, Zhi; Siembab, Valerie C; Zhang, Ying; Velasquez, Tomoko; Alvarez, Francisco J; Frank, Eric; Goulding, Martyn

2014-04-02

Reciprocal activation of flexor and extensor muscles constitutes the fundamental mechanism that tetrapod vertebrates use for locomotion and limb-driven reflex behaviors. This aspect of motor coordination is controlled by inhibitory neurons in the spinal cord; however, the identity of the spinal interneurons that serve this function is not known. Here, we show that the production of an alternating flexor-extensor motor rhythm depends on the composite activities of two classes of ventrally located inhibitory neurons, V1 and V2b interneurons (INs). Abrogating V1 and V2b IN-derived neurotransmission in the isolated spinal cord results in a synchronous pattern of L2 flexor-related and L5 extensor-related locomotor activity. Mice lacking V1 and V2b inhibition are unable to articulate their limb joints and display marked deficits in limb-driven reflex movements. Taken together, these findings identify V1- and V2b-derived neurons as the core interneuronal components of the limb central pattern generator (CPG) that coordinate flexor-extensor motor activity. Copyright © 2014 Elsevier Inc. All rights reserved.

V1 and V2b interneurons secure the alternating flexor-extensor motor activity mice require for limbed locomotion

PubMed Central

Zhang, Jingming; Lanuza, Guillermo M.; Britz, Olivier; Wang, Zhi; Siembab, Valerie C.; Zhang, Ying; Velasquez, Tomoko; Alvarez, Francisco J.; Frank, Eric; Goulding, Martyn

2014-01-01

SUMMARY The reciprocal activation of flexor and extensor muscles constitutes the fundamental mechanism that tetrapod vertebrates use for locomotion and limb-driven reflex behaviors. This aspect of motor coordination is controlled by inhibitory neurons in the spinal cord; however, the identity of the spinal interneurons that serve this function is not known. Here we show that the production of an alternating flexor-extensor motor rhythm depends on the composite activities of two classes of ventrally-located inhibitory neurons, V1 and V2b interneurons (INs). Abrogating V1 and V2b IN-derived neurotransmission in the isolated spinal cord results in a synchronous pattern of L2 flexor-related and L5 extensor-related locomotor activity. Mice lacking V1 and V2b inhibition are unable to articulate their limb joints and display marked deficits in limb-driven reflex movements. Taken together, these findings identify V1- and V2b-derived neurons as the core interneuronal components of the limb central pattern generator (CPG) that coordinate flexor-extensor motor activity. PMID:24698273

Depression of excitatory synapses onto parvalbumin interneurons in the medial prefrontal cortex in susceptibility to stress.

PubMed

Perova, Zinaida; Delevich, Kristen; Li, Bo

2015-02-18

In response to extreme stress, individuals either show resilience or succumb to despair. The prefrontal cortex (PFC) is required for coping with stress, and PFC dysfunction has been implicated in stress-related mental disorders, including depression. Nevertheless, the mechanisms by which the PFC participates in stress responses remain unclear. Here, we investigate the role of parvalbumin (PV) interneurons in the medial PFC (mPFC) in shaping behavioral responses to stress induced by the learned helplessness procedure, in which animals are subjected to an unpredictable and inescapable stressor. PV interneurons in the mPFC were probed and manipulated in knock-in mice expressing the Cre recombinase under the endogenous parvalbumin promoter. Notably, we found that excitatory synaptic transmission onto these neurons was decreased in mice showing helplessness, a behavioral state that is thought to resemble features of human depression. Furthermore, selective suppression of PV interneurons in the mPFC using hM4Di, a DREADD (designer receptor exclusively activated by designer drug), promoted helplessness, indicating that activation of these neurons during stress promotes the establishment of resilient behavior. Our results reveal a cellular mechanism of mPFC dysfunction that may contribute to the emergence of maladaptive behavioral responses in the face of adverse life events. Copyright © 2015 the authors 0270-6474/15/353201-06$15.00/0.

Preferential Representation of Past Outcome Information and Future Choice Behavior by Putative Inhibitory Interneurons Rather Than Putative Pyramidal Neurons in the Primate Dorsal Anterior Cingulate Cortex.

PubMed

Kawai, Takashi; Yamada, Hiroshi; Sato, Nobuya; Takada, Masahiko; Matsumoto, Masayuki

2018-05-02

The dorsal anterior cingulate cortex (dACC) plays crucial roles in monitoring the outcome of a choice and adjusting a subsequent choice behavior based on the outcome information. In the present study, we investigated how different types of dACC neurons, that is, putative pyramidal neurons and putative inhibitory interneurons, contribute to these processes. We analyzed single-unit database obtained from the dACC in monkeys performing a reversal learning task. The monkey was required to adjust choice behavior from past outcome experiences. Depending on their action potential waveforms, the recorded neurons were classified into putative pyramidal neurons and putative inhibitory interneurons. We found that these neurons do not equally contribute to outcome monitoring and behavioral adjustment. Although both neuron types evenly responded to the current outcome, a larger proportion of putative inhibitory interneurons than putative pyramidal neurons stored the information about the past outcome. The putative inhibitory interneurons further represented choice-related signals more frequently, such as whether the monkey would shift the last choice to an alternative at the next choice opportunity. Our findings suggest that putative inhibitory interneurons, which are thought not to project to brain areas outside the dACC, preferentially transmit signals that would adjust choice behavior based on past outcome experiences.

The number of striatal cholinergic interneurons expressing calretinin is increased in parkinsonian monkeys.

PubMed

Petryszyn, Sarah; Di Paolo, Thérèse; Parent, André; Parent, Martin

2016-11-01

The most abundant interneurons in the primate striatum are those expressing the calcium-binding protein calretinin (CR). The present immunohistochemical study provides detailed assessments of their morphological traits, number, and topographical distribution in normal monkeys (Macaca fascicularis) and in monkeys rendered parkinsonian (PD) by MPTP intoxication. In primates, the CR+ striatal interneurons comprise small (8-12μm), medium (12-20μm) and large-sized (20-45μm) neurons, each with distinctive morphologies. The small CR+ neurons were 2-3 times more abundant than the medium-sized CR+ neurons, which were 20-40 times more numerous than the large CR+ neurons. In normal and PD monkeys, the density of small and medium-sized CR+ neurons was twice as high in the caudate nucleus than in the putamen, whereas the inverse occurred for the large CR+ neurons. Double immunostaining experiments revealed that only the large-sized CR+ neurons expressed choline acetyltransferase (ChAT). The number of large CR+ neurons was found to increase markedly (4-12 times) along the entire anteroposterior extent of both the caudate nucleus and putamen of PD monkeys compared to controls. Comparison of the number of large CR-/ChAT+ and CR+/ChAT+ neurons together with experiments involving the use of bromo-deoxyuridine (BrdU) as a marker of newly generated cells showed that it is the expression of CR by the large ChAT+ striatal interneurons, and not their absolute number, that is increased in the dopamine-depleted striatum. These findings reveal the modulatory role of dopamine in the phenotypic expression of the large cholinergic striatal neurons, which are known to play a crucial role in PD pathophysiology. Copyright © 2016 Elsevier Inc. All rights reserved.

Prolonged withdrawal from cocaine self-administration affects prefrontal cortex- and basolateral amygdala-nucleus accumbens core circuits but not accumbens GABAergic local interneurons.

PubMed

Purgianto, Anthony; Weinfeld, Michael E; Wolf, Marina E

2017-11-01

Withdrawal from extended-access cocaine self-administration leads to progressive intensification ('incubation') of cocaine craving. After prolonged withdrawal (1-2 months), when craving is high, expression of incubation depends on strengthening of excitatory inputs to medium spiny neurons (MSN) of the nucleus accumbens (NAc). These excitatory inputs interact with the intra-NAc GABAergic 'microcircuit', composed of MSN axon collaterals and GABAergic interneurons. Here, we investigated whether the increased glutamatergic neurotransmission observed after prolonged withdrawal is accompanied by altered GABAergic neurotransmission, focusing on NAc core. Rats self-administered cocaine or saline (6 hours/day) and then underwent >40 days of withdrawal. First, we investigated parvalbumin positive (PV+) interneurons, GABAergic fast-spiking interneurons that regulate MSN activity. Immunohistochemical studies revealed no significant change in PV signal intensity or the number of PV+ cells in cocaine rats versus saline controls. We then screened PV and other interneuron markers using immunoblotting. We detected no changes in levels of PV, calretinin, calbindin or neuronal nitric oxide synthase. Because expression of these markers is activity dependent, our results suggest no marked changes in interneuron activity. Finally, we utilized local field potential recording, which can detect GABA-mediated alterations at the circuit level, to investigate potential changes in two circuits implicated in cocaine craving: prelimbic prefrontal cortex to NAc core and basolateral amygdala to NAc core. We detected differential adaptations in these circuits, some of which may involve GABA. Overall, our results suggest that alterations in GABA transmission may accompany incubation of cocaine craving, but they are circuit specific and less pronounced than alterations in glutamate transmission. © 2016 Society for the Study of Addiction.

Layer-specific gene expression in epileptogenic type II focal cortical dysplasia: normal-looking neurons reveal the presence of a hidden laminar organization

PubMed Central

2014-01-01

Background Type II focal cortical dysplasias (FCDs) are malformations of cortical development characterised by the disorganisation of the normal neocortical structure and the presence of dysmorphic neurons (DNs) and balloon cells (BCs). The pathogenesis of FCDs has not yet been clearly established, although a number of histopathological patterns and molecular findings suggest that they may be due to abnormal neuronal and glial proliferation and migration processes. In order to gain further insights into cortical layering disruption and investigate the origin of DNs and BCs, we used in situ RNA hybridisation of human surgical specimens with a neuropathologically definite diagnosis of Type IIa/b FCD and a panel of layer-specific genes (LSGs) whose expression covers all cortical layers. We also used anti-phospho-S6 ribosomal protein antibody to investigate mTOR pathway hyperactivation. Results LSGs were expressed in both normal and abnormal cells (BCs and DNs) but their distribution was different. Normal-looking neurons, which were visibly reduced in the core of the lesion, were apparently located in the appropriate cortical laminae thus indicating a partial laminar organisation. On the contrary, DNs and BCs, labelled with anti-phospho-S6 ribosomal protein antibody, were spread throughout the cortex without any apparent rule and showed a highly variable LSG expression pattern. Moreover, LSGs did not reveal any differences between Type IIa and IIb FCD. Conclusion These findings suggest the existence of hidden cortical lamination involving normal-looking neurons, which retain their ability to migrate correctly in the cortex, unlike DNs which, in addition to their morphological abnormalities and mTOR hyperactivation, show an altered migratory pattern. Taken together these data suggest that an external or environmental hit affecting selected precursor cells during the very early stages of cortical development may disrupt normal cortical development. PMID:24735483

Nonspiking local interneurons in insect leg motor control. I. Common layout and species-specific response properties of femur-tibia joint control pathways in stick insect and locust.

PubMed

Büschges, A; Wolf, H

1995-05-01

1. Locusts (Locusta migratoria) and stick insects (Carausius morosus) exhibit different strategies for predator avoidance. Locusts rely primarily on walking and jumping to evade predators, whereas stick insects become cataleptic, catalepsy forming a major component of the twig mimesis exhibited by this species. The neuronal networks that control postural leg movements in locusts and stick insects are tuned differently to their specific behavioral tasks. An important prerequisite for the production of catalepsy in the stick insect is the marked velocity dependency of the control network, which appears to be generated at the level of nonspiking local interneurons. We examined interneuronal pathways in the network controlling the femur-tibia joint of the locust middle leg and compared its properties with those described for the stick insect middle leg. It was our aim to identify possible neural correlates of the species-specific behavior with regard to postural leg motor control. 2. We obtained evidence that the neuronal networks that control the femur-tibia joints in the two species consist of morphologically and physiologically similar--and thus probably homologous--interneurons. Qualitatively, these interneurons receive the same input from the femoral chordotonal organ receptors and they drive the same pools of leg motoneurons in both species. 3. Pathways that contribute to the control of the femur-tibia joint include interneurons that support both "resisting" and "assisting" responses with respect to the motoneuron activity that is actually elicited during reflex movements. Signal processing via parallel, antagonistic pathways therefore appears to be a common principle in insect leg motor control. 4. Differences between the two insect species were found with regard to the processing of velocity information provided by the femoral chordotonal organ. Interneuronal pathways are sensitive to stimulus velocity in both species. However, in the locust there is no marked

Firing-rate based network modeling of the dLGN circuit: Effects of cortical feedback on spatiotemporal response properties of relay cells.

PubMed

Mobarhan, Milad Hobbi; Halnes, Geir; Martínez-Cañada, Pablo; Hafting, Torkel; Fyhn, Marianne; Einevoll, Gaute T

2018-05-01

Visually evoked signals in the retina pass through the dorsal geniculate nucleus (dLGN) on the way to the visual cortex. This is however not a simple feedforward flow of information: there is a significant feedback from cortical cells back to both relay cells and interneurons in the dLGN. Despite four decades of experimental and theoretical studies, the functional role of this feedback is still debated. Here we use a firing-rate model, the extended difference-of-Gaussians (eDOG) model, to explore cortical feedback effects on visual responses of dLGN relay cells. For this model the responses are found by direct evaluation of two- or three-dimensional integrals allowing for fast and comprehensive studies of putative effects of different candidate organizations of the cortical feedback. Our analysis identifies a special mixed configuration of excitatory and inhibitory cortical feedback which seems to best account for available experimental data. This configuration consists of (i) a slow (long-delay) and spatially widespread inhibitory feedback, combined with (ii) a fast (short-delayed) and spatially narrow excitatory feedback, where (iii) the excitatory/inhibitory ON-ON connections are accompanied respectively by inhibitory/excitatory OFF-ON connections, i.e. following a phase-reversed arrangement. The recent development of optogenetic and pharmacogenetic methods has provided new tools for more precise manipulation and investigation of the thalamocortical circuit, in particular for mice. Such data will expectedly allow the eDOG model to be better constrained by data from specific animal model systems than has been possible until now for cat. We have therefore made the Python tool pyLGN which allows for easy adaptation of the eDOG model to new situations.

Spinal Interneurons and Forelimb Plasticity after Incomplete Cervical Spinal Cord Injury in Adult Rats

PubMed Central

Rombola, Angela M.; Rousseau, Celeste A.; Mercier, Lynne M.; Fitzpatrick, Garrett M.; Reier, Paul J.; Fuller, David D.; Lane, Michael A.

2015-01-01

Abstract Cervical spinal cord injury (cSCI) disrupts bulbospinal projections to motoneurons controlling the upper limbs, resulting in significant functional impairments. Ongoing clinical and experimental research has revealed several lines of evidence for functional neuroplasticity and recovery of upper extremity function after SCI. The underlying neural substrates, however, have not been thoroughly characterized. The goals of the present study were to map the intraspinal motor circuitry associated with a defined upper extremity muscle, and evaluate chronic changes in the distribution of this circuit following incomplete cSCI. Injured animals received a high cervical (C2) lateral hemisection (Hx), which compromises supraspinal input to ipsilateral spinal motoneurons controlling the upper extremities (forelimb) in the adult rat. A battery of behavioral tests was used to characterize the time course and extent of forelimb motor recovery over a 16 week period post-injury. A retrograde transneuronal tracer – pseudorabies virus – was used to define the motor and pre-motor circuitry controlling the extensor carpi radialis longus (ECRL) muscle in spinal intact and injured animals. In the spinal intact rat, labeling was observed unilaterally within the ECRL motoneuron pool and within spinal interneurons bilaterally distributed within the dorsal horn and intermediate gray matter. No changes in labeling were observed 16 weeks post-injury, despite a moderate degree of recovery of forelimb motor function. These results suggest that recovery of the forelimb function assessed following C2Hx injury does not involve recruitment of new interneurons into the ipsilateral ECRL motor pathway. However, the functional significance of these existing interneurons to motor recovery requires further exploration. PMID:25625912

Interneurons in the Honeybee Primary Auditory Center Responding to Waggle Dance-Like Vibration Pulses.

PubMed

Ai, Hiroyuki; Kai, Kazuki; Kumaraswamy, Ajayrama; Ikeno, Hidetoshi; Wachtler, Thomas

2017-11-01

Female honeybees use the "waggle dance" to communicate the location of nectar sources to their hive mates. Distance information is encoded in the duration of the waggle phase (von Frisch, 1967). During the waggle phase, the dancer produces trains of vibration pulses, which are detected by the follower bees via Johnston's organ located on the antennae. To uncover the neural mechanisms underlying the encoding of distance information in the waggle dance follower, we investigated morphology, physiology, and immunohistochemistry of interneurons arborizing in the primary auditory center of the honeybee ( Apis mellifera ). We identified major interneuron types, named DL-Int-1, DL-Int-2, and bilateral DL-dSEG-LP, that responded with different spiking patterns to vibration pulses applied to the antennae. Experimental and computational analyses suggest that inhibitory connection plays a role in encoding and processing the duration of vibration pulse trains in the primary auditory center of the honeybee. SIGNIFICANCE STATEMENT The waggle dance represents a form of symbolic communication used by honeybees to convey the location of food sources via species-specific sound. The brain mechanisms used to decipher this symbolic information are unknown. We examined interneurons in the honeybee primary auditory center and identified different neuron types with specific properties. The results of our computational analyses suggest that inhibitory connection plays a role in encoding waggle dance signals. Our results are critical for understanding how the honeybee deciphers information from the sound produced by the waggle dance and provide new insights regarding how common neural mechanisms are used by different species to achieve communication. Copyright © 2017 the authors 0270-6474/17/3710624-12$15.00/0.

Visual experience and subsequent sleep induce sequential plastic changes in putative inhibitory and excitatory cortical neurons

PubMed Central

Aton, Sara J.; Broussard, Christopher; Dumoulin, Michelle; Seibt, Julie; Watson, Adam; Coleman, Tammi; Frank, Marcos G.

2013-01-01

Ocular dominance plasticity in the developing primary visual cortex is initiated by monocular deprivation (MD) and consolidated during subsequent sleep. To clarify how visual experience and sleep affect neuronal activity and plasticity, we continuously recorded extragranular visual cortex fast-spiking (FS) interneurons and putative principal (i.e., excitatory) neurons in freely behaving cats across periods of waking MD and post-MD sleep. Consistent with previous reports in mice, MD induces two related changes in FS interneurons: a response shift in favor of the closed eye and depression of firing. Spike-timing–dependent depression of open-eye–biased principal neuron inputs to FS interneurons may mediate these effects. During post-MD nonrapid eye movement sleep, principal neuron firing increases and becomes more phase-locked to slow wave and spindle oscillations. Ocular dominance (OD) shifts in favor of open-eye stimulation—evident only after post-MD sleep—are proportional to MD-induced changes in FS interneuron activity and to subsequent sleep-associated changes in principal neuron activity. OD shifts are greatest in principal neurons that fire 40–300 ms after neighboring FS interneurons during post-MD slow waves. Based on these data, we propose that MD-induced changes in FS interneurons play an instructive role in ocular dominance plasticity, causing disinhibition among open-eye–biased principal neurons, which drive plasticity throughout the visual cortex during subsequent sleep. PMID:23300282

Robust Formation and Maintenance of Continuous Stratified Cortical Neuroepithelium by Laminin-Containing Matrix in Mouse ES Cell Culture

PubMed Central

Nasu, Makoto; Takata, Nozomu; Danjo, Teruko; Sakaguchi, Hideya; Kadoshima, Taisuke; Futaki, Sugiko; Sekiguchi, Kiyotoshi; Eiraku, Mototsugu; Sasai, Yoshiki

2012-01-01

In the mammalian cortex, the dorsal telencephalon exhibits a characteristic stratified structure. We previously reported that three-dimensional (3D) culture of mouse ES cells (mESCs) can efficiently generate cortical neuroepithelium (NE) and layer-specific cortical neurons. However, the cortical NE generated in this mESC culture was structurally unstable and broke into small neural rosettes by culture day 7, suggesting that some factors for reinforcing the structural integrity were missing. Here we report substantial supporting effects of the extracellular matrix (ECM) protein laminin on the continuous formation of properly polarized cortical NE in floating aggregate culture of mESCs. The addition of purified laminin and entactin (a laminin-associated protein), even at low concentrations, stabilized the formation of continuous cortical NE as well as the maintenance of basement membrane and prevented rosette formation. Treatment with the neutralizing ß1-integrin antibody impaired the continuous NE formation. The stabilized cortical NE exhibited typical interkinetic nuclear migration of cortical progenitors, as seen in the embryonic cortex. The laminin-treated cortical NE maintained a continuous structure even on culture days 12 and 15, and contained ventricular, basal-progenitor, cortical-plate and Cajal-Retzius cell layers. The cortical NE in this culture was flanked by cortical hem-like tissue. Furthermore, when Shh was added, ventral telencephalic structures such as lateral ganglionic eminence–like tissue formed in the region adjacent to the cortical NE. Thus, our results indicate that laminin-entactin ECM promotes the formation of structurally stable telencephalic tissues in 3D ESC culture, and supports the morphogenetic recapitulation of cortical development. PMID:23300850

Expression and distribution of Kv4 potassium channel subunits and potassium channel interacting proteins in subpopulations of interneurons in the basolateral amygdala.

PubMed

Dabrowska, J; Rainnie, D G

2010-12-15

The Kv4 potassium channel α subunits, Kv4.1, Kv4.2, and Kv4.3, determine some of the fundamental physiological properties of neurons in the CNS. Kv4 subunits are associated with auxiliary β-subunits, such as the potassium channel interacting proteins (KChIP1 - 4), which are thought to regulate the trafficking and gating of native Kv4 potassium channels. Intriguingly, KChIP1 is thought to show cell type-selective expression in GABA-ergic inhibitory interneurons, while other β-subunits (KChIP2-4) are associated with principal glutamatergic neurons. However, nothing is known about the expression of Kv4 family α- and β-subunits in specific interneurons populations in the BLA. Here, we have used immunofluorescence, co-immunoprecipitation, and Western Blotting to determine the relative expression of KChIP1 in the different interneuron subtypes within the BLA, and its co-localization with one or more of the Kv4 α subunits. We show that all three α-subunits of Kv4 potassium channel are found in rat BLA neurons, and that the immunoreactivity of KChIP1 closely resembles that of Kv4.3. Indeed, Kv4.3 showed almost complete co-localization with KChIP1 in the soma and dendrites of a distinct subpopulation of BLA neurons. Dual-immunofluorescence studies revealed this to be in BLA interneurons immunoreactive for parvalbumin, cholecystokin-8, and somatostatin. Finally, co-immunoprecipitation studies showed that KChIP1 was associated with all three Kv4 α subunits. Together our results suggest that KChIP1 is selectively expressed in BLA interneurons where it may function to regulate the activity of A-type potassium channels. Hence, KChIP1 might be considered as a cell type-specific regulator of GABAergic inhibitory circuits in the BLA. Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

Impaired action potential initiation in GABAergic interneurons causes hyperexcitable networks in an epileptic mouse model carrying a human Na(V)1.1 mutation.

PubMed

Hedrich, Ulrike B S; Liautard, Camille; Kirschenbaum, Daniel; Pofahl, Martin; Lavigne, Jennifer; Liu, Yuanyuan; Theiss, Stephan; Slotta, Johannes; Escayg, Andrew; Dihné, Marcel; Beck, Heinz; Mantegazza, Massimo; Lerche, Holger

2014-11-05

Mutations in SCN1A and other ion channel genes can cause different epileptic phenotypes, but the precise mechanisms underlying the development of hyperexcitable networks are largely unknown. Here, we present a multisystem analysis of an SCN1A mouse model carrying the NaV1.1-R1648H mutation, which causes febrile seizures and epilepsy in humans. We found a ubiquitous hypoexcitability of interneurons in thalamus, cortex, and hippocampus, without detectable changes in excitatory neurons. Interestingly, somatic Na(+) channels in interneurons and persistent Na(+) currents were not significantly changed. Instead, the key mechanism of interneuron dysfunction was a deficit of action potential initiation at the axon initial segment that was identified by analyzing action potential firing. This deficit increased with the duration of firing periods, suggesting that increased slow inactivation, as recorded for recombinant mutated channels, could play an important role. The deficit in interneuron firing caused reduced action potential-driven inhibition of excitatory neurons as revealed by less frequent spontaneous but not miniature IPSCs. Multiple approaches indicated increased spontaneous thalamocortical and hippocampal network activity in mutant mice, as follows: (1) more synchronous and higher-frequency firing was recorded in primary neuronal cultures plated on multielectrode arrays; (2) thalamocortical slices examined by field potential recordings revealed spontaneous activities and pathological high-frequency oscillations; and (3) multineuron Ca(2+) imaging in hippocampal slices showed increased spontaneous neuronal activity. Thus, an interneuron-specific generalized defect in action potential initiation causes multisystem disinhibition and network hyperexcitability, which can well explain the occurrence of seizures in the studied mouse model and in patients carrying this mutation. Copyright © 2014 the authors 0270-6474/14/3414874-16$15.00/0.

Generation of Cre-transgenic mice using Dlx1/Dlx2 enhancers and their characterization in GABAergic interneurons

PubMed Central

Potter, Gregory B.; Petryniak, Magdalena A.; Shevchenko, Eugenia; McKinsey, Gabriel L.; Ekker, Marc; Rubenstein, John L.R.

2009-01-01

DLX1 and DLX2 transcription factors are necessary for forebrain GABAergic neuron differentiation, migration, and survival. We generated transgenic mice that express Cre-recombinase under the control of two ultra-conserved DNA elements near the Dlx1&2 locus termed I12b and URE2. We show that Cre-recombinase is active in a “Dlx-pattern” in the embryonic forebrain of transgenic mice. I12b-Cre is more active than URE2-Cre in the medial ganglionic eminences and its derivatives. Fate-mapping of EGFP+ cells in adult Cre;Z/EG animals demonstrated that GABAergic neurons, but not glia, are labeled. Most NPY+, nNOS+, parvalbumin+, and somatostatin+ cells are marked by I12b-Cre in the cortex and hippocampus, while 25-40% of these interneuron subtypes are labeled by URE2-Cre. Labeling of neurons generated between E12.5 to E15.5 indicated differences in birth-dates of EGFP+ cells that populate the olfactory bulb, hippocampus, and cortex. Finally, we provide the first in vivo evidence that both I12b and URE2 are direct targets of DLX2 and require Dlx1 and Dlx2 expression for proper activity. PMID:19026749

Muscimol increases acetylcholine release by directly stimulating adult striatal cholinergic interneurons.

PubMed

Login, I S; Pal, S N; Adams, D T; Gold, P E

1998-01-01

Because GabaA ligands increase acetylcholine (ACh) release from adult striatal slices, we hypothesized that activation of GabaA receptors on striatal cholinergic interneurons directly stimulates ACh secretion. Fractional [3H]ACh release was recorded during perifusion of acutely dissociated, [3H]choline-labeled, adult male rat striata. The GabaA agonist, muscimol, immediately stimulated release maximally approximately 300% with EC50 = approximately 1 microM. This action was enhanced by the allosteric GabaA receptor modulators, diazepam and secobarbital, and inhibited by the GabaA antagonist, bicuculline, by ligands for D2 or muscarinic cholinergic receptors or by low calcium buffer, tetrodotoxin or vesamicol. Membrane depolarization inversely regulated muscimol-stimulated secretion. Release of endogenous and newly synthesized ACh was stimulated in parallel by muscimol without changing choline release. Muscimol pretreatment inhibited release evoked by K+ depolarization or by receptor-mediated stimulation with glutamate. Thus, GabaA receptors on adult striatal cholinergic interneurons directly stimulate voltage- and calcium-dependent exocytosis of ACh stored in vesamicol-sensitive synaptic vesicles. The action depends on the state of membrane polarization and apparently depolarizes the membrane in turn. This functional assay demonstrates that excitatory GabaA actions are not limited to neonatal tissues. GabaA-stimulated ACh release may be prevented in situ by normal tonic dopaminergic and muscarinic input to cholinergic neurons.

Anatomy and physiology of a set of low-frequency vibratory interneurons in a nonhearing ensiferan (Troglophilus neglectus, rhaphidophoridae).

PubMed

Stritih, Natasa

2009-10-20

Vibratory interneurons were investigated in a primitive nonhearing ensiferan (orthopteran) species (Troglophilus neglectus, Rhaphidophoridae), using intracellular recording and staining technique. The study included 26 morphologically and/or physiologically distinct types of neurons from the prothoracic ganglion responding to vibration of the front legs. Most of these neurons are tuned to frequencies below 400 Hz. The morphology, anatomical position in the ganglion, and physiological responses are described in particular for a set of these low-frequency-tuned elements, including one local neuron, two T-shaped fibers, and five descending neurons, for which no putative homologues are known from the hearing Orthoptera. Their lowest thresholds are between about 0.01 and 0.4 m/second(2) at frequencies of 50-400 Hz, and the shortest latencies between 10 and 16 msec, suggesting that they are first- or second-order interneurons. Six interneurons have dendritic arborizations in the neuropile region that contains projections of tibial organ vibratory receptors, but their sensitivity suggests predominating inputs from vibrational sensilla of another origin. Responses of most neurons are composed of frequency-specific excitatory and inhibitory synaptic potentials, most of the latter being received in the high-frequency range. The function of these neurons in predator detection and intraspecific communication is discussed.

DMRTA2 (DMRT5) is mutated in a novel cortical brain malformation.

PubMed

Urquhart, J E; Beaman, G; Byers, H; Roberts, N A; Chervinsky, E; O'Sullivan, J; Pilz, D; Fry, A; Williams, S G; Bhaskar, S S; Khayat, M; Simanovsky, N; Shachar, I B; Shalev, S A; Newman, W G

2016-06-01

Lissencephaly is a phenotypically and genetically heterogeneous group of cortical brain malformations due to abnormal neuronal migration. The identification of many causative genes has increased the understanding of normal brain development. A consanguineous family was ascertained with three siblings affected by a severe prenatal neurodevelopmental disorder characterised by fronto-parietal pachygyria, agenesis of the corpus callosum and progressive severe microcephaly. Autozygosity mapping and exome sequencing identified a homozygous novel single base pair deletion, c.1197delT in DMRTA2, predicted to result in a frameshift variant p.(Pro400Leufs*33). DMRTA2 encodes doublesex and mab-3-related transcription factor a2, a transcription factor key to the development of the dorsal telencephalon. Data from murine and zebrafish knockout models are consistent with the variant of DMTRA2 (DMRT5) as responsible for the cortical brain phenotype. Our study suggests that loss of function of DMRTA2 leads to a novel disorder of cortical development. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Cholinergic interneurons in the feeding system of the pond snail Lymnaea stagnalis. II. N1 interneurons make cholinergic synapses with feeding motoneurons.

PubMed

Elliott, C J; Kemenes, G

1992-05-29

The N1 neurons are a population of interneurons active during the protraction phase of the feeding rhythm. All the N1 neurons are coupled by electrical synapses which persist in a high Mg/low Ca saline which blocks chemical synapses. Individual N1 spikes produce discrete electrotonic postsynaptic potentials (PSPS) in other N1 cells, but the coupling is not strong enough to ensure 1:1 firing. Bursts of N1 spikes generate compound PSPS in the feeding motoneurons. The sign (excitation or inhibition) of the N1 input corresponds with the synaptic barrage recorded during the protraction phase. Discrete PSPS are only resolved in a Hi-Di saline. Their variation in latency and number can be explained by variation in electrotonic propagation within the electrically coupled network of N1 cells. The excitatory postsynaptic potentials (ESPS) in the 1 cell are reduced by 0.5 mM antagonists hexamethonium (HMT), atropine (ATR), curare (d-TC) and by methylxylocholine (MeXCh), all of which block the excitatory cholinergic receptor (Elliott et al. (Phil. Trans. R. Soc. Lond. 336, 157-166 (Preceding paper.) (1992)). The 1 cell EPSPS were transiently blocked by phenyltrimethylammonium (PTMA), which is both an agonist and antagonist at the 1 cell excitatory acetylcholine (ACh) receptor (Elliott et al. 1992). The inhibitory postsynaptic potential (IPSP) in the 3 cell is blocked by bath applications of MeXCh and PTMA, which both abolish the response of the 3 cell to ACh (Elliott et. al. 1992). The effects of the cholinergic antagonists on the response of 4 cluster and 5 cells to N1 stimulation matches their response to ACh (Elliott et al. 1992). It is concluded that the population of N1 cells are multiaction, premotor cholinergic interneurons.

Time-lapse imaging of neuroblast migration in acute slices of the adult mouse forebrain.

PubMed

Khlghatyan, Jivan; Saghatelyan, Armen

2012-09-12

There is a substantial body of evidence indicating that new functional neurons are constitutively generated from an endogenous pool of neural stem cells in restricted areas of the adult mammalian brain. Newborn neuroblasts from the subventricular zone (SVZ) migrate along the rostral migratory stream (RMS) to their final destination in the olfactory bulb (OB). In the RMS, neuroblasts migrate tangentially in chains ensheathed by astrocytic processes using blood vessels as a structural support and a source of molecular factors required for migration. In the OB, neuroblasts detach from the chains and migrate radially into the different bulbar layers where they differentiate into interneurons and integrate into the existing network. In this manuscript we describe the procedure for monitoring cell migration in acute slices of the rodent brain. The use of acute slices allows the assessment of cell migration in the microenvironment that closely resembling to in vivo conditions and in brain regions that are difficult to access for in vivo imaging. In addition, it avoids long culturing condition as in the case of organotypic and cell cultures that may eventually alter the migration properties of the cells. Neuronal precursors in acute slices can be visualized using DIC optics or fluorescent proteins. Viral labeling of neuronal precursors in the SVZ, grafting neuroblasts from reporter mice into the SVZ of wild-type mice, and using transgenic mice that express fluorescent protein in neuroblasts are all suitable methods for visualizing neuroblasts and following their migration. The later method, however, does not allow individual cells to be tracked for long periods of time because of the high density of labeled cells. We used a wide-field fluorescent upright microscope equipped with a CCD camera to achieve a relatively rapid acquisition interval (one image every 15 or 30 sec) to reliably identify the stationary and migratory phases. A precise identification of the duration of

Movement Rate Is Encoded and Influenced by Widespread, Coherent Activity of Cerebellar Molecular Layer Interneurons.

PubMed

Gaffield, Michael A; Christie, Jason M

2017-05-03

Inhibition from molecular layer interneurons (MLIs) is thought to play an important role in cerebellar function by sharpening the precision of Purkinje cell spike output. Yet the coding features of MLIs during behavior are poorly understood. To study MLI activity, we used in vivo Ca 2+ imaging in head-fixed mice during the performance of a rhythmic motor behavior, licking during water consumption. MLIs were robustly active during lick-related movement across a lobule-specific region of the cerebellum showing high temporal correspondence within their population. Average MLI Ca 2+ activity strongly correlated with movement rate but not to the intentional, or unexpected, adjustment of lick position or to sensory feedback that varied with task condition. Chemogenetic suppression of MLI output reduced lick rate and altered tongue movements, indicating that activity of these interneurons not only encodes temporal aspects of movement kinematics but also influences motor outcome pointing to an integral role in online control of rhythmic behavior. SIGNIFICANCE STATEMENT The cerebellum helps fine-tune coordinated motor actions via signaling from projection neurons called Purkinje cells. Molecular layer interneurons (MLIs) provide powerful inhibition onto Purkinje cells, but little is understood about how this inhibitory circuit is engaged during behavior or what type of information is transmitted through these neurons. Our work establishes that MLIs in the lateral cerebellum are broadly activated during movement with calcium activity corresponding to movement rate. We also show that suppression of MLI output slows and disorganizes the precise movement pattern. Therefore, MLIs are an important circuit element in the cerebellum allowing for accurate motor control. Copyright © 2017 the authors 0270-6474/17/374751-15$15.00/0.

A combined electrophysiological and morphological study of neuropeptide Y–expressing inhibitory interneurons in the spinal dorsal horn of the mouse

PubMed Central

Iwagaki, Noboru; Ganley, Robert P.; Dickie, Allen C.; Polgár, Erika; Hughes, David I.; Del Rio, Patricia; Revina, Yulia; Watanabe, Masahiko; Todd, Andrew J.; Riddell, John S.

2015-01-01

Abstract The spinal dorsal horn contains numerous inhibitory interneurons that control transmission of somatosensory information. Although these cells have important roles in modulating pain, we still have limited information about how they are incorporated into neuronal circuits, and this is partly due to difficulty in assigning them to functional populations. Around 15% of inhibitory interneurons in laminae I-III express neuropeptide Y (NPY), but little is known about this population. We therefore used a combined electrophysiological/morphological approach to investigate these cells in mice that express green fluorescent protein (GFP) under control of the NPY promoter. We show that GFP is largely restricted to NPY-immunoreactive cells, although it is only expressed by a third of those in lamina I-II. Reconstructions of recorded neurons revealed that they were morphologically heterogeneous, but never islet cells. Many NPY-GFP cells (including cells in lamina III) appeared to be innervated by C fibres that lack transient receptor potential vanilloid-1, and consistent with this, we found that some lamina III NPY-immunoreactive cells were activated by mechanical noxious stimuli. Projection neurons in lamina III are densely innervated by NPY-containing axons. Our results suggest that this input originates from a small subset of NPY-expressing interneurons, with the projection cells representing only a minority of their output. Taken together with results of previous studies, our findings indicate that somatodendritic morphology is of limited value in classifying functional populations among inhibitory interneurons in the dorsal horn. Because many NPY-expressing cells respond to noxious stimuli, these are likely to have a role in attenuating pain and limiting its spread. PMID:26882346

Inter-individual variation in reciprocal Ia inhibition is dependent on the descending volleys delivered from corticospinal neurons to Ia interneurons.

PubMed

Kubota, Shinji; Uehara, Kazumasa; Morishita, Takuya; Hirano, Masato; Funase, Kozo

2014-02-01

We investigated the extent to which the corticospinal inputs delivered to Ia inhibitory interneurons influence the strength of disynaptic reciprocal Ia inhibition. Seventeen healthy subjects participated in this study. The degree of reciprocal Ia inhibition was determined via short-latency (condition-test interval: 1-3ms) suppression of Sol H-reflex by conditioning stimulation of common peroneal nerve. The effect of corticospinal descending inputs on Ia inhibitory interneurons was assessed by evaluating the conditioning effect of transcranial magnetic stimulation (TMS) on the Sol H-reflex. Then, we determined the relationship between the degree of reciprocal Ia inhibition and the conditioning effect of TMS on the Sol H-reflex. We found that the degree of reciprocal Ia inhibition and the extent of change in the amplitude of the TMS-conditioned H-reflex, which was measured from short latency facilitation to inhibition, displayed a strong correlation (r=0.76, p<0.01) in the resting conditions. The extent of reciprocal Ia inhibition is affected by the corticospinal descending inputs delivered to Ia inhibitory interneurons, which might explain the inter-individual variations in reciprocal Ia inhibition. Copyright © 2013 Elsevier Ltd. All rights reserved.

Encoding of Tactile Stimuli by Mechanoreceptors and Interneurons of the Medicinal Leech

PubMed Central

Kretzberg, Jutta; Pirschel, Friederice; Fathiazar, Elham; Hilgen, Gerrit

2016-01-01

For many animals processing of tactile information is a crucial task in behavioral contexts like exploration, foraging, and stimulus avoidance. The leech, having infrequent access to food, developed an energy efficient reaction to tactile stimuli, avoiding unnecessary muscle movements: The local bend behavior moves only a small part of the body wall away from an object touching the skin, while the rest of the animal remains stationary. Amazingly, the precision of this localized behavioral response is similar to the spatial discrimination threshold of the human fingertip, although the leech skin is innervated by an order of magnitude fewer mechanoreceptors and each midbody ganglion contains only 400 individually identified neurons in total. Prior studies suggested that this behavior is controlled by a three-layered feed-forward network, consisting of four mechanoreceptors (P cells), approximately 20 interneurons and 10 individually characterized motor neurons, all of which encode tactile stimulus location by overlapping, symmetrical tuning curves. Additionally, encoding of mechanical force was attributed to three types of mechanoreceptors reacting to distinct intensity ranges: T cells for touch, P cells for pressure, and N cells for strong, noxious skin stimulation. In this study, we provide evidences that tactile stimulus encoding in the leech is more complex than previously thought. Combined electrophysiological, anatomical, and voltage sensitive dye approaches indicate that P and T cells both play a major role in tactile information processing resulting in local bending. Our results indicate that tactile encoding neither relies on distinct force intensity ranges of different cell types, nor location encoding is restricted to spike count tuning. Instead, we propose that P and T cells form a mixed type population, which simultaneously employs temporal response features and spike counts for multiplexed encoding of touch location and force intensity. This hypothesis

Early Developmental Disturbances of Cortical Inhibitory Neurons: Contribution to Cognitive Deficits in Schizophrenia

PubMed Central

Volk, David W.; Lewis, David A.

2014-01-01

Cognitive dysfunction is a disabling and core feature of schizophrenia. Cognitive impairments have been linked to disturbances in inhibitory (gamma-aminobutyric acid [GABA]) neurons in the prefrontal cortex. Cognitive deficits are present well before the onset of psychotic symptoms and have been detected in early childhood with developmental delays reported during the first year of life. These data suggest that the pathogenetic process that produces dysfunction of prefrontal GABA neurons in schizophrenia may be related to altered prenatal development. Interestingly, adult postmortem schizophrenia brain tissue studies have provided evidence consistent with a disease process that affects different stages of prenatal development of specific subpopulations of prefrontal GABA neurons. Prenatal ontogeny (ie, birth, proliferation, migration, and phenotypic specification) of distinct subpopulations of cortical GABA neurons is differentially regulated by a host of transcription factors, chemokine receptors, and other molecular markers. In this review article, we propose a strategy to investigate how alterations in the expression of these developmental regulators of subpopulations of cortical GABA neurons may contribute to the pathogenesis of cortical GABA neuron dysfunction and consequently cognitive impairments in schizophrenia. PMID:25053651

The Generation of Superficial Cortical Layers Is Regulated by Levels of the Transcription Factor Pax6

PubMed Central

Manuel, Martine; Price, David J.

2011-01-01

The ventricular zone (VZ) of the embryonic dorsal telencephalon is a major site for generating cortical projection neurons. The transcription factor Pax6 is highly expressed in apical progenitors (APs) residing in the VZ from the earliest stages of corticogenesis. Previous studies mainly focused on Pax6−/− mice have implicated Pax6 in regulating cortical progenitor proliferation, neurogenesis, and formation of superficial cortical layers. We analyzed the developing cortex of PAX77 transgenic mice that overexpress Pax6 in its normal domains of expression. We show that Pax6 overexpression increases cell cycle length of APs and drives the system toward neurogenesis. These effects are specific to late stages of corticogenesis, when superficial layer neurons are normally generated, in cortical regions that express Pax6 at the highest levels. The number of superficial layer neurons is reduced in postnatal PAX77 mice, whereas radial migration and lamina specification of cortical neurons are not affected by Pax6 overexpression. Conditional deletion of Pax6 in cortical progenitors at midstages of corticogenesis, by using a tamoxifen-inducible Emx1-CreER line, affected both numbers and specification of late-born neurons in superficial layers of the mutant cortex. Our analyses suggest that correct levels of Pax6 are essential for normal production of superficial layers of the cortex. PMID:20413449

Cortical presynaptic control of dorsal horn C-afferents in the rat.

PubMed

Moreno-López, Yunuen; Pérez-Sánchez, Jimena; Martínez-Lorenzana, Guadalupe; Condés-Lara, Miguel; Rojas-Piloni, Gerardo

2013-01-01

Lamina 5 sensorimotor cortex pyramidal neurons project to the spinal cord, participating in the modulation of several modalities of information transmission. A well-studied mechanism by which the corticospinal projection modulates sensory information is primary afferent depolarization, which has been characterized in fast muscular and cutaneous, but not in slow-conducting nociceptive skin afferents. Here we investigated whether the inhibition of nociceptive sensory information, produced by activation of the sensorimotor cortex, involves a direct presynaptic modulation of C primary afferents. In anaesthetized male Wistar rats, we analyzed the effects of sensorimotor cortex activation on post tetanic potentiation (PTP) and the paired pulse ratio (PPR) of dorsal horn field potentials evoked by C-fiber stimulation in the sural (SU) and sciatic (SC) nerves. We also explored the time course of the excitability changes in nociceptive afferents produced by cortical stimulation. We observed that the development of PTP was completely blocked when C-fiber tetanic stimulation was paired with cortex stimulation. In addition, sensorimotor cortex activation by topical administration of bicuculline (BIC) produced a reduction in the amplitude of C-fiber responses, as well as an increase in the PPR. Furthermore, increases in the intraspinal excitability of slow-conducting fiber terminals, produced by sensorimotor cortex stimulation, were indicative of primary afferent depolarization. Topical administration of BIC in the spinal cord blocked the inhibition of C-fiber neuronal responses produced by cortical stimulation. Dorsal horn neurons responding to sensorimotor cortex stimulation also exhibited a peripheral receptive field and responded to stimulation of fast cutaneous myelinated fibers. Our results suggest that corticospinal inhibition of nociceptive responses is due in part to a modulation of the excitability of primary C-fibers by means of GABAergic inhibitory interneurons.

Cortical Presynaptic Control of Dorsal Horn C–Afferents in the Rat

PubMed Central

Martínez-Lorenzana, Guadalupe; Condés-Lara, Miguel; Rojas-Piloni, Gerardo

2013-01-01

Lamina 5 sensorimotor cortex pyramidal neurons project to the spinal cord, participating in the modulation of several modalities of information transmission. A well-studied mechanism by which the corticospinal projection modulates sensory information is primary afferent depolarization, which has been characterized in fast muscular and cutaneous, but not in slow-conducting nociceptive skin afferents. Here we investigated whether the inhibition of nociceptive sensory information, produced by activation of the sensorimotor cortex, involves a direct presynaptic modulation of C primary afferents. In anaesthetized male Wistar rats, we analyzed the effects of sensorimotor cortex activation on post tetanic potentiation (PTP) and the paired pulse ratio (PPR) of dorsal horn field potentials evoked by C–fiber stimulation in the sural (SU) and sciatic (SC) nerves. We also explored the time course of the excitability changes in nociceptive afferents produced by cortical stimulation. We observed that the development of PTP was completely blocked when C-fiber tetanic stimulation was paired with cortex stimulation. In addition, sensorimotor cortex activation by topical administration of bicuculline (BIC) produced a reduction in the amplitude of C–fiber responses, as well as an increase in the PPR. Furthermore, increases in the intraspinal excitability of slow-conducting fiber terminals, produced by sensorimotor cortex stimulation, were indicative of primary afferent depolarization. Topical administration of BIC in the spinal cord blocked the inhibition of C–fiber neuronal responses produced by cortical stimulation. Dorsal horn neurons responding to sensorimotor cortex stimulation also exhibited a peripheral receptive field and responded to stimulation of fast cutaneous myelinated fibers. Our results suggest that corticospinal inhibition of nociceptive responses is due in part to a modulation of the excitability of primary C–fibers by means of GABAergic inhibitory

Rapamycin prevents, but does not reverse, aberrant migration in Pten knockout neurons.

PubMed

Getz, Stephanie A; DeSpenza, Tyrone; Li, Meijie; Luikart, Bryan W

2016-09-01

Phosphatase and tensin homolog (PTEN) is a major negative regulator of the Akt/mammalian target of rapamycin (MTOR) pathway. Mutations in PTEN have been found in a subset of individuals with autism and macrocephaly. Further, focal cortical dysplasia (FCD) has been observed in patients with PTEN mutations prompting us to examine the role of Pten in neuronal migration. The dentate gyrus of Pten(Flox/Flox) mice was injected with Cre- and non-Cre-expressing retroviral particles, which integrate into the dividing genome to birthdate cells. Control and Pten knockout (KO) cell position in the granule cell layer was quantified over time to reveal that Pten KO neurons exhibit an aberrant migratory phenotype beginning at 7.5days-post retroviral injection (DPI). We then assessed whether rapamycin, a mTor inhibitor, could prevent or reverse aberrant migration of granule cells. The preventative group received daily intraperitoneal (IP) injections of rapamycin from 3 to 14 DPI, before discrepancies in cell position have been established, while the reversal group received rapamycin afterward, from 14 to 24 DPI. We found that rapamycin prevented and reversed somal hypertrophy. However, rapamycin prevented, but did not reverse aberrant migration in Pten KO cells. We also find that altered migration occurs through mTorC1 and not mTorC2 activity. Together, these findings suggest a temporal window by which rapamycin can treat aberrant migration, and may have implications for the use of rapamycin to treat PTEN-mutation associated disorders. Mutations in phosphatase and tensin homolog (PTEN) have been linked to a subset of individuals with autism and macrocephaly, as well as Cowden Syndrome and focal cortical dysplasia. Pten loss leads to neuronal hypertrophy, but the role of Pten in neuronal migration is unclear. Here we have shown that loss of Pten leads to aberrant migration, which can be prevented but not reversed by treatment with rapamycin, a mTor inhibitor. These results are

Spatio-temporal specialization of GABAergic septo-hippocampal neurons for rhythmic network activity.

PubMed

Unal, Gunes; Crump, Michael G; Viney, Tim J; Éltes, Tímea; Katona, Linda; Klausberger, Thomas; Somogyi, Peter

2018-03-03

Medial septal GABAergic neurons of the basal forebrain innervate the hippocampus and related cortical areas, contributing to the coordination of network activity, such as theta oscillations and sharp wave-ripple events, via a preferential innervation of GABAergic interneurons. Individual medial septal neurons display diverse activity patterns, which may be related to their termination in different cortical areas and/or to the different types of innervated interneurons. To test these hypotheses, we extracellularly recorded and juxtacellularly labeled single medial septal neurons in anesthetized rats in vivo during hippocampal theta and ripple oscillations, traced their axons to distant cortical target areas, and analyzed their postsynaptic interneurons. Medial septal GABAergic neurons exhibiting different hippocampal theta phase preferences and/or sharp wave-ripple related activity terminated in restricted hippocampal regions, and selectively targeted a limited number of interneuron types, as established on the basis of molecular markers. We demonstrate the preferential innervation of bistratified cells in CA1 and of basket cells in CA3 by individual axons. One group of septal neurons was suppressed during sharp wave-ripples, maintained their firing rate across theta and non-theta network states and mainly fired along the descending phase of CA1 theta oscillations. In contrast, neurons that were active during sharp wave-ripples increased their firing significantly during "theta" compared to "non-theta" states, with most firing during the ascending phase of theta oscillations. These results demonstrate that specialized septal GABAergic neurons contribute to the coordination of network activity through parallel, target area- and cell type-selective projections to the hippocampus.

Distinct interneuron types express m2 muscarinic receptor immunoreactivity on their dendrites or axon terminals in the hippocampus.

PubMed

Hájos, N; Papp, E C; Acsády, L; Levey, A I; Freund, T F

1998-01-01

In previous studies m2 muscarinic acetylcholine receptor-immunoreactive interneurons and various types of m2-positive axon terminals have been described in the hippocampal formation. The aim of the present study was to identify the types of interneurons expressing m2 receptor and to examine whether the somadendritic and axonal m2 immunostaining labels the same or distinct cell populations. In the CA1 subfield, neurons immunoreactive for m2 have horizontal dendrites, they are located at the stratum oriens/alveus border and have an axon that project to the dendritic region of pyramidal cells. In the CA3 subfield and the hilus, m2-positive neurons are multipolar and are scattered in all layers except stratum lacunosum-moleculare. In stratum pyramidale of the CA1 and CA3 regions, striking axon terminal staining for m2 was observed, surrounding the somata and axon initial segments of pyramidal cells in a basket-like manner. The co-localization of m2 with neurochemical markers and GABA was studied using the "mirror" technique and fluorescent double-immunostaining at the light microscopic level and with double-labelling using colloidal gold-conjugated antisera and immunoperoxidase reaction (diaminobenzidine) at the electron microscopic level. GABA was shown to be present in the somata of most m2-immunoreactive interneurons, as well as in the majority of m2-positive terminals in all layers. The calcium-binding protein parvalbumin was absent from practically all m2-immunoreactive cell bodies and dendrites. In contrast, many of the terminals synapsing on pyramidal cell somata and axon initial segments co-localized parvalbumin and m2, suggesting a differential distribution of m2 receptor immunoreactivity on the axonal and somadendritic membrane of parvalbumin-containing basket and axo-axonic cells. The co-existence of m2 receptors with the calcium-binding protein calbindin and the neuropeptides cholecystokinin and vasoactive intestinal polypeptide was rare throughout the

CCL11 promotes migration and proliferation of mouse neural progenitor cells.

PubMed

Wang, Feifei; Baba, Nobuyasu; Shen, Yuan; Yamashita, Tatsuyuki; Tsuru, Emi; Tsuda, Masayuki; Maeda, Nagamasa; Sagara, Yusuke

2017-02-07

Neonatal hypoxia-ischemia induces massive brain damage during the perinatal period, resulting in long-term consequences to central nervous system structural and functional maturation. Although neural progenitor cells (NPCs) migrate through the parenchyma and home in to injury sites in the rodent brain, the molecular mechanisms are unknown. We examined the role of chemokines in mediating NPC migration after neonatal hypoxic-ischemic brain injury. Nine-day-old mice were exposed to a 120-minute hypoxia following unilateral carotid occlusion. Chemokine levels were quantified in mouse brain extract. Migration and proliferation assays were performed using embryonic and infant mouse NPCs. The neonatal hypoxic-ischemic brain injury resulted in an ipsilateral lesion, which was extended to the cortical and striatal areas. NPCs migrated toward an injured area, where a marked increase of CC chemokines was detected. In vitro studies showed that incubation of NPCs with recombinant mouse CCL11 promoted migration and proliferation. These effects were partly inhibited by a CCR3 antagonist, SB297006. Our data implicate an important effect of CCL11 for mouse NPCs. The effective activation of NPCs may offer a promising strategy for neuroregeneration in neonatal hypoxic-ischemic brain injury.

Striatal cholinergic interneurons and D2 receptor-expressing GABAergic medium spiny neurons regulate tardive dyskinesia.

PubMed

Bordia, Tanuja; Zhang, Danhui; Perez, Xiomara A; Quik, Maryka

2016-12-01

Tardive dyskinesia (TD) is a drug-induced movement disorder that arises with antipsychotics. These drugs are the mainstay of treatment for schizophrenia and bipolar disorder, and are also prescribed for major depression, autism, attention deficit hyperactivity, obsessive compulsive and post-traumatic stress disorder. There is thus a need for therapies to reduce TD. The present studies and our previous work show that nicotine administration decreases haloperidol-induced vacuous chewing movements (VCMs) in rodent TD models, suggesting a role for the nicotinic cholinergic system. Extensive studies also show that D2 dopamine receptors are critical to TD. However, the precise involvement of striatal cholinergic interneurons and D2 medium spiny neurons (MSNs) in TD is uncertain. To elucidate their role, we used optogenetics with a focus on the striatum because of its close links to TD. Optical stimulation of striatal cholinergic interneurons using cholineacetyltransferase (ChAT)-Cre mice expressing channelrhodopsin2-eYFP decreased haloperidol-induced VCMs (~50%), with no effect in control-eYFP mice. Activation of striatal D2 MSNs using Adora2a-Cre mice expressing channelrhodopsin2-eYFP also diminished antipsychotic-induced VCMs, with no change in control-eYFP mice. In both ChAT-Cre and Adora2a-Cre mice, stimulation or mecamylamine alone similarly decreased VCMs with no further decline with combined treatment, suggesting nAChRs are involved. Striatal D2 MSN activation in haloperidol-treated Adora2a-Cre mice increased c-Fos + D2 MSNs and decreased c-Fos + non-D2 MSNs, suggesting a role for c-Fos. These studies provide the first evidence that optogenetic stimulation of striatal cholinergic interneurons and GABAergic MSNs modulates VCMs, and thus possibly TD. Moreover, they suggest nicotinic receptor drugs may reduce antipsychotic-induced TD. Copyright © 2016 Elsevier Inc. All rights reserved.

Striatal cholinergic interneurons and D2 receptor-expressing GABAergic medium spiny neurons regulate tardive dyskinesia

PubMed Central

Bordia, Tanuja; Zhang, Danhui; Perez, Xiomara A.; Quik, Maryka

2016-01-01

Tardive dyskinesia (TD) is a drug-induced movement disorder that arises with antipsychotics. These drugs are the mainstay of treatment for schizophrenia and bipolar disorder, and are also prescribed for major depression, autism, attention deficit hyperactivity, obsessive compulsive and post-traumatic stress disorder. There is thus a need for therapies to reduce TD. The present studies and our previous work show that nicotine administration decreases haloperidol-induced vacuous chewing movements (VCMs) in rodent TD models, suggesting a role for the nicotinic cholinergic system. Extensive studies also show that D2 dopamine receptors are critical to TD. However, the precise involvement of striatal cholinergic interneurons and D2 medium spiny neurons (MSNs) in TD is uncertain. To elucidate their role, we used optogenetics with a focus on the striatum because of its close links to TD. Optical stimulation of striatal cholinergic interneurons using cholineacetyltransferase (ChAT)-Cre mice expressing channelrhodopsin2-eYFP decreased haloperidol-induced VCMs (~50%), with no effect in control-eYFP mice. Activation of striatal D2 MSNs using Adora2a-Cre mice expressing channelrhodopsin2-eYFP also diminished antipsychotic-induced VCMs, with no change in control-eYFP mice. In both ChAT-Cre and Adora2a-Cre mice, stimulation or mecamylamine alone similarly decreased VCMs with no further decline with combined treatment, suggesting nAChRs are involved. Striatal D2 MSN activation in haloperidol-treated Adora2a-Cre mice increased c-Fos+ D2 MSNs and decreased c-Fos+ non-D2 MSNs, suggesting a role for c-Fos. These studies provide the first evidence that optogenetic stimulation of striatal cholinergic interneurons and GABAergic MSNs modulates VCMs, and thus possibly TD. Moreover, they suggest nicotinic receptor drugs may reduce antipsychotic-induced TD. PMID:27658674

Differential distribution of neurons in the gyral white matter of the human cerebral cortex.

PubMed

García-Marín, V; Blazquez-Llorca, L; Rodriguez, J R; Gonzalez-Soriano, J; DeFelipe, J

2010-12-01

The neurons in the cortical white matter (WM neurons) originate from the first set of postmitotic neurons that migrates from the ventricular zone. In particular, they arise in the subplate that contains the earliest cells generated in the telencephalon, prior to the appearance of neurons in gray matter cortical layers. These cortical WM neurons are very numerous during development, when they are thought to participate in transient synaptic networks, although many of these cells later die, and relatively few cells survive as WM neurons in the adult. We used light and electron microscopy to analyze the distribution and density of WM neurons in various areas of the adult human cerebral cortex. Furthermore, we examined the perisomatic innervation of these neurons and estimated the density of synapses in the white matter. Finally, we examined the distribution and neurochemical nature of interneurons that putatively innervate the somata of WM neurons. From the data obtained, we can draw three main conclusions: first, the density of WM neurons varies depending on the cortical areas; second, calretinin-immunoreactive neurons represent the major subpopulation of GABAergic WM neurons; and, third, the somata of WM neurons are surrounded by both glutamatergic and GABAergic axon terminals, although only symmetric axosomatic synapses were found. By contrast, both symmetric and asymmetric axodendritic synapses were observed in the neuropil. We discuss the possible functional implications of these findings in terms of cortical circuits. © 2010 Wiley-Liss, Inc.

Acetylcholine-dependent upregulation of TASK-1 channels in thalamic interneurons by a smooth muscle-like signalling pathway.

PubMed

Leist, Michael; Rinné, Susanne; Datunashvili, Maia; Aissaoui, Ania; Pape, Hans-Christian; Decher, Niels; Meuth, Sven G; Budde, Thomas

2017-09-01

The ascending brainstem transmitter acetylcholine depolarizes thalamocortical relay neurons while it induces hyperpolarization in local circuit inhibitory interneurons. Sustained K + currents are modulated in thalamic neurons to control their activity modes; for the interneurons the molecular nature of the underlying ion channels is as yet unknown. Activation of TASK-1 K + channels results in hyperpolarization of interneurons and suppression of their action potential firing. The modulation cascade involves a non-receptor tyrosine kinase, c-Src. The present study identifies a novel pathway for the activation of TASK-1 channels in CNS neurons that resembles cholinergic signalling and TASK-1 current modulation during hypoxia in smooth muscle cells. The dorsal part of the lateral geniculate nucleus (dLGN) is the main thalamic site for state-dependent transmission of visual information. Non-retinal inputs from the ascending arousal system and inhibition provided by γ-aminobutyric acid (GABA)ergic local circuit interneurons (INs) control neuronal activity within the dLGN. In particular, acetylcholine (ACh) depolarizes thalamocortical relay neurons by inhibiting two-pore domain potassium (K 2P ) channels. Conversely, ACh also hyperpolarizes INs via an as-yet-unknown mechanism. By using whole cell patch-clamp recordings in brain slices and appropriate pharmacological tools we here report that stimulation of type 2 muscarinic ACh receptors induces IN hyperpolarization by recruiting the G-protein βγ subunit (Gβγ), class-1A phosphatidylinositol-4,5-bisphosphate 3-kinase, and cellular and sarcoma (c-Src) tyrosine kinase, leading to activation of two-pore domain weakly inwardly rectifying K + channel (TWIK)-related acid-sensitive K + (TASK)-1 channels. The latter was confirmed by the use of TASK-1-deficient mice. Furthermore inhibition of phospholipase Cβ as well as an increase in the intracellular level of phosphatidylinositol-3,4,5-trisphosphate facilitated the

Normal radial migration and lamination are maintained in dyslexia-susceptibility candidate gene homolog Kiaa0319 knockout mice.

PubMed

Martinez-Garay, Isabel; Guidi, Luiz G; Holloway, Zoe G; Bailey, Melissa A G; Lyngholm, Daniel; Schneider, Tomasz; Donnison, Timothy; Butt, Simon J B; Monaco, Anthony P; Molnár, Zoltán; Velayos-Baeza, Antonio

2017-04-01

Developmental dyslexia is a common disorder with a strong genetic component, but the underlying molecular mechanisms are still unknown. Several candidate dyslexia-susceptibility genes, including KIAA0319, DYX1C1, and DCDC2, have been identified in humans. RNA interference experiments targeting these genes in rat embryos have shown impairments in neuronal migration, suggesting that defects in radial cortical migration could be involved in the disease mechanism of dyslexia. Here we present the first characterisation of a Kiaa0319 knockout mouse line. Animals lacking KIAA0319 protein do not show anatomical abnormalities in any of the layered structures of the brain. Neurogenesis and radial migration of cortical projection neurons are not altered, and the intrinsic electrophysiological properties of Kiaa0319-deficient neurons do not differ from those of wild-type neurons. Kiaa0319 overexpression in cortex delays radial migration, but does not affect final neuronal position. However, knockout animals show subtle differences suggesting possible alterations in anxiety-related behaviour and in sensorimotor gating. Our results do not reveal a migration disorder in the mouse model, adding to the body of evidence available for Dcdc2 and Dyx1c1 that, unlike in the rat in utero knockdown models, the dyslexia-susceptibility candidate mouse homolog genes do not play an evident role in neuronal migration. However, KIAA0319 protein expression seems to be restricted to the brain, not only in early developmental stages but also in adult mice, indicative of a role of this protein in brain function. The constitutive and conditional knockout lines reported here will be useful tools for further functional analyses of Kiaa0319.

Polarization-Sensitive Interneurons in the Optic Lobe of the Desert Ant Cataglyphis bicolor

NASA Astrophysics Data System (ADS)

Labhart, Thomas

Desert ants, Cataglyphis bicolor (Hymenoptera), navigate by using compass information provided by skylight polarization. In this study, electrophysiological recordings were made from polarization-sensitive interneurons (POL-neurons) in the optic lobe of Cataglyphis. The POL-neurons exhibit a characteristic polarization opponency. They receive monochromatic input from the UV receptors of the specialized dorsal rim area of the compound eye. Both polarization opponency and monochromacy are features also found in the POL-neurons of crickets (Orthoptera).

Myosin-II controls cellular branching morphogenesis and migration in 3D by minimizing cell surface curvature

PubMed Central

Elliott, Hunter; Fischer, Robert A.; Myers, Kenneth A.; Desai, Ravi A.; Gao, Lin; Chen, Christopher S.; Adelstein, Robert; Waterman, Clare M.; Danuser, Gaudenz

2014-01-01

In many cases cell function is intimately linked to cell shape control. We utilized endothelial cell branching morphogenesis as a model to understand the role of myosin-II in shape control of invasive cells migrating in 3D collagen gels. We applied principles of differential geometry and mathematical morphology to 3D image sets to parameterize cell branch structure and local cell surface curvature. We find that Rho/ROCK-stimulated myosin-II contractility minimizes cell-scale branching by recognizing and minimizing local cell surface curvature. Utilizing micro-fabrication to constrain cell shape identifies a positive feedback mechanism in which low curvature stabilizes myosin-II cortical association, where it acts to maintain minimal curvature. The feedback between myosin-II regulation by and control of curvature drives cycles of localized cortical myosin-II assembly and disassembly. These cycles in turn mediate alternating phases of directionally biased branch initiation and retraction to guide 3D cell migration. PMID:25621949

Four GABAergic interneurons impose feeding restraint in Drosophila

PubMed Central

Pool, Allan-Hermann; Kvello, Pal; Mann, Kevin; Cheung, Samantha K.; Gordon, Michael D.; Wang, Liming; Scott, Kristin

2014-01-01

Summary Feeding is dynamically regulated by the palatability of the food source and the physiological needs of the animal. How consumption is controlled by external sensory cues and internal metabolic state remains under intense investigation. Here, we identify four GABAergic interneurons in the Drosophila brain that establish a central feeding threshold which is required to inhibit consumption. Inactivation of these cells results in indiscriminate and excessive intake of all compounds, independent of taste quality or nutritional state. Conversely, acute activation of these neurons suppresses consumption of water and nutrients. The output from these neurons is required to gate activity in motor neurons that control meal initiation and consumption. Thus, our study reveals a new layer of inhibitory control in feeding circuits that is required to suppress a latent state of unrestricted and non-selective consumption. PMID:24991960

MDMA-induced loss of parvalbumin interneurons within the dentate gyrus is mediated by 5HT2A and NMDA receptors

PubMed Central

Collins, Stuart A.; Gudelsky, Gary A.; Yamamoto, Bryan K.

2015-01-01

MDMA is a widely abused psychostimulant which causes a rapid and robust release of the monoaminergic neurotransmitters dopamine and serotonin. Recently, it was shown that MDMA increases extracellular glutamate concentrations in the dorsal hippocampus, which is dependent on serotonin release and 5HT2A/2C receptor activation. The increased extracellular glutamate concentration coincides with a loss of parvalbumin-immunoreactive (PV-IR) interneurons of the dentate gyrus region. Given the known susceptibility of PV interneurons to excitotoxicity, we examined whether MDMA-induced increases in extracellular glutamate in the dentate gyrus are necessary for the loss of PV cells in rats. Extracellular glutamate concentrations increased in the dentate gyrus during systemic and local administration of MDMA. Administration of the NMDA receptor antagonist, MK-801, during systemic injections of MDMA, prevented the loss of PV-IR interneurons seen 10 days after MDMA exposure. Local administration of MDL100907, a selective 5HT2A receptor antagonist, prevented the increases in glutamate caused by reverse dialysis of MDMA directly into the dentate gyrus and prevented the reduction of PV-IR. These findings provide evidence that MDMA causes decreases in PV within the dentate gyrus through a 5HT2A receptor-mediated increase in glutamate and subsequent NMDA receptor activation. PMID:25936514

Biophysical network modeling of the dLGN circuit: Effects of cortical feedback on spatial response properties of relay cells

PubMed Central

Martínez-Cañada, Pablo; Halnes, Geir; Fyhn, Marianne

2018-01-01

Despite half-a-century of research since the seminal work of Hubel and Wiesel, the role of the dorsal lateral geniculate nucleus (dLGN) in shaping the visual signals is not properly understood. Placed on route from retina to primary visual cortex in the early visual pathway, a striking feature of the dLGN circuit is that both the relay cells (RCs) and interneurons (INs) not only receive feedforward input from retinal ganglion cells, but also a prominent feedback from cells in layer 6 of visual cortex. This feedback has been proposed to affect synchronicity and other temporal properties of the RC firing. It has also been seen to affect spatial properties such as the center-surround antagonism of thalamic receptive fields, i.e., the suppression of the response to very large stimuli compared to smaller, more optimal stimuli. Here we explore the spatial effects of cortical feedback on the RC response by means of a a comprehensive network model with biophysically detailed, single-compartment and multicompartment neuron models of RCs, INs and a population of orientation-selective layer 6 simple cells, consisting of pyramidal cells (PY). We have considered two different arrangements of synaptic feedback from the ON and OFF zones in the visual cortex to the dLGN: phase-reversed (‘push-pull’) and phase-matched (‘push-push’), as well as different spatial extents of the corticothalamic projection pattern. Our simulation results support that a phase-reversed arrangement provides a more effective way for cortical feedback to provide the increased center-surround antagonism seen in experiments both for flashing spots and, even more prominently, for patch gratings. This implies that ON-center RCs receive direct excitation from OFF-dominated cortical cells and indirect inhibitory feedback from ON-dominated cortical cells. The increased center-surround antagonism in the model is accompanied by spatial focusing, i.e., the maximum RC response occurs for smaller stimuli when

Experience-Dependent Plasticity in Accessory Olfactory Bulb Interneurons following Male-Male Social Interaction.

PubMed

Cansler, Hillary L; Maksimova, Marina A; Meeks, Julian P

2017-07-26

Chemosensory information processing in the mouse accessory olfactory system guides the expression of social behavior. After salient chemosensory encounters, the accessory olfactory bulb (AOB) experiences changes in the balance of excitation and inhibition at reciprocal synapses between mitral cells (MCs) and local interneurons. The mechanisms underlying these changes remain controversial. Moreover, it remains unclear whether MC-interneuron plasticity is unique to specific behaviors, such as mating, or whether it is a more general feature of the AOB circuit. Here, we describe targeted electrophysiological studies of AOB inhibitory internal granule cells (IGCs), many of which upregulate the immediate-early gene Arc after male-male social experience. Following the resident-intruder paradigm, Arc -expressing IGCs in acute AOB slices from resident males displayed stronger excitation than nonexpressing neighbors when sensory inputs were stimulated. The increased excitability of Arc -expressing IGCs was not correlated with changes in the strength or number of excitatory synapses with MCs but was instead associated with increased intrinsic excitability and decreased HCN channel-mediated I H currents. Consistent with increased inhibition by IGCs, MCs responded to sensory input stimulation with decreased depolarization and spiking following resident-intruder encounters. These results reveal that nonmating behaviors drive AOB inhibitory plasticity and indicate that increased MC inhibition involves intrinsic excitability changes in Arc -expressing interneurons. SIGNIFICANCE STATEMENT The accessory olfactory bulb (AOB) is a site of experience-dependent plasticity between excitatory mitral cells (MCs) and inhibitory internal granule cells (IGCs), but the physiological mechanisms and behavioral conditions driving this plasticity remain unclear. Here, we report studies of AOB neuronal plasticity following male-male social chemosensory encounters. We show that the plasticity

Experience-Dependent Plasticity in Accessory Olfactory Bulb Interneurons following Male–Male Social Interaction

PubMed Central

Maksimova, Marina A.

2017-01-01

Chemosensory information processing in the mouse accessory olfactory system guides the expression of social behavior. After salient chemosensory encounters, the accessory olfactory bulb (AOB) experiences changes in the balance of excitation and inhibition at reciprocal synapses between mitral cells (MCs) and local interneurons. The mechanisms underlying these changes remain controversial. Moreover, it remains unclear whether MC–interneuron plasticity is unique to specific behaviors, such as mating, or whether it is a more general feature of the AOB circuit. Here, we describe targeted electrophysiological studies of AOB inhibitory internal granule cells (IGCs), many of which upregulate the immediate-early gene Arc after male–male social experience. Following the resident–intruder paradigm, Arc-expressing IGCs in acute AOB slices from resident males displayed stronger excitation than nonexpressing neighbors when sensory inputs were stimulated. The increased excitability of Arc-expressing IGCs was not correlated with changes in the strength or number of excitatory synapses with MCs but was instead associated with increased intrinsic excitability and decreased HCN channel-mediated IH currents. Consistent with increased inhibition by IGCs, MCs responded to sensory input stimulation with decreased depolarization and spiking following resident–intruder encounters. These results reveal that nonmating behaviors drive AOB inhibitory plasticity and indicate that increased MC inhibition involves intrinsic excitability changes in Arc-expressing interneurons. SIGNIFICANCE STATEMENT The accessory olfactory bulb (AOB) is a site of experience-dependent plasticity between excitatory mitral cells (MCs) and inhibitory internal granule cells (IGCs), but the physiological mechanisms and behavioral conditions driving this plasticity remain unclear. Here, we report studies of AOB neuronal plasticity following male–male social chemosensory encounters. We show that the plasticity

Effects of environmental risks and polygenic loading for schizophrenia on cortical thickness.

PubMed

Neilson, Emma; Bois, Catherine; Gibson, Jude; Duff, Barbara; Watson, Andrew; Roberts, Neil; Brandon, Nicholas J; Dunlop, John; Hall, Jeremy; McIntosh, Andrew M; Whalley, Heather C; Lawrie, Stephen M

2017-06-01

There are established differences in cortical thickness (CT) in schizophrenia (SCZ) and bipolar (BD) patients when compared to healthy controls (HC). However, it is unknown to what extent environmental or genetic risk factors impact on CT in these populations. We have investigated the effect of Environmental Risk Scores (ERS) and Polygenic Risk Scores for SCZ (PGRS-SCZ) on CT. Structural MRI scans were acquired at 3T for patients with SCZ or BD (n=57) and controls (n=41). Cortical reconstructions were generated in FreeSurfer (v5.3). The ERS was created by determining exposure to cannabis use, childhood adverse events, migration, urbanicity and obstetric complications. The PGRS-SCZ were generated, for a subset of the sample (Patients=43, HC=32), based on the latest PGC GWAS findings. ANCOVAs were used to test the hypotheses that ERS and PGRS-SCZ relate to CT globally, and in frontal and temporal lobes. An increase in ERS was negatively associated with CT within temporal lobe for patients. A higher PGRS-SCZ was also related to global cortical thinning for patients. ERS effects remained significant when including PGRS-SCZ as a fixed effect. No relationship which survived FDR correction was found for ERS and PGRS-SCZ in controls. Environmental risk for SCZ was related to localised cortical thinning in patients with SCZ and BD, while increased PGRS-SCZ was associated with global cortical thinning. Genetic and environmental risk factors for SCZ appear therefore to have differential effects. This provides a mechanistic means by which different risk factors may contribute to the development of SCZ and BD. Copyright © 2016 Elsevier B.V. All rights reserved.

The effect of propofol postconditioning on the expression of K(+)-Cl(-)-co-transporter 2 in GABAergic inhibitory interneurons of acute ischemia/reperfusion injury rats.

PubMed

Wang, Hongbai; Liu, Shuying; Wang, Haiyun; Wang, Guolin; Zhu, Ai

2015-02-09

It has been shown in our previous study that propofol postconditioning enhanced the activity of phosphatidylinositol-3-kinase (PI3K) and prevented the internalization of GluR2 subunit of α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, thus provided neuroprotection in cerebral ischemia/reperfusion (I/R) injury. Regarding inhibitory system in CNS, K(+)-Cl(-)-co-transporter 2 (KCC2), a Cl(-) extruder, plays a critical role in gamma-aminobutyric acid (GABA) inhibitory effect in mature central neurons. However, the effect of propofol postconditioning on the expression of KCC2 in GABAergic interneurons is unclear. Therefore, in this article we describe the role of KCC2 in GABAergic interneurons in the ipsilateral hippocampal CA1 region of adult rats and the effects of propofol postconditioning on this region. Herein we demonstrate that propofol postconditioning (20mg/kg/h, 2h) improved rats' neurobehavioral abilities, increased the number of survival neurons, and up-regulated neuronal KCC2 expression in glutamic acid decarboxylase 67 (GAD67) expressing GABAergic interneurons in hippocampal CA1 region at 24h after I/R. In contrast, when rats were injected with the KCC2 antagonist, [(dihydroindenyl)oxy] alkanoic acid (DIOA), the neuroprotective effects induced by propofol postconditioning were reversed. Our study indicated that propofol postconditioning increased the expression of KCC2 in inhibitory GABAergic interneurons, thus providing acute neuroprotection to rats who had undergone cerebral I/R injury. Copyright © 2014 Elsevier B.V. All rights reserved.

Responses of cricket cercal interneurons to realistic naturalistic stimuli in the field

PubMed Central

Dupuy, Fabienne; Steinmann, Thomas; Pierre, Dominique; Christidès, Jean-Philippe; Cummins, Graham; Lazzari, Claudio; Miller, John; Casas, Jérôme

2012-01-01

SUMMARY The ability of the insect cercal system to detect approaching predators has been studied extensively in the laboratory and in the field. Some previous studies have assessed the extent to which sensory noise affects the operational characteristics of the cercal system, but these studies have only been carried out in laboratory settings using white noise stimuli of unrealistic nature. Using a piston mimicking the natural airflow of an approaching predator, we recorded the neural activity through the abdominal connectives from the terminal abdominal ganglion of freely moving wood crickets (Nemobius sylvestris) in a semi-field situation. A cluster analysis of spike amplitudes revealed six clusters, or ‘units’, corresponding to six different subsets of cercal interneurons. No spontaneous activity was recorded for the units of larger amplitude, reinforcing the idea they correspond to the largest giant interneurons. Many of the cercal units are already activated by background noise, sometimes only weakly, and the approach of a predator is signaled by an increase in their activity, in particular for the larger-amplitude units. A scaling law predicts that the cumulative number of spikes is a function of the velocity of the flow perceived at the rear of the cricket, including a multiplicative factor that increases linearly with piston velocity. We discuss the implications of this finding in terms of how the cricket might infer the imminence and nature of a predatory attack. PMID:22723476

Singing modulates parvalbumin interneurons throughout songbird forebrain vocal control circuitry

PubMed Central

Zengin-Toktas, Yildiz

2017-01-01

Across species, the performance of vocal signals can be modulated by the social environment. Zebra finches, for example, adjust their song performance when singing to females (‘female-directed’ or FD song) compared to when singing in isolation (‘undirected’ or UD song). These changes are salient, as females prefer the FD song over the UD song. Despite the importance of these performance changes, the neural mechanisms underlying this social modulation remain poorly understood. Previous work in finches has established that expression of the immediate early gene EGR1 is increased during singing and modulated by social context within the vocal control circuitry. Here, we examined whether particular neural subpopulations within those vocal control regions exhibit similar modulations of EGR1 expression. We compared EGR1 expression in neurons expressing parvalbumin (PV), a calcium buffer that modulates network plasticity and homeostasis, among males that performed FD song, males that produced UD song, or males that did not sing. We found that, overall, singing but not social context significantly affected EGR1 expression in PV neurons throughout the vocal control nuclei. We observed differences in EGR1 expression between two classes of PV interneurons in the basal ganglia nucleus Area X. Additionally, we found that singing altered the amount of PV expression in neurons in HVC and Area X and that distinct PV interneuron types in Area X exhibited different patterns of modulation by singing. These data indicate that throughout the vocal control circuitry the singing-related regulation of EGR1 expression in PV neurons may be less influenced by social context than in other neuron types and raise the possibility of cell-type specific differences in plasticity and calcium buffering. PMID:28235074

Local Optogenetic Induction of Fast (20-40 Hz) Pyramidal-Interneuron Network Oscillations in the In Vitro and In Vivo CA1 Hippocampus: Modulation by CRF and Enforcement of Perirhinal Theta Activity.

PubMed

Dine, Julien; Genewsky, Andreas; Hladky, Florian; Wotjak, Carsten T; Deussing, Jan M; Zieglgänsberger, Walter; Chen, Alon; Eder, Matthias

2016-01-01

The neurophysiological processes that can cause theta-to-gamma frequency range (4-80 Hz) network oscillations in the rhinal cortical-hippocampal system and the potential connectivity-based interactions of such forebrain rhythms are a topic of intensive investigation. Here, using selective Channelrhodopsin-2 (ChR2) expression in mouse forebrain glutamatergic cells, we were able to locally, temporally precisely, and reliably induce fast (20-40 Hz) field potential oscillations in hippocampal area CA1 in vitro (at 25°C) and in vivo (i.e., slightly anesthetized NEX-Cre-ChR2 mice). As revealed by pharmacological analyses and patch-clamp recordings from pyramidal cells and GABAergic interneurons in vitro, these light-triggered oscillations can exclusively arise from sustained suprathreshold depolarization (~200 ms or longer) and feedback inhibition of CA1 pyramidal neurons, as being mandatory for prototypic pyramidal-interneuron network (P-I) oscillations. Consistently, the oscillations comprised rhythmically occurring population spikes (generated by pyramidal cells) and their frequency increased with increasing spectral power. We further demonstrate that the optogenetically driven CA1 oscillations, which remain stable over repeated evocations, are impaired by the stress hormone corticotropin-releasing factor (CRF, 125 nM) in vitro and, even more remarkably, found that they are accompanied by concurrent states of enforced theta activity in the memory-associated perirhinal cortex (PrC) in vivo. The latter phenomenon most likely derives from neurotransmission via a known, but poorly studied excitatory CA1→PrC pathway. Collectively, our data provide evidence for the existence of a prototypic (CRF-sensitive) P-I gamma rhythm generator in area CA1 and suggest that CA1 P-I oscillations can rapidly up-regulate theta activity strength in hippocampus-innervated rhinal networks, at least in the PrC.

Cortical tremor: a variant of cortical reflex myoclonus.

PubMed

Ikeda, A; Kakigi, R; Funai, N; Neshige, R; Kuroda, Y; Shibasaki, H

1990-10-01

Two patients with action tremor that was thought to originate in the cerebral cortex showed fine shivering-like finger twitching provoked mainly by action and posture. Surface EMG showed relatively rhythmic discharge at a rate of about 9 Hz, which resembled essential tremor. However, electrophysiologic studies revealed giant somatosensory evoked potentials (SEPs) with enhanced long-loop reflex and premovement cortical spike by the jerk-locked averaging method. Treatment with beta-blocker showed no effect, but anticonvulsants such as clonazepam, valproate, and primidone were effective to suppress the tremor and the amplitude of SEPs. We call this involuntary movement "cortical tremor," which is in fact a variant of cortical reflex myoclonus.

Altered Markers of Cortical γ-Aminobutyric Acid Neuronal Activity in Schizophrenia

PubMed Central

Kimoto, Sohei; Zaki, Mark M.; Bazmi, H. Holly; Lewis, David A.

2016-01-01

IMPORTANCE In schizophrenia, working memory deficits appear to reflect abnormalities in the generation of gamma oscillations in the dorsolateral prefrontal cortex. The generation of gamma oscillations requires the phasic excitation of inhibitory parvalbumin-containing interneurons. Thus, gamma oscillations depend, in part, on the number of synaptic glutamate receptors on parvalbumin interneurons. However, little is known about the molecular factors that regulate glutamate receptor–mediated excitation of parvalbumin interneurons in schizophrenia. OBJECTIVE To quantify in individuals with schizophrenia the expression of immediate early genes (NARP, ARC, and SGK1) regulating glutamate synaptic neurotransmission. DESIGN, SETTING, AND PARTICIPANTS Postmortem brain specimens (n = 206) were obtained from individuals with schizophrenia, bipolar disorder, or major depressive disorder and from well-matched healthy persons (controls). For a study of brain tissue, quantitative polymerase chain reaction, in situ hybridization, or microarray analyses were used to measure transcript levels in the dorsolateral prefrontal cortex at gray matter, laminar, and cellular levels of resolutions. This study was conducted between January 1, 2013, and November 30, 2014. MAIN OUTCOMES AND MEASURES Expression levels for NARP, ARC, and SGK1 messenger RNA (mRNA) were compared between specimens from individuals with schizophrenia and controls. Diagnostic specificity was assessed by quantifying NARP mRNA levels in specimens from individuals with mood disorders. RESULTS By quantitative polymerase chain reaction, levels of NARP mRNA were significantly lower by 25.6%in specimens from individuals with schizophrenia compared with the controls (mean [SD], 0.036 [0.018] vs 0.049 [0.015]; F1,114 = 21.0; P < .001). Levels of ARC (F1,112 = 0.93; P = .34) and SGK1 (F1,110 = 2.52; P = .12) were not significant. These findings were supported by in situ hybridization (NARP; individuals with schizophrenia vs

Methamphetamine induces striatal neurokinin-1 receptor endocytosis primarily in somatostatin/NPY/NOS interneurons and the role of dopamine receptors in mice.

PubMed

Wang, Jing; Angulo, Jesus A

2011-04-01

Methamphetamine (METH) is a psychostimulant that induces long-term deficits of dopamine terminal markers and apoptotic cell death in the striatum. Our laboratory demonstrated that pharmacological blockade of the neurokinin-1 receptor attenuated the METH-induced damage to the striatal dopamine terminals and the apoptotic cell death of some striatal neurons. Here, we used histological methods to assess the effect of METH on neurokinin-1 receptor trafficking in the striatum as an indirect index of signaling by the neuropeptide substance P (natural ligand for this receptor). Male mice received a single injection of METH (30 mg/kg, i.p.) and were sacrificed 30 min later. Immunohistofluorescence confocal microscopy confirmed that the neurokinin-1 receptor is located on cholinergic and somatostatin interneurons of the striatum. METH induced the trafficking of the neurokinin-1 receptor from the membrane into cytoplasmic endosomes primarily in the somatostatin/NPY/NOS interneurons, and this phenomenon was attenuated by antagonists of the dopamine D1 (SCH-23390), D2 (raclopride), or neurokinin-1 (WIN-51,708) receptors. These data demonstrate that METH induces the trafficking of the striatal neurokinin-1 receptors principally in the somatostatin/NPY/NOS interneurons and that this phenomenon is dependent on the activity of dopamine D1 and D2 receptors. Copyright © 2010 Wiley-Liss, Inc.

Calretinin and parvalbumin immunoreactive interneurons in the retrosplenial cortex of the rat brain: Qualitative and quantitative analyses.

PubMed

Salaj, Martin; Druga, Rastislav; Cerman, Jiří; Kubová, Hana; Barinka, Filip

2015-11-19

The retrosplenial cortex (RSC) is a mesocortical region broadly involved with memory and navigation. It shares many characteristics with the perirhinal cortex (PRC), both of which appear to be significantly involved in the spreading of epileptic activity. We hypothesized that RSC possesses an interneuronal composition similar to that of PRC. To prove the hypothesis we studied the general pattern of calretinin (CR) and parvalbumin (PV) immunoreactivity in the RSC of the rat brain, its optical density as well as the morphological features and density of CR- and PV-immunoreactive (CR+ and PV+) interneurons. We also analyzed the overall neuronal density on Nissl-stained sections in RSC. Finally, we compared our results with our earlier analysis of PRC (Barinka et al., 2012). Compared to PRC, RSC was observed to have a higher intensity of PV staining and lower intensity of CR staining of neuropil. Vertically-oriented bipolar neurons were the most common morphological type among CR+ neurons. The staining pattern did not allow for a similarly detailed analysis of somatodendritic morphology of PV+ neurons. RSC possessed lower absolute (i.e., neurons/mm(3)) and relative (i.e., percentage of the overall neuronal population) densities of CR+ neurons and similar absolute and lower relative densities of PV+ neurons relative to PRC. CR: PV neuronal ratio in RSC (1:2 in area 29 and 1:2.2 in area 30) differed from PRC (1:1.2 in area 35 and 1:1.7 in area 36). In conclusion, RSC, although similar in many aspects to PRC, differs strikingly in the interneuronal composition relative to PRC. Copyright © 2015 Elsevier B.V. All rights reserved.

Focal inhibitory interneuron loss and principal cell hyperexcitability in the rat hippocampus after microinjection of a neurotoxic conjugate of saporin and a peptidase-resistant analog of Substance P.

PubMed

Martin, J L; Sloviter, R S

2001-07-23

Episodes of prolonged seizures or head trauma produce chronic hippocampal network hyperexcitability hypothesized to result primarily from inhibitory interneuron loss or dysfunction. The possibly causal role of inhibitory neuron failure in the development of epileptiform pathophysiology remains unclear because global neurologic injuries produce such a multitude of effects. The recent finding that Substance P receptors (SPRs) are expressed exclusively in the rat hippocampus by inhibitory interneurons provided the rationale for attempting to ablate interneurons selectively by using neurotoxic conjugates of SPR ligands and the ribosome inactivating protein saporin that specifically target Substance P receptor-expressing cells. Whereas intrahippocampal microinjection of a conjugate of native SP and saporin produced significant nonspecific damage at concentrations needed to produce even limited selective loss of SPR-positive cells, a conjugate of saporin and the more potent and peptidase-resistant SP analog [Sar(9), Met(O(2))(11)] Substance P (SSP-saporin) caused negligible nonspecific damage at the injection site, and a virtually complete loss of SPR-like immunoreactivity (LI) up to 1 mm from the injection site. Within the SPR depletion zone, immunoreactivities for most GABA-, parvalbumin-, somatostatin-, and cholecystokinin-immunoreactive cells and fibers were eliminated. The few interneurons detectable within the affected zone were devoid of SPR-LI. The apparent loss of interneurons was selective in that calbindin- and glutamate receptor subunit 2 (GluR2) -positive principal cells survived within the affected zone, as did myelinated fibers and the extrinsic calretinin- and tyrosine hydroxylase--immunoreactive terminals of subcortical afferents. An apparent lack of reactive synaptic reorganization in response to interneuron loss was indicated by zinc transporter-3 (ZnT3)-- and beta-synuclein--LI, as well as by Timm staining, all of which revealed relatively normal

Knockout Mice for Dyslexia Susceptibility Gene Homologs KIAA0319 and KIAA0319L have Unaffected Neuronal Migration but Display Abnormal Auditory Processing

PubMed Central

Guidi, Luiz G; Mattley, Jane; Martinez-Garay, Isabel; Monaco, Anthony P; Linden, Jennifer F; Velayos-Baeza, Antonio

2017-01-01

Abstract Developmental dyslexia is a neurodevelopmental disorder that affects reading ability caused by genetic and non-genetic factors. Amongst the susceptibility genes identified to date, KIAA0319 is a prime candidate. RNA-interference experiments in rats suggested its involvement in cortical migration but we could not confirm these findings in Kiaa0319-mutant mice. Given its homologous gene Kiaa0319L (AU040320) has also been proposed to play a role in neuronal migration, we interrogated whether absence of AU040320 alone or together with KIAA0319 affects migration in the developing brain. Analyses of AU040320 and double Kiaa0319;AU040320 knockouts (dKO) revealed no evidence for impaired cortical lamination, neuronal migration, neurogenesis or other anatomical abnormalities. However, dKO mice displayed an auditory deficit in a behavioral gap-in-noise detection task. In addition, recordings of click-evoked auditory brainstem responses revealed suprathreshold deficits in wave III amplitude in AU040320-KO mice, and more general deficits in dKOs. These findings suggest that absence of AU040320 disrupts firing and/or synchrony of activity in the auditory brainstem, while loss of both proteins might affect both peripheral and central auditory function. Overall, these results stand against the proposed role of KIAA0319 and AU040320 in neuronal migration and outline their relationship with deficits in the auditory system. PMID:29045729

MDMA-induced loss of parvalbumin interneurons within the dentate gyrus is mediated by 5HT2A and NMDA receptors.

PubMed

Collins, Stuart A; Gudelsky, Gary A; Yamamoto, Bryan K

2015-08-15

MDMA is a widely abused psychostimulant which causes a rapid and robust release of the monoaminergic neurotransmitters dopamine and serotonin. Recently, it was shown that MDMA increases extracellular glutamate concentrations in the dorsal hippocampus, which is dependent on serotonin release and 5HT2A/2C receptor activation. The increased extracellular glutamate concentration coincides with a loss of parvalbumin-immunoreactive (PV-IR) interneurons of the dentate gyrus region. Given the known susceptibility of PV interneurons to excitotoxicity, we examined whether MDMA-induced increases in extracellular glutamate in the dentate gyrus are necessary for the loss of PV cells in rats. Extracellular glutamate concentrations increased in the dentate gyrus during systemic and local administration of MDMA. Administration of the NMDA receptor antagonist, MK-801, during systemic injections of MDMA, prevented the loss of PV-IR interneurons seen 10 days after MDMA exposure. Local administration of MDL100907, a selective 5HT2A receptor antagonist, prevented the increases in glutamate caused by reverse dialysis of MDMA directly into the dentate gyrus and prevented the reduction of PV-IR. These findings provide evidence that MDMA causes decreases in PV within the dentate gyrus through a 5HT2A receptor-mediated increase in glutamate and subsequent NMDA receptor activation. Copyright © 2015 Elsevier B.V. All rights reserved.

A Brain-Machine-Brain Interface for Rewiring of Cortical Circuitry after Traumatic Brain Injury

DTIC Science & Technology

2014-09-01

810. 22. Plow EB, Carey JR, Nudo RJ, Pascual-Leone A (2009) Invasive cortical stimulation to promote recovery of function after stroke: A critical...stimulation of the motor cortex enhances pro- genitor cell migration in the adult rat brain. Exp Brain Res 231(2):165–177. 28. Edwardson MA, Lucas TH, Carey ...The screws and rod were further secured with dental acrylic (all animals). In both the ADS and OLS groups, a hybrid, 16-channel, single-shank, chronic

Brain Injury-Induced Synaptic Reorganization in Hilar Inhibitory Neurons Is Differentially Suppressed by Rapamycin

PubMed Central

2017-01-01

Abstract Following traumatic brain injury (TBI), treatment with rapamycin suppresses mammalian (mechanistic) target of rapamycin (mTOR) activity and specific components of hippocampal synaptic reorganization associated with altered cortical excitability and seizure susceptibility. Reemergence of seizures after cessation of rapamycin treatment suggests, however, an incomplete suppression of epileptogenesis. Hilar inhibitory interneurons regulate dentate granule cell (DGC) activity, and de novo synaptic input from both DGCs and CA3 pyramidal cells after TBI increases their excitability but effects of rapamycin treatment on the injury-induced plasticity of interneurons is only partially described. Using transgenic mice in which enhanced green fluorescent protein (eGFP) is expressed in the somatostatinergic subset of hilar inhibitory interneurons, we tested the effect of daily systemic rapamycin treatment (3 mg/kg) on the excitability of hilar inhibitory interneurons after controlled cortical impact (CCI)-induced focal brain injury. Rapamycin treatment reduced, but did not normalize, the injury-induced increase in excitability of surviving eGFP+ hilar interneurons. The injury-induced increase in response to selective glutamate photostimulation of DGCs was reduced to normal levels after mTOR inhibition, but the postinjury increase in synaptic excitation arising from CA3 pyramidal cell activity was unaffected by rapamycin treatment. The incomplete suppression of synaptic reorganization in inhibitory circuits after brain injury could contribute to hippocampal hyperexcitability and the eventual reemergence of the epileptogenic process upon cessation of mTOR inhibition. Further, the cell-selective effect of mTOR inhibition on synaptic reorganization after CCI suggests possible mechanisms by which rapamycin treatment modifies epileptogenesis in some models but not others. PMID:29085896

Brain Injury-Induced Synaptic Reorganization in Hilar Inhibitory Neurons Is Differentially Suppressed by Rapamycin.

PubMed

Butler, Corwin R; Boychuk, Jeffery A; Smith, Bret N

2017-01-01

Following traumatic brain injury (TBI), treatment with rapamycin suppresses mammalian (mechanistic) target of rapamycin (mTOR) activity and specific components of hippocampal synaptic reorganization associated with altered cortical excitability and seizure susceptibility. Reemergence of seizures after cessation of rapamycin treatment suggests, however, an incomplete suppression of epileptogenesis. Hilar inhibitory interneurons regulate dentate granule cell (DGC) activity, and de novo synaptic input from both DGCs and CA3 pyramidal cells after TBI increases their excitability but effects of rapamycin treatment on the injury-induced plasticity of interneurons is only partially described. Using transgenic mice in which enhanced green fluorescent protein (eGFP) is expressed in the somatostatinergic subset of hilar inhibitory interneurons, we tested the effect of daily systemic rapamycin treatment (3 mg/kg) on the excitability of hilar inhibitory interneurons after controlled cortical impact (CCI)-induced focal brain injury. Rapamycin treatment reduced, but did not normalize, the injury-induced increase in excitability of surviving eGFP+ hilar interneurons. The injury-induced increase in response to selective glutamate photostimulation of DGCs was reduced to normal levels after mTOR inhibition, but the postinjury increase in synaptic excitation arising from CA3 pyramidal cell activity was unaffected by rapamycin treatment. The incomplete suppression of synaptic reorganization in inhibitory circuits after brain injury could contribute to hippocampal hyperexcitability and the eventual reemergence of the epileptogenic process upon cessation of mTOR inhibition. Further, the cell-selective effect of mTOR inhibition on synaptic reorganization after CCI suggests possible mechanisms by which rapamycin treatment modifies epileptogenesis in some models but not others.

EphrinB3 restricts endogenous neural stem cell migration after traumatic brain injury.

PubMed

Dixon, Kirsty J; Mier, Jose; Gajavelli, Shyam; Turbic, Alisa; Bullock, Ross; Turnley, Ann M; Liebl, Daniel J

2016-11-01

Traumatic brain injury (TBI) leads to a series of pathological events that can have profound influences on motor, sensory and cognitive functions. Conversely, TBI can also stimulate neural stem/progenitor cell proliferation leading to increased numbers of neuroblasts migrating outside their restrictive neurogenic zone to areas of damage in support of tissue integrity. Unfortunately, the factors that regulate migration are poorly understood. Here, we examine whether ephrinB3 functions to restrict neuroblasts from migrating outside the subventricular zone (SVZ) and rostral migratory stream (RMS). We have previously shown that ephrinB3 is expressed in tissues surrounding these regions, including the overlying corpus callosum (CC), and is reduced after controlled cortical impact (CCI) injury. Our current study takes advantage of ephrinB3 knockout mice to examine the influences of ephrinB3 on neuroblast migration into CC and cortex tissues after CCI injury. Both injury and/or ephrinB3 deficiency led to increased neuroblast numbers and enhanced migration outside the SVZ/RMS zones. Application of soluble ephrinB3-Fc molecules reduced neuroblast migration into the CC after injury and limited neuroblast chain migration in cultured SVZ explants. Our findings suggest that ephrinB3 expression in tissues surrounding neurogenic regions functions to restrict neuroblast migration outside the RMS by limiting chain migration. Copyright © 2016 Michael Boutros, German Cancer Research Center, Heidelberg, Germany. Published by Elsevier B.V. All rights reserved.

Cholinergic interneurons in the feeding system of the pond snail Lymnaea stagnalis. III. Pharmacological dissection of the feeding rhythm.

PubMed

Elliott, C J

1992-05-29

The feeding activity of the pond snail Lymnaea stagnalis was stimulated by depolarization of a modulatory interneuron (SO) or of a N1 pattern-generating interneuron. The cholinergic antagonists phenyltrimethylammonium (PTMA), methylxylocholine (MeXCh), hexamethonium (HMT) and atropine (ATR) were applied at 0.5 mM in the bath and their effects on the rhythmic feeding pattern were monitored. Each of the antagonists slowed or blocked the feeding rhythm. The block was due to interference in the pattern generating network, not to disturbance of modulatory inputs. The experimental results favour a model in which the alternation of protraction (N1) and retraction (N2) phases occurs by recurrent inhibition. The results would be more difficult to explain on the reciprocal inhibition model. When all the N1 output was blocked, the N1 neurons fired rhythmic bursts endogenously.

Dcx Re-expression Reduces Subcortical Band Heterotopia and Seizure Threshold in an Animal Model of Neuronal Migration Disorder

PubMed Central

Manent, Jean-Bernard; Wang, Yu; Chang, YoonJeung; Paramasivam, Murugan; LoTurco, Joseph J

2009-01-01

Disorders of neuronal migration can lead to malformations of the cerebral neocortex that greatly increase the risk of seizures. It remains untested whether malformations caused by disorders in neuronal migration can be reduced by reactivating cellular migration, and whether such repair can decrease seizure risk. Here we show, in a rat model of subcortical band heterotopia (SBH) generated by in utero RNAi of Dcx, that aberrantly positioned neurons can be stimulated to migrate by re-expressing Dcx after birth. Re-starting migration in this way both reduces neocortical malformations and restores neuronal patterning. We find further that the capacity to reduce SBH has a critical period in early postnatal development. Moreover, intervention after birth reduces convulsant-induced seizure threshold to levels similar to that of malformation-free controls. These results suggest that disorders of neuronal migration may be eventually treatable by re-engaging developmental programs both to reduce the size of cortical malformations and to reduce seizure risk. PMID:19098909

Normalization for sparse encoding of odors by a wide-field interneuron.

PubMed

Papadopoulou, Maria; Cassenaer, Stijn; Nowotny, Thomas; Laurent, Gilles

2011-05-06

Sparse coding presents practical advantages for sensory representations and memory storage. In the insect olfactory system, the representation of general odors is dense in the antennal lobes but sparse in the mushroom bodies, only one synapse downstream. In locusts, this transformation relies on the oscillatory structure of antennal lobe output, feed-forward inhibitory circuits, intrinsic properties of mushroom body neurons, and connectivity between antennal lobe and mushroom bodies. Here we show the existence of a normalizing negative-feedback loop within the mushroom body to maintain sparse output over a wide range of input conditions. This loop consists of an identifiable "giant" nonspiking inhibitory interneuron with ubiquitous connectivity and graded release properties.

Balanced feedforward inhibition and dominant recurrent inhibition in olfactory cortex

PubMed Central

Large, Adam M.; Vogler, Nathan W.; Mielo, Samantha; Oswald, Anne-Marie M.

2016-01-01

Throughout the brain, the recruitment of feedforward and recurrent inhibition shapes neural responses. However, disentangling the relative contributions of these often-overlapping cortical circuits is challenging. The piriform cortex provides an ideal system to address this issue because the interneurons responsible for feedforward and recurrent inhibition are anatomically segregated in layer (L) 1 and L2/3 respectively. Here we use a combination of optical and electrical activation of interneurons to profile the inhibitory input received by three classes of principal excitatory neuron in the anterior piriform cortex. In all classes, we find that L1 interneurons provide weaker inhibition than L2/3 interneurons. Nonetheless, feedforward inhibitory strength covaries with the amount of afferent excitation received by each class of principal neuron. In contrast, intracortical stimulation of L2/3 evokes strong inhibition that dominates recurrent excitation in all classes. Finally, we find that the relative contributions of feedforward and recurrent pathways differ between principal neuron classes. Specifically, L2 neurons receive more reliable afferent drive and less overall inhibition than L3 neurons. Alternatively, L3 neurons receive substantially more intracortical inhibition. These three features—balanced afferent drive, dominant recurrent inhibition, and differential recruitment by afferent vs. intracortical circuits, dependent on cell class—suggest mechanisms for olfactory processing that may extend to other sensory cortices. PMID:26858458

Postnatal day 7 ethanol treatment causes persistent reductions in adult mouse brain volume and cortical neurons with sex specific effects on neurogenesis

PubMed Central

Coleman, Leon G.; Oguz, Ipek; Lee, Joohwi; Styner, Martin; Crews, Fulton T.

2013-01-01

Ethanol treatment on postnatal day seven (P7) causes robust brain cell death and is a model of late gestational alcohol exposure (Ikonomidou et al., 2000). To investigate the long-term effects of P7 ethanol treatment on adult brain, mice received either two doses of saline or ethanol on P7 (2.5g/kg, s.c., 2 hours apart) and were assessed as adults (P82) for brain volume (using postmortem MRI) and cellular architecture (using immunohistochemistry). Adult mice that received P7 ethanol had reduced MRI total brain volume (4%) with multiple brain regions being reduced in both males and females. Immunohistochemistry indicated reduced frontal cortical parvalbumin immunoreactive (PV+IR) interneurons (18-33%) and reduced Cux1+IR layer II pyramidal neurons (15%) in both sexes. Interestingly, markers of adult hippocampal neurogenesis differed between sexes, with only ethanol treated males showing increased doublecortin and Ki67 expression (52 and 57% respectively) in the dentate gyrus, consistent with increased neurogenesis compared to controls. These findings suggest that P7 ethanol treatment causes persistent reductions in adult brain volume and frontal cortical neurons in both males and females. Increased adult neurogenesis in males, but not females, is consistent with differential adaptive responses to P7 ethanol toxicity between the sexes. One day of ethanol exposure, e.g. P7, causes persistent adult brain dysmorphology. PMID:22572057

Coordinate High-Frequency Pattern of Stimulation and Calcium Levels Control the Induction of LTP in Striatal Cholinergic Interneurons

ERIC Educational Resources Information Center

Bonsi, Paola; De Persis, Cristiano; Calabresi, Paolo; Bernardi, Giorgio; Pisani, Antonio

2004-01-01

Current evidence appoints a central role to cholinergic interneurons in modulating striatal function. Recently, a long-term potentiation (LTP) of synaptic transmission has been reported to occur in these neurons. The relationship between the pattern of cortico/thalamostriatal fibers stimulation, the consequent changes in the intracellular calcium…

Syllabic discrimination in premature human infants prior to complete formation of cortical layers

PubMed Central

Mahmoudzadeh, Mahdi; Dehaene-Lambertz, Ghislaine; Fournier, Marc; Kongolo, Guy; Goudjil, Sabrina; Dubois, Jessica; Grebe, Reinhard; Wallois, Fabrice

2013-01-01

The ontogeny of linguistic functions in the human brain remains elusive. Although some auditory capacities are described before term, whether and how such immature cortical circuits might process speech are unknown. Here we used functional optical imaging to evaluate the cerebral responses to syllables at the earliest age at which cortical responses to external stimuli can be recorded in humans (28- to 32-wk gestational age). At this age, the cortical organization in layers is not completed. Many neurons are still located in the subplate and in the process of migrating to their final location. Nevertheless, we observed several points of similarity with the adult linguistic network. First, whereas syllables elicited larger right than left responses, the posterior temporal region escaped this general pattern, showing faster and more sustained responses over the left than over the right hemisphere. Second, discrimination responses to a change of phoneme (ba vs. ga) and a change of human voice (male vs. female) were already present and involved inferior frontal areas, even in the youngest infants (29-wk gestational age). Third, whereas both types of changes elicited responses in the right frontal region, the left frontal region only reacted to a change of phoneme. These results demonstrate a sophisticated organization of perisylvian areas at the very onset of cortical circuitry, 3 mo before term. They emphasize the influence of innate factors on regions involved in linguistic processing and social communication in humans. PMID:23440196

Upper thoracic respiratory interneurons integrate noxious somatic and visceral information in rats.

PubMed

Qin, Chao; Chandler, Margaret J; Foreman, Robert D; Farber, Jay P

2002-11-01

The aim of this study was to determine if thoracic respiratory interneurons (TRINs) might receive peripheral noxious somatic and visceral inputs. Extracellular potentials of 78 respiration-related T(3) neurons, whose activity was driven by central respiratory output, were recorded from the intermediate zone in pentobarbital anesthetized, paralyzed, and ventilated male rats. These neurons were identified as interneurons by their locations and by the absence of antidromic activation from the cervical sympathetic trunk and cerebellum. Thoracic esophageal distension (ED) was produced by water inflation of a latex balloon (0.1-0.5 ml, 20 s). A catheter was placed in the pericardial sac to administer 0.2 ml bradykinin (10(-5) M) for noxious cardiac stimulation. Of 78 TRINs examined for ED, activity of 24 TRINs increased and activity of 8 TRINs decreased. Intrapericardial bradykinin increased activity in 26/65 TRINs tested and decreased activity in 5 TRINs. Seventy-four TRINs were tested for effects of brush, pressure, and pinch of the chest and upper back areas. No TRINs responded to brushing hair. Low-threshold responses to pressure were observed in 27 TRINs. Fourteen TRINs were wide dynamic range and 4 TRINs had high-threshold responses. Peripheral stimuli affected all types of TRINs, including inspiratory, expiratory, and biphasic neurons. Simultaneous phrenic recordings showed that effects of various somatic and visceral stimuli on TRINs were independent of central respiratory drive. Various somatovisceral and viscerovisceral patterns of input were observed in TRINs. The results suggested that TRINs participate in intraspinal processing and integration of nociceptive information from somatic fields and visceral organs.

Riding the glial monorail: a common mechanism for glial-guided neuronal migration in different regions of the developing mammalian brain.

PubMed

Hatten, M E

1990-05-01

In vitro studies from our laboratory indicate that granule neurons, purified from early postnatal mouse cerebellum, migrate on astroglial fibers by forming a 'migration junction' with the glial fiber along the length of the neuronal soma and extending a motile 'leading process' in the direction of migration. Similar dynamics are seen for hippocampal neurons migrating along hippocampal astroglial fibers in vitro. In heterotypic recombinations of neurons and glia from mouse cerebellum and rat hippocampus, neurons migrate on astroglial processes with a cytology and neuron-glia relationship identical to that of homotypic neuronal migration in vitro. In all four cases, the migrating neuron presents a stereotyped posture, speed and mode of movement, suggesting that glial fibers provide a generic pathway for neuronal migration in developing brain. Studies on the molecular basis of glial-guided migration suggest that astrotactin, a neuronal antigen that functions as a neuron-glia ligand, is likely to play a crucial role in the locomotion of the neuron along glial fibers. The navigation of neurons from glial fibers into cortical layers, in turn, is likely to involve neuron-neuron adhesion ligands.

Discovering Cortical Folding Patterns in Neonatal Cortical Surfaces Using Large-Scale Dataset

PubMed Central

Meng, Yu; Li, Gang; Wang, Li; Lin, Weili; Gilmore, John H.

2017-01-01

The cortical folding of the human brain is highly complex and variable across individuals. Mining the major patterns of cortical folding from modern large-scale neuroimaging datasets is of great importance in advancing techniques for neuroimaging analysis and understanding the inter-individual variations of cortical folding and its relationship with cognitive function and disorders. As the primary cortical folding is genetically influenced and has been established at term birth, neonates with the minimal exposure to the complicated postnatal environmental influence are the ideal candidates for understanding the major patterns of cortical folding. In this paper, for the first time, we propose a novel method for discovering the major patterns of cortical folding in a large-scale dataset of neonatal brain MR images (N = 677). In our method, first, cortical folding is characterized by the distribution of sulcal pits, which are the locally deepest points in cortical sulci. Because deep sulcal pits are genetically related, relatively consistent across individuals, and also stable during brain development, they are well suitable for representing and characterizing cortical folding. Then, the similarities between sulcal pit distributions of any two subjects are measured from spatial, geometrical, and topological points of view. Next, these different measurements are adaptively fused together using a similarity network fusion technique, to preserve their common information and also catch their complementary information. Finally, leveraging the fused similarity measurements, a hierarchical affinity propagation algorithm is used to group similar sulcal folding patterns together. The proposed method has been applied to 677 neonatal brains (the largest neonatal dataset to our knowledge) in the central sulcus, superior temporal sulcus, and cingulate sulcus, and revealed multiple distinct and meaningful folding patterns in each region. PMID:28229131

MACF1 regulates the migration of pyramidal neurons via microtubule dynamics and GSK-3 signaling

PubMed Central

Ka, Minhan; Jung, Eui-Man; Mueller, Ulrich; Kim, Woo-Yang

2014-01-01

Neuronal migration and subsequent differentiation play critical roles for establishing functional neural circuitry in the developing brain. However, the molecular mechanisms that regulate these processes are poorly understood. Here, we show that microtubule actin crosslinking factor 1 (MACF1) determines neuronal positioning by regulating microtubule dynamics and mediating GSK-3 signaling during brain development. First, using MACF1 floxed allele mice and in utero gene manipulation, we find that MACF1 deletion suppresses migration of cortical pyramidal neurons and results in aberrant neuronal positioning in the developing brain. The cell autonomous deficit in migration is associated with abnormal dynamics of leading processes and centrosomes. Furthermore, microtubule stability is severely damaged in neurons lacking MACF1, resulting in abnormal microtubule dynamics. Finally, MACF1 interacts with and mediates GSK-3 signaling in developing neurons. Our findings establish a cellular mechanism underlying neuronal migration and provide insights into the regulation of cytoskeleton dynamics in developing neurons. PMID:25224226

MACF1 regulates the migration of pyramidal neurons via microtubule dynamics and GSK-3 signaling.

PubMed

Ka, Minhan; Jung, Eui-Man; Mueller, Ulrich; Kim, Woo-Yang

2014-11-01

Neuronal migration and subsequent differentiation play critical roles for establishing functional neural circuitry in the developing brain. However, the molecular mechanisms that regulate these processes are poorly understood. Here, we show that microtubule actin crosslinking factor 1 (MACF1) determines neuronal positioning by regulating microtubule dynamics and mediating GSK-3 signaling during brain development. First, using MACF1 floxed allele mice and in utero gene manipulation, we find that MACF1 deletion suppresses migration of cortical pyramidal neurons and results in aberrant neuronal positioning in the developing brain. The cell autonomous deficit in migration is associated with abnormal dynamics of leading processes and centrosomes. Furthermore, microtubule stability is severely damaged in neurons lacking MACF1, resulting in abnormal microtubule dynamics. Finally, MACF1 interacts with and mediates GSK-3 signaling in developing neurons. Our findings establish a cellular mechanism underlying neuronal migration and provide insights into the regulation of cytoskeleton dynamics in developing neurons. Copyright © 2014 Elsevier Inc. All rights reserved.

Area 4 has layer IV in adult primates

PubMed Central

García-Cabezas, Miguel Ángel; Barbas, Helen

2014-01-01

There are opposing views about the status of layer IV in primary motor cortex (area 4). Cajal described a layer IV in area 4 of adult humans. In contrast, Brodmann found layer IV in development but not in adult primates and called area 4 ‘agranular’. We addressed this issue in rhesus monkeys using the neural marker SMI-32, which labels neurons in lower layer III and upper V, but not in layer IV. SMI-32 delineated a central unlabeled cortical stripe in area 4 that corresponds to layer IV, which was populated with small interneurons also found in layer IV in ‘granular’ areas (such as area 46). We distinguished layer IV interneurons from projection neurons in the layers above and below using cellular criteria. The commonly used term ‘agranular’ for area 4 is also used for the phylogenetically ancient limbic cortices, confusing areas that differ markedly in laminar structure. This issue pertains to the systematic variation in the architecture across cortices, traced from limbic cortices through areas with increasingly more elaborate laminar structure. The principle of systematic variation can be used to predict laminar patterns of connections across cortical systems. This principle places area 4 and agranular anterior cingulate cortices at opposite poles of the graded laminar differentiation of motor cortices. The status of layer IV in area 4 thus pertains to core organizational features of the cortex, its connections and evolution. PMID:24735460

Comparing the influence of crestal cortical bone and sinus floor cortical bone in posterior maxilla bi-cortical dental implantation: a three-dimensional finite element analysis.

PubMed

Yan, Xu; Zhang, Xinwen; Chi, Weichao; Ai, Hongjun; Wu, Lin

2015-05-01

This study aimed to compare the influence of alveolar ridge cortical bone and sinus floor cortical bone in sinus areabi-cortical dental implantation by means of 3D finite element analysis. Three-dimensional finite element (FE) models in a posterior maxillary region with sinus membrane and the same height of alveolar ridge of 10 mm were generated according to the anatomical data of the sinus area. They were either with fixed thickness of crestal cortical bone and variable thickness of sinus floor cortical bone or vice versa. Ten models were assumed to be under immediate loading or conventional loading. The standard implant model based on the Nobel Biocare implant system was created via computer-aided design software. All materials were assumed to be isotropic and linearly elastic. An inclined force of 129 N was applied. Von Mises stress mainly concentrated on the surface of crestal cortical bone around the implant neck. For all the models, both the axial and buccolingual resonance frequencies of conventional loading were higher than those of immediate loading; however, the difference is less than 5%. The results showed that bi-cortical implant in sinus area increased the stability of the implant, especially for immediately loading implantation. The thickness of both crestal cortical bone and sinus floor cortical bone influenced implant micromotion and stress distribution; however, crestal cortical bone may be more important than sinus floor cortical bone.

Optogenetic activation of striatal cholinergic interneurons regulates L-dopa-induced dyskinesias

PubMed Central

Heiss, Jaime; Zhang, Danhui; Quik, Maryka

2016-01-01

L-dopa-induced dyskinesias (LIDs) are a serious complication of L-dopa therapy for Parkinson's disease. Emerging evidence indicates that the nicotinic cholinergic system plays a role in LIDs, although the pathways and mechanisms are poorly understood. Here we used optogenetics to investigate the role of striatal cholinergic interneurons in LIDs. Mice expressing cre-recombinase under the control of the choline acetyltransferase promoter (ChAT-Cre) were lesioned by unilateral injection of 6-hydroxydopamine. AAV5-ChR2-eYFP or AAV5-control-eYFP was injected into the dorsolateral striatum, and optical fibers implanted. After stable virus expression, mice were treated with L-dopa. They were then subjected to various stimulation protocols for 2 h and LIDs rated. Continuous stimulation with a short duration optical pulse (1-5 ms) enhanced LIDs. This effect was blocked by the general muscarinic acetylcholine receptor (mAChR) antagonist atropine indicating it was mAChR-mediated. By contrast, continuous stimulation with a longer duration optical pulse (20 ms to 1 s) reduced LIDs to a similar extent as nicotine treatment (~50%). The general nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine blocked the decline in LIDs with longer optical pulses showing it was nAChR-mediated. None of the stimulation regimens altered LIDs in control-eYFP mice. Lesion-induced motor impairment was not affected by optical stimulation indicating that cholinergic transmission selectively regulates LIDs. Longer pulse stimulation increased the number of c-Fos expressing ChAT neurons, suggesting that changes in this immediate early gene may be involved. These results demonstrate that striatal cholinergic interneurons play a critical role in LIDs and support the idea that nicotine treatment reduces LIDs via nAChR desensitization. PMID:26921469

Pax2/8 act redundantly to specify glycinergic and GABAergic fates of multiple spinal interneurons.

PubMed

Batista, Manuel F; Lewis, Katharine E

2008-11-01

The spinal cord contains several distinct classes of neurons but it is still unclear how many of the functional characteristics of these cells are specified. One of the most crucial functional characteristics of a neuron is its neurotransmitter fate. In this paper, we show that in zebrafish most glycinergic and many GABAergic spinal interneurons express Pax2a, Pax2b and Pax8 and that these transcription factors are redundantly required for the neurotransmitter fates of many of these cells. We also demonstrate that the function of these Pax2/8 transcription factors is very specific: in embryos in which Pax2a, Pax2b and Pax8 are simultaneously knocked-down, many neurons lose their glycinergic and/or GABAergic characteristics, but they do not become glutamatergic or cholinergic and their soma morphologies and axon trajectories are unchanged. In mouse, Pax2 is required for correct specification of GABAergic interneurons in the dorsal horn, but it is not required for the neurotransmitter fates of other Pax2-expressing spinal neurons. Our results suggest that this is probably due to redundancy with Pax8 and that the function of Pax2/8 in specifying GABAergic and glycinergic neuronal fates is much broader than was previously appreciated and is highly conserved between different vertebrates.

Drosophila Ovipositor Extension in Mating Behavior and Egg Deposition Involves Distinct Sets of Brain Interneurons

PubMed Central

Kimura, Ken-ichi; Sato, Chiaki; Koganezawa, Masayuki; Yamamoto, Daisuke

2015-01-01

Oviposition is a female-specific behavior that directly affects fecundity, and therefore fitness. If a fertilized female encounters another male that she has evaluated to be of better quality than her previous mate, it would be beneficial for her to remate with this male rather than depositing her eggs. Females who decided not to remate exhibited rejection behavior toward a courting male and engaged in oviposition. Although recent studies of Drosophila melanogaster identified sensory neurons and putative second-order ascending interneurons that mediate uterine afferents affecting female reproductive behavior, little is known about the brain circuitry that selectively activates rejection versus oviposition behaviors. We identified the sexually dimorphic pC2l and female-specific pMN2 neurons, two distinct classes of doublesex (dsx)-expressing neurons that can initiate ovipositor extension associated with rejection and oviposition behavior, respectively. pC2l interneurons, which induce ovipositor extrusion for rejection in females, have homologues that control courtship behavior in males. Activation of these two classes of neurons appears to be mutually exclusive and each governs hierarchical control of the motor program in the VNC either for rejection or oviposition, contributing centrally to the switching on or off of the alternative motor programs. PMID:25955600

Intermittent Hypoxia Enhances Functional Connectivity of Midcervical Spinal Interneurons

PubMed Central

Streeter, Kristi A.; Sunshine, Michael D.; Patel, Shreya; Gonzalez-Rothi, Elisa J.; Reier, Paul J.

2017-01-01

Brief, intermittent oxygen reductions [acute intermittent hypoxia (AIH)] evokes spinal plasticity. Models of AIH-induced neuroplasticity have focused on motoneurons; however, most midcervical interneurons (C-INs) also respond to hypoxia. We hypothesized that AIH would alter the functional connectivity between C-INs and induce persistent changes in discharge. Bilateral phrenic nerve activity was recorded in anesthetized and ventilated adult male rats and a multielectrode array was used to record C4/5 spinal discharge before [baseline (BL)], during, and 15 min after three 5 min hypoxic episodes (11% O2, H1–H3). Most C-INs (94%) responded to hypoxia by either increasing or decreasing firing rate. Functional connectivity was examined by cross-correlating C-IN discharge. Correlograms with a peak or trough were taken as evidence for excitatory or inhibitory connectivity between C-IN pairs. A subset of C-IN pairs had increased excitatory cross-correlations during hypoxic episodes (34%) compared with BL (19%; p < 0.0001). Another subset had a similar response following each episode (40%) compared with BL (19%; p < 0.0001). In the latter group, connectivity remained elevated 15 min post-AIH (30%; p = 0.0002). Inhibitory C-IN connectivity increased during H1–H3 (4.5%; p = 0.0160), but was reduced 15 min post-AIH (0.5%; p = 0.0439). Spike-triggered averaging indicated that a subset of C-INs is synaptically coupled to phrenic motoneurons and excitatory inputs to these “pre-phrenic” cells increased during AIH. We conclude that AIH alters connectivity of the midcervical spinal network. To our knowledge, this is the first demonstration that AIH induces plasticity within the propriospinal network. SIGNIFICANCE STATEMENT Acute intermittent hypoxia (AIH) can trigger spinal plasticity associated with sustained increases in respiratory, somatic, and/or autonomic motor output. The impact of AIH on cervical spinal interneuron (C-IN) discharge and connectivity is unknown. Our

Higher gamma-aminobutyric acid neuron density in the white matter of orbital frontal cortex in schizophrenia.

PubMed

Joshi, Dipesh; Fung, Samantha J; Rothwell, Alice; Weickert, Cynthia Shannon

2012-11-01

In the orbitofrontal cortex (OFC), reduced gray matter volume and reduced glutamic acid decarboxylase 67kDa isoform (GAD67) messenger (m)RNA are found in schizophrenia; however, how these alterations relate to developmental pathology of interneurons is unclear. The present study therefore aimed to determine if increased interstitial white matter neuron (IWMN) density exists in the OFC; whether gamma-aminobutyric acid (GABA)ergic neuron density in OFC white matter was altered; and how IWMN density may be related to an early-expressed inhibitory neuron marker, Dlx1, in OFC gray matter in schizophrenia. IWMN densities were determined (38 schizophrenia and 38 control subjects) for neuronal nuclear antigen (NeuN+) and 65/67 kDa isoform of glutamic acid decarboxylase immunopositive (GAD65/67+) neurons. In situ hybridization was performed to determine Dlx1 and GAD67 mRNA expression in the OFC gray matter. NeuN and GAD65/67 immunopositive cell density was significantly increased in the superficial white matter in schizophrenia. Gray matter Dlx1 and GAD67 mRNA expression were reduced in schizophrenia. Dlx1 mRNA levels were negatively correlated with GAD65/67 IWMN density. Our study provides evidence that pathology of IWMNs in schizophrenia includes GABAergic interneurons and that increased IWMN density may be related to GABAergic deficits in the overlying gray matter. These findings provide evidence at the cellular level that the OFC is a site of pathology in schizophrenia and support the hypothesis that inappropriate migration of cortical inhibitory interneurons occurs in schizophrenia. Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

A Role for Prefrontal Cortical NMDA Receptors in Murine Alcohol-Heightened Aggression.

PubMed

Newman, Emily L; Terunuma, Miho; Wang, Tiffany L; Hewage, Nishani; Bicakci, Matthew B; Moss, Stephen J; DeBold, Joseph F; Miczek, Klaus A

2018-05-01

-heightened aggression. GluN2D-containing NMDARs are highly expressed on cortical parvalbumin-containing interneurons, suggesting that, in a subset of individuals, alcohol may functionally alter signal integration within cortical microcircuits to dysregulate threat reactivity and promote aggression. This work suggests that targeting GluN2D-NMDARs may be of use in reducing the impact of alcohol-related violence in the human population.

Predictors of seizure freedom after surgery for malformations of cortical development.

PubMed

Chang, Edward F; Wang, Doris D; Barkovich, A James; Tihan, Tarik; Auguste, Kurtis I; Sullivan, Joseph E; Garcia, Paul A; Barbaro, Nicholas M

2011-07-01

Malformations of cortical development (MCDs) are a major cause of medically refractory epilepsy. Our aim was to examine a surgical series of patients with cortical malformations to determine the prognostic factors associated with long-term seizure control. We conducted a retrospective review of 143 patients with MCD who underwent resective surgery for medically refractory epilepsy. Demographic, imaging, histopathologic, and surgical variables were analyzed for potential association with seizure freedom. Preoperative magnetic resonance imaging (MRI) was evaluated in a blind fashion and classified according to a new imaging/embryologic MCD classification system. Gray-white blurring on MRI, smaller lesions, complete resection of structural lesions, complete resection of abnormal electrocorticographic areas, and locally confined electrocorticographic abnormalities are favorable prognosticators of seizure freedom on univariate analysis. Imaging features consistent with abnormal proliferation (Barkovich class I) were associated with better outcome compared to those related to abnormal neuronal migration (class II) or abnormal cortical organization (class III). Multivariate logistic regression revealed complete resection of tissue manifesting electrocorticographic and/or MRI anatomic abnormalities as the main independent predictor of seizure freedom. Other histopathologic or demographic factors were not associated with seizure control. Long-term follow-up of patients demonstrated sustained overall rates of seizure control (72% at 2 years, 65% at 5 years, and 67% at 10 years). Surgery for MCDs can result in high rates of seizure freedom. Complete resection of electrocorticographic and anatomic abnormalities appears to be most predictive of long-term seizure control. Copyright © 2011 American Neurological Association.

Inversin modulates the cortical actin network during mitosis

PubMed Central

Werner, Michael E.; Ward, Heather H.; Phillips, Carrie L.; Miller, Caroline; Gattone, Vincent H.

2013-01-01

Mutations in inversin cause nephronophthisis type II, an autosomal recessive form of polycystic kidney disease associated with situs inversus, dilatation, and kidney cyst formation. Since cyst formation may represent a planar polarity defect, we investigated whether inversin plays a role in cell division. In developing nephrons from inv−/− mouse embryos we observed heterogeneity of nuclear size, increased cell membrane perimeters, cells with double cilia, and increased frequency of binuclear cells. Depletion of inversin by siRNA in cultured mammalian cells leads to an increase in bi- or multinucleated cells. While spindle assembly, contractile ring formation, or furrow ingression appears normal in the absence of inversin, mitotic cell rounding and the underlying rearrangement of the cortical actin cytoskeleton are perturbed. We find that inversin loss causes extensive filopodia formation in both interphase and mitotic cells. These cells also fail to round up in metaphase. The resultant spindle positioning defects lead to asymmetric division plane formation and cell division. In a cell motility assay, fibroblasts isolated from inv−/− mouse embryos migrate at half the speed of wild-type fibroblasts. Together these data suggest that inversin is a regulator of cortical actin required for cell rounding and spindle positioning during mitosis. Furthermore, cell division defects resulting from improper spindle position and perturbed actin organization contribute to altered nephron morphogenesis in the absence of inversin. PMID:23515530

Oxytocin Depolarizes Fast-Spiking Hilar Interneurons and Induces GABA Release onto Mossy Cells of the Rat Dentate Gyrus

PubMed Central

Harden, Scott W.; Frazier, Charles J.

2016-01-01

Delivery of exogenous oxytocin (OXT) to central oxytocin receptors (OXT-Rs) is currently being investigated as a potential treatment for conditions such as post-traumatic stress disorder (PTSD), depression, social anxiety, and autism spectrum disorder (ASD). Despite significant research implicating central OXT signaling in modulation of mood, affect, social behavior, and stress response, relatively little is known about the cellular and synaptic mechanisms underlying these complex actions, particularly in brain regions which express the OXT-R but lie outside of the hypothalamus (where OXT-synthesizing neurons reside). We report that bath application of low concentrations of the selective OXT-R agonist Thr4,Gly7-OXT (TGOT) reliably and robustly drives GABA release in the dentate gyrus in an action potential dependent manner. Additional experiments led to identification of a small subset of small hilar interneurons that are directly depolarized by acute application of TGOT. From a physiological perspective, TGOT-responsive hilar interneurons have high input resistance, rapid repolarization velocity during an action potential, and a robust afterhyperpolarization. Further, they fire irregularly (or stutter) in response to moderate depolarization, and fire quickly with minimal spike frequency accommodation in response to large current injections. From an anatomical perspective, TGOT responsive hilar interneurons have dense axonal arborizations in the hilus that were found close proximity with mossy cell somata and/or proximal dendrites, and also invade the granule cell layer. Further, they have primary dendrites that always extend into the granule cell layer, and sometimes have clear arborizations in the molecular layer. Overall, these data reveal a novel site of action for OXT in an important limbic circuit, and represent a significant step towards better understanding how endogenous OXT may modulate flow of information in hippocampal networks. PMID:27068005

Oxytocin depolarizes fast-spiking hilar interneurons and induces GABA release onto mossy cells of the rat dentate gyrus.

PubMed

Harden, Scott W; Frazier, Charles J

2016-09-01

Delivery of exogenous oxytocin (OXT) to central oxytocin receptors (OXT-Rs) is currently being investigated as a potential treatment for conditions such as post-traumatic stress disorder (PTSD), depression, social anxiety, and autism spectrum disorder (ASD). Despite significant research implicating central OXT signaling in modulation of mood, affect, social behavior, and stress response, relatively little is known about the cellular and synaptic mechanisms underlying these complex actions, particularly in brain regions which express the OXT-R but lie outside of the hypothalamus (where OXT-synthesizing neurons reside). We report that bath application of low concentrations of the selective OXT-R agonist Thr4,Gly7-OXT (TGOT) reliably and robustly drives GABA release in the dentate gyrus in an action potential dependent manner. Additional experiments led to identification of a small subset of small hilar interneurons that are directly depolarized by acute application of TGOT. From a physiological perspective, TGOT-responsive hilar interneurons have high input resistance, rapid repolarization velocity during an action potential, and a robust afterhyperpolarization. Further, they fire irregularly (or stutter) in response to moderate depolarization, and fire quickly with minimal spike frequency accommodation in response to large current injections. From an anatomical perspective, TGOT responsive hilar interneurons have dense axonal arborizations in the hilus that were found in close proximity with mossy cell somata and/or proximal dendrites, and also invade the granule cell layer. Further, they have primary dendrites that always extend into the granule cell layer, and sometimes have clear arborizations in the molecular layer. Overall, these data reveal a novel site of action for OXT in an important limbic circuit, and represent a significant step towards better understanding how endogenous OXT may modulate flow of information in hippocampal networks. © 2016 Wiley