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Sample records for neocortical fastspiking gabaergic

  1. Specific functions of synaptically localized potassium channels in synaptic transmission at the neocortical GABAergic fast-spiking cell synapse.

    PubMed

    Goldberg, Ethan M; Watanabe, Shigeo; Chang, Su Ying; Joho, Rolf H; Huang, Z Josh; Leonard, Christopher S; Rudy, Bernardo

    2005-05-25

    Potassium (K+) channel subunits of the Kv3 subfamily (Kv3.1-Kv3.4) display a positively shifted voltage dependence of activation and fast activation/deactivation kinetics when compared with other voltage-gated K+ channels, features that confer on Kv3 channels the ability to accelerate the repolarization of the action potential (AP) efficiently and specifically. In the cortex, the Kv3.1 and Kv3.2 proteins are expressed prominently in a subset of GABAergic interneurons known as fast-spiking (FS) cells and in fact are a significant determinant of the fast-spiking discharge pattern. However, in addition to expression at FS cell somata, Kv3.1 and Kv3.2 proteins also are expressed prominently at FS cell terminals, suggesting roles for Kv3 channels in neurotransmitter release. We investigated the effect of 1.0 mM tetraethylammonium (TEA; which blocks Kv3 channels) on inhibitory synaptic currents recorded in layer II/III neocortical pyramidal cells. Spike-evoked GABA release by FS cells was enhanced nearly twofold by 1.0 mM TEA, with a decrease in the paired pulse ratio (PPR), effects not reproduced by blockade of the non-Kv3 subfamily K+ channels also blocked by low concentrations of TEA. Moreover, in Kv3.1/Kv3.2 double knock-out (DKO) mice, the large effects of TEA were absent, spike-evoked GABA release was larger, and the PPR was lower than in wild-type mice. Together, these results suggest specific roles for Kv3 channels at FS cell terminals that are distinct from those of Kv1 and large-conductance Ca2+-activated K+ channels (also present at the FS cell synapse). We propose that at FS cell terminals synaptically localized Kv3 channels keep APs brief, limiting Ca2+ influx and hence release probability, thereby influencing synaptic depression at a synapse designed for sustained high-frequency synaptic transmission.

  2. Function of specific K(+) channels in sustained high-frequency firing of fast-spiking neocortical interneurons.

    PubMed

    Erisir, A; Lau, D; Rudy, B; Leonard, C S

    1999-11-01

    Fast-spiking GABAergic interneurons of the neocortex and hippocampus fire high-frequency trains of brief action potentials with little spike-frequency adaptation. How these striking properties arise is unclear, although recent evidence suggests K(+) channels containing Kv3.1-Kv3.2 proteins play an important role. We investigated the role of these channels in the firing properties of fast-spiking neocortical interneurons from mouse somatosensory cortex using a pharmacological and modeling approach. Low tetraethylammonium (TEA) concentrations (fast-spiking neurons, but not in other interneurons. Analysis of spike shape changes during the spike trains suggested that Na(+) channel inactivation plays a significant role in the firing-rate slowdown produced by TEA, a conclusion that was supported by computer simulations. These findings indicate that the unique properties of Kv3.1-Kv3.2 channels enable sustained high-frequency firing by facilitating the recovery of Na(+) channel inactivation and by minimizing the duration of the afterhyperpolarization in neocortical interneurons.

  3. The early fetal development of human neocortical GABAergic interneurons.

    PubMed

    Al-Jaberi, Nahidh; Lindsay, Susan; Sarma, Subrot; Bayatti, Nadhim; Clowry, Gavin J

    2015-03-01

    GABAergic interneurons are crucial to controlling the excitability and responsiveness of cortical circuitry. Their developmental origin may differ between rodents and human. We have demonstrated the expression of 12 GABAergic interneuron-associated genes in samples from human neocortex by quantitative rtPCR from 8 to 12 postconceptional weeks (PCW) and shown a significant anterior to posterior expression gradient, confirmed by in situ hybridization or immunohistochemistry for GAD1 and 2, DLX1, 2, and 5, ASCL1, OLIG2, and CALB2. Following cortical plate (CP) formation from 8 to 9 PCW, a proportion of cells were strongly stained for all these markers in the CP and presubplate. ASCL1 and DLX2 maintained high expression in the proliferative zones and showed extensive immunofluorescent double-labeling with the cell division marker Ki-67. CALB2-positive cells increased steadily in the SVZ/VZ from 10 PCW but were not double-labeled with Ki-67. Expression of GABAergic genes was generally higher in the dorsal pallium than in the ganglionic eminences, with lower expression in the intervening ventral pallium. It is widely accepted that the cortical proliferative zones may generate CALB2-positive interneurons from mid-gestation; we now show that the anterior neocortical proliferative layers especially may be a rich source of interneurons in the early neocortex.

  4. Interneurons. Fast-spiking, parvalbumin⁺ GABAergic interneurons: from cellular design to microcircuit function.

    PubMed

    Hu, Hua; Gan, Jian; Jonas, Peter

    2014-08-01

    The success story of fast-spiking, parvalbumin-positive (PV(+)) GABAergic interneurons (GABA, γ-aminobutyric acid) in the mammalian central nervous system is noteworthy. In 1995, the properties of these interneurons were completely unknown. Twenty years later, thanks to the massive use of subcellular patch-clamp techniques, simultaneous multiple-cell recording, optogenetics, in vivo measurements, and computational approaches, our knowledge about PV(+) interneurons became more extensive than for several types of pyramidal neurons. These findings have implications beyond the "small world" of basic research on GABAergic cells. For example, the results provide a first proof of principle that neuroscientists might be able to close the gaps between the molecular, cellular, network, and behavioral levels, representing one of the main challenges at the present time. Furthermore, the results may form the basis for PV(+) interneurons as therapeutic targets for brain disease in the future. However, much needs to be learned about the basic function of these interneurons before clinical neuroscientists will be able to use PV(+) interneurons for therapeutic purposes.

  5. Electrical and chemical synapses among parvalbumin fast-spiking GABAergic interneurons in adult mouse neocortex

    PubMed Central

    Galarreta, Mario; Hestrin, Shaul

    2002-01-01

    Networks of γ-aminobutyric acid (GABA)ergic interneurons connected via electrical and chemical synapses are thought to play an important role in detecting and promoting synchronous activity in the cerebral cortex. Although the properties of electrical and chemical synaptic interactions among inhibitory interneurons are critical for their function as a network, they have only been studied systematically in juvenile animals. Here, we have used transgenic mice expressing the enhanced green fluorescent protein in cells containing parvalbumin (PV) to study the synaptic connectivity among fast-spiking (FS) cells in slices from adult animals (2–7 months old). We have recorded from pairs of PV-FS cells and found that the majority of them were electrically coupled (61%, 14 of 23 pairs). In addition, 78% of the pairs were connected via GABAergic chemical synapses, often reciprocally. The average coupling coefficient for step injections was 1.5% (n = 14), a smaller value than that reported in juvenile animals. GABA-mediated inhibitory postsynaptic currents and potentials decayed with exponential time constants of 2.6 and 5.9 ms, respectively, and exhibited paired-pulse depression (50-ms interval). The inhibitory synaptic responses in the adult were faster than those observed in young animals. Our results indicate that PV-FS cells are highly interconnected in the adult cerebral cortex by both electrical and chemical synapses, establishing networks that can have important implications for coordinating activity in cortical circuits. PMID:12213962

  6. Synchrony of fast-spiking interneurons interconnected by GABAergic and electrical synapses.

    PubMed

    Nomura, Masaki; Fukai, Tomoki; Aoyagi, Toshio

    2003-09-01

    Fast-spiking (FS) interneurons have specific types (Kv3.1/3.2 type) of the delayed potassium channel, which differ from the conventional Hodgkin-Huxley (HH) type potassium channel (Kv1.3 type) in several aspects. In this study, we show dramatic effects of the Kv3.1/3.2 potassium channel on the synchronization of the FS interneurons. We show analytically that two identical electrically coupled FS interneurons modeled with Kv3.1/3.2 channel fire synchronously at arbitrary firing frequencies, unlike similarly coupled FS neurons modeled with Kv1.3 channel that show frequency-dependent synchronous and antisynchronous firing states. Introducing GABA(A) receptor-mediated synaptic connections into an FS neuron pair tends to induce an antisynchronous firing state, even if the chemical synapses are bidirectional. Accordingly, an FS neuron pair connected simultaneously by electrical and chemical synapses achieves both synchronous firing state and antisynchronous firing state in a physiologically plausible range of the conductance ratio between electrical and chemical synapses. Moreover, we find that a large-scale network of FS interneurons connected by gap junctions and bidirectional GABAergic synapses shows similar bistability in the range of gamma frequencies (30-70 Hz).

  7. Genetics and Function of Neocortical GABAergic Interneurons in Neurodevelopmental Disorders

    PubMed Central

    Rossignol, E.

    2011-01-01

    A dysfunction of cortical and limbic GABAergic circuits has been postulated to contribute to multiple neurodevelopmental disorders in humans, including schizophrenia, autism, and epilepsy. In the current paper, I summarize the characteristics that underlie the great diversity of cortical GABAergic interneurons and explore how the multiple roles of these cells in developing and mature circuits might contribute to the aforementioned disorders. Furthermore, I review the tightly controlled genetic cascades that determine the fate of cortical interneurons and summarize how the dysfunction of genes important for the generation, specification, maturation, and function of cortical interneurons might contribute to these disorders. PMID:21876820

  8. Thalamo-cortical axons regulate the radial dispersion of neocortical GABAergic interneurons

    PubMed Central

    Zechel, Sabrina; Nakagawa, Yasushi; Ibáñez, Carlos F

    2016-01-01

    Neocortical GABAergic interneuron migration and thalamo-cortical axon (TCA) pathfinding follow similar trajectories and timing, suggesting they may be interdependent. The mechanisms that regulate the radial dispersion of neocortical interneurons are incompletely understood. Here we report that disruption of TCA innervation, or TCA-derived glutamate, affected the laminar distribution of GABAergic interneurons in mouse neocortex, resulting in abnormal accumulation in deep layers of interneurons that failed to switch from tangential to radial orientation. Expression of the KCC2 cotransporter was elevated in interneurons of denervated cortex, and KCC2 deletion restored normal interneuron lamination in the absence of TCAs. Disruption of interneuron NMDA receptors or pharmacological inhibition of calpain also led to increased KCC2 expression and defective radial dispersion of interneurons. Thus, although TCAs are not required to guide the tangential migration of GABAergic interneurons, they provide crucial signals that restrict interneuron KCC2 levels, allowing coordinated neocortical invasion of TCAs and interneurons. DOI: http://dx.doi.org/10.7554/eLife.20770.001 PMID:27935475

  9. Possible role of GABAergic depolarization in neocortical neurons in generating hyperexcitatory behaviors during emergence from sevoflurane anesthesia in the rat

    PubMed Central

    Lim, Byung-Gun; Shen, Feng-Yan; Kim, Young-Beom; Kim, Woong Bin; Kim, Yoon Sik; Han, Hee Chul; Lee, Mi-Kyoung; Kong, Myoung-Hoon; Kim, Yang In

    2014-01-01

    Hyperexcitatory behaviors occurring after sevoflurane anesthesia are of serious clinical concern, but the underlying mechanism is unknown. These behaviors may result from the potentiation by sevoflurane of GABAergic depolarization/excitation in neocortical neurons, cells implicated in the genesis of consciousness and arousal. The current study sought to provide evidence for this hypothesis with rats, the neocortical neurons of which are known to respond to GABA (γ-aminobutyric acid) with depolarization/excitation at early stages of development (i.e., until the second postnatal week) and with hyperpolarization/inhibition during adulthood. Employing behavioral tests and electrophysiological recordings in neocortical slice preparations, we found: (1) sevoflurane produced PAHBs (post-anesthetic hyperexcitatory behaviors) in postnatal day (P)1–15 rats, whereas it failed to elicit PAHBs in P16 or older rats; (2) GABAergic PSPs (postsynaptic potentials) were depolarizing/excitatory in the neocortical neurons of P5 and P10 rats, whereas mostly hyperpolarizing/inhibitory in the cells of adult rats; (3) at P14–15, <50% of rats had PAHBs and, in general, the cells of the animals with PAHBs exhibited strongly depolarizing GABAergic PSPs, whereas those without PAHBs showed hyperpolarizing or weakly depolarizing GABAergic PSPs; (4) bumetanide [inhibitor of the Cl− importer NKCC (Na+–K+–2Cl− cotransporter)] treatment at P5 suppressed PAHBs and depolarizing GABAergic responses; and (5) sevoflurane at 1% (i.e., concentration <1 minimum alveolar concentration) potentiated depolarizing GABAergic PSPs in the neurons of P5 and P10 rats and of P14–15 animals with PAHBs, evoking action potentials in ≥50% of these cells. On the basis of these results, we conclude that sevoflurane may produce PAHBs by potentiating GABAergic depolarization/excitation in neocortical neurons. PMID:24597723

  10. A key mechanism underlying sensory experience-dependent maturation of neocortical GABAergic circuits in vivo.

    PubMed

    Jiao, Yuanyuan; Zhang, Zhi; Zhang, Chunzhao; Wang, Xinjun; Sakata, Kazuko; Lu, Bai; Sun, Qian-Quan

    2011-07-19

    Mechanisms underlying experience-dependent refinement of cortical connections, especially GABAergic inhibitory circuits, are unknown. By using a line of mutant mice that lack activity-dependent BDNF expression (bdnf-KIV), we show that experience regulation of cortical GABAergic network is mediated by activity-driven BDNF expression. Levels of endogenous BDNF protein in the barrel cortex are strongly regulated by sensory inputs from whiskers. There is a severe alteration of excitation and inhibition balance in the barrel cortex of bdnf-KIV mice as a result of reduced inhibitory but not excitatory conductance. Within the inhibitory circuits, the mutant barrel cortex exhibits significantly reduced levels of GABA release only from the parvalbumin-expressing fast-spiking (FS) interneurons, but not other interneuron subtypes. Postnatal deprivation of sensory inputs markedly decreased perisomatic inhibition selectively from FS cells in wild-type but not bdnf-KIV mice. These results suggest that postnatal experience, through activity-driven BDNF expression, controls cortical development by regulating FS cell-mediated perisomatic inhibition in vivo.

  11. Distinct nonuniform cable properties optimize rapid and efficient activation of fast-spiking GABAergic interneurons

    PubMed Central

    Nörenberg, Anja; Hu, Hua; Vida, Imre; Bartos, Marlene; Jonas, Peter

    2009-01-01

    Fast-spiking, parvalbumin-expressing basket cells (BCs) play a key role in feedforward and feedback inhibition in the hippocampus. However, the dendritic mechanisms underlying rapid interneuron recruitment have remained unclear. To quantitatively address this question, we developed detailed passive cable models of BCs in the dentate gyrus based on dual somatic or somatodendritic recordings and complete morphologic reconstructions. Both specific membrane capacitance and axial resistivity were comparable to those of pyramidal neurons, but the average somatodendritic specific membrane resistance (Rm) was substantially lower in BCs. Furthermore, Rm was markedly nonuniform, being lowest in soma and proximal dendrites, intermediate in distal dendrites, and highest in the axon. Thus, the somatodendritic gradient of Rm was the reverse of that in pyramidal neurons. Further computational analysis revealed that these unique cable properties accelerate the time course of synaptic potentials at the soma in response to fast inputs, while boosting the efficacy of slow distal inputs. These properties will facilitate both rapid phasic and efficient tonic activation of BCs in hippocampal microcircuits. PMID:20080772

  12. Distinct nonuniform cable properties optimize rapid and efficient activation of fast-spiking GABAergic interneurons.

    PubMed

    Nörenberg, Anja; Hu, Hua; Vida, Imre; Bartos, Marlene; Jonas, Peter

    2010-01-12

    Fast-spiking, parvalbumin-expressing basket cells (BCs) play a key role in feedforward and feedback inhibition in the hippocampus. However, the dendritic mechanisms underlying rapid interneuron recruitment have remained unclear. To quantitatively address this question, we developed detailed passive cable models of BCs in the dentate gyrus based on dual somatic or somatodendritic recordings and complete morphologic reconstructions. Both specific membrane capacitance and axial resistivity were comparable to those of pyramidal neurons, but the average somatodendritic specific membrane resistance (R(m)) was substantially lower in BCs. Furthermore, R(m) was markedly nonuniform, being lowest in soma and proximal dendrites, intermediate in distal dendrites, and highest in the axon. Thus, the somatodendritic gradient of R(m) was the reverse of that in pyramidal neurons. Further computational analysis revealed that these unique cable properties accelerate the time course of synaptic potentials at the soma in response to fast inputs, while boosting the efficacy of slow distal inputs. These properties will facilitate both rapid phasic and efficient tonic activation of BCs in hippocampal microcircuits.

  13. Brain-derived neurotrophic factor controls functional differentiation and microcircuit formation of selectively isolated fast-spiking GABAergic interneurons.

    PubMed

    Berghuis, Paul; Dobszay, Marton B; Sousa, Kyle M; Schulte, Gunnar; Mager, Peter P; Härtig, Wolfgang; Görcs, Tamás J; Zilberter, Yuri; Ernfors, Patrik; Harkany, Tibor

    2004-09-01

    GABAergic interneurons with high-frequency firing, fast-spiking (FS) cells, form synapses on perisomatic regions of principal cells in the neocortex and hippocampus to control the excitability of cortical networks. Brain-derived neurotrophic factor (BDNF) is essential for the differentiation of multiple interneuron subtypes and the formation of their synaptic contacts. Here, we examined whether BDNF, alone or in conjunction with sustained KCl-induced depolarization, drives functional FS cell differentiation and the formation of inhibitory microcircuits. Homogeneous FS cell cultures were established by target-specific isolation using the voltage-gated potassium channel 3.1b subunit as the selection marker. Isolated FS cells expressed parvalbumin, were surrounded by perineuronal nets, formed immature inhibitory connections and generated slow action potentials at 12 days in vitro. Brain-derived neurotrophic factor (BDNF) promoted FS cell differentiation by increasing the somatic diameter, dendritic branching and the frequency of action potential firing. In addition, BDNF treatment led to a significant up-regulation of synaptophysin and vesicular GABA transporter expression, components of the synaptic machinery critical for GABA release, which was paralleled by an increase in synaptic strength. Long-term membrane depolarization alone was detrimental to dendritic branching. However, we observed that BDNF and KCl exerted additive effects, as reflected by the significantly accelerated maturation of synaptic contacts and high discharge frequencies, and was required for the formation of reciprocal connections between FS cells. Our results show that BDNF, along with membrane depolarization, is critical for FS cells to establish inhibitory circuitries during corticogenesis.

  14. Kv3.1/Kv3.2 channel positive modulators enable faster activating kinetics and increase firing frequency in fast-spiking GABAergic interneurons.

    PubMed

    Boddum, Kim; Hougaard, Charlotte; Xiao-Ying Lin, Julie; von Schoubye, Nadia Lybøl; Jensen, Henrik Sindal; Grunnet, Morten; Jespersen, Thomas

    2017-02-24

    Due to their fast kinetic properties, Kv3.1 voltage gated potassium channels are important in setting and controlling firing frequency in neurons and pivotal in generating high frequency firing of interneurons. Pharmacological activation of Kv3.1 channels may possess therapeutic potential for treatment of epilepsy, hearing disorders, schizophrenia and cognitive impairments. Here we thoroughly investigate the selectivity and positive modulation of the two small molecules, EX15 and RE01, on Kv3 channels. Selectivity studies, conducted in Xenopus laevis oocytes confirmed a positive modulatory effect of the two compounds on Kv3.1 and to a minor extent on Kv3.2 channels. RE01 had no effect on the Kv3.3 and Kv3.4 channels, whereas EX15 had an inhibitory impact on the Kv3.4 mediated current. Voltage-clamp experiments in monoclonal hKv3.1b/HEK293 cells (34 °C) revealed that the two compounds indeed induced larger currents and faster activation kinetics. They also decrease the speed of deactivation and shifted the voltage dependence of activation, to a more negative activation threshold. Application of action potential clamping and repetitive stimulation protocols of hKv3.1b expressing HEK293 cells revealed that EX15 and RE01 significantly increased peak amplitude, half width and decay time of Kv3.1 mediated currents, even during high-frequency action potential clamping (250 Hz). In rat hippocampal slices, EX15 and RE01 increased neuronal excitability in fast-spiking interneurons in dentate gyrus. Action potential frequency was prominently increased at minor depolarizing steps, whereas more marginal effects of EX15 and RE01 were observed after stronger depolarizations. In conclusion, our results suggest that EX15 and RE01 positive modulation of Kv3.1 and Kv3.2 currents facilitate increased firing frequency in fast-spiking GABAergic interneurons.

  15. Neocortical Post-Traumatic Epileptogenesis Is Associated with Loss of GABAergic Neurons

    PubMed Central

    Avramescu, Sinziana; Nita, Dragos A.

    2009-01-01

    Abstract The subtle mechanisms of post-traumatic epileptogenesis remain unknown, although the incidence of chronic epilepsy after penetrating cortical wounds is high. Here, we investigated whether the increased frequency of seizures occurring within 6 weeks following partial deafferentation of the suprasylvian gyrus in cats is accompanied with a change in the ratio between the number of excitatory and inhibitory neurons. Immuno-histochemical labeling of all neurons with neuronal-specific nuclear protein (NeuN) antibody, and of the GABAergic inhibitory neurons with either gamma-aminobutyric acid (GABA) or glutamic acid decarboxylase (GAD 65&67) antibodies, was performed on sections obtained from control and epileptic animals with chronically deafferented suprasylvian gyrus. Quantification of the labeled neurons was performed in control animals and at 2, 4, and 6 weeks following cortical deafferentation, in the suprasylvian and marginal gyri, both ipsi- and contra-lateral to the cortical trauma. In all epileptic animals, the neuronal loss was circumscribed to the deafferented suprasylvian gyrus. Inhibitory GABAergic neurons were particularly more sensitive to cortical deafferentation than excitatory ones, leading to a progressively increasing ratio between excitation and inhibition towards excitation, potentially explaining the increased propensity to seizures in chronic undercut cortex. PMID:19422294

  16. 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.

  17. Plasticity in Single Axon Glutamatergic Connection to GABAergic Interneurons Regulates Complex Events in the Human Neocortex.

    PubMed

    Szegedi, Viktor; Paizs, Melinda; Csakvari, Eszter; Molnar, Gabor; Barzo, Pal; Tamas, Gabor; Lamsa, Karri

    2016-11-01

    In the human neocortex, single excitatory pyramidal cells can elicit very large glutamatergic EPSPs (VLEs) in inhibitory GABAergic interneurons capable of triggering their firing with short (3-5 ms) delay. Similar strong excitatory connections between two individual neurons have not been found in nonhuman cortices, suggesting that these synapses are specific to human interneurons. The VLEs are crucial for generating neocortical complex events, observed as single pyramidal cell spike-evoked discharge of cell assemblies in the frontal and temporal cortices. However, long-term plasticity of the VLE connections and how the plasticity modulates neocortical complex events has not been studied. Using triple and dual whole-cell recordings from synaptically connected human neocortical layers 2-3 neurons, we show that VLEs in fast-spiking GABAergic interneurons exhibit robust activity-induced long-term depression (LTD). The LTD by single pyramidal cell 40 Hz spike bursts is specific to connections with VLEs, requires group I metabotropic glutamate receptors, and has a presynaptic mechanism. The LTD of VLE connections alters suprathreshold activation of interneurons in the complex events suppressing the discharge of fast-spiking GABAergic cells. The VLEs triggering the complex events may contribute to cognitive processes in the human neocortex, and their long-term plasticity can alter the discharging cortical cell assemblies by learning.

  18. Plasticity in Single Axon Glutamatergic Connection to GABAergic Interneurons Regulates Complex Events in the Human Neocortex

    PubMed Central

    Szegedi, Viktor; Paizs, Melinda; Csakvari, Eszter; Molnar, Gabor; Barzo, Pal; Tamas, Gabor; Lamsa, Karri

    2016-01-01

    In the human neocortex, single excitatory pyramidal cells can elicit very large glutamatergic EPSPs (VLEs) in inhibitory GABAergic interneurons capable of triggering their firing with short (3–5 ms) delay. Similar strong excitatory connections between two individual neurons have not been found in nonhuman cortices, suggesting that these synapses are specific to human interneurons. The VLEs are crucial for generating neocortical complex events, observed as single pyramidal cell spike-evoked discharge of cell assemblies in the frontal and temporal cortices. However, long-term plasticity of the VLE connections and how the plasticity modulates neocortical complex events has not been studied. Using triple and dual whole-cell recordings from synaptically connected human neocortical layers 2–3 neurons, we show that VLEs in fast-spiking GABAergic interneurons exhibit robust activity-induced long-term depression (LTD). The LTD by single pyramidal cell 40 Hz spike bursts is specific to connections with VLEs, requires group I metabotropic glutamate receptors, and has a presynaptic mechanism. The LTD of VLE connections alters suprathreshold activation of interneurons in the complex events suppressing the discharge of fast-spiking GABAergic cells. The VLEs triggering the complex events may contribute to cognitive processes in the human neocortex, and their long-term plasticity can alter the discharging cortical cell assemblies by learning. PMID:27828957

  19. 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

  20. 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.

  1. K(+) channel expression distinguishes subpopulations of parvalbumin- and somatostatin-containing neocortical interneurons.

    PubMed

    Chow, A; Erisir, A; Farb, C; Nadal, M S; Ozaita, A; Lau, D; Welker, E; Rudy, B

    1999-11-01

    Kv3.1 and Kv3.2 K(+) channel proteins form similar voltage-gated K(+) channels with unusual properties, including fast activation at voltages positive to -10 mV and very fast deactivation rates. These properties are thought to facilitate sustained high-frequency firing. Kv3.1 subunits are specifically found in fast-spiking, parvalbumin (PV)-containing cortical interneurons, and recent studies have provided support for a crucial role in the generation of the fast-spiking phenotype. Kv3.2 mRNAs are also found in a small subset of neocortical neurons, although the distribution of these neurons is different. We raised antibodies directed against Kv3.2 proteins and used dual-labeling methods to identify the neocortical neurons expressing Kv3.2 proteins and to determine their subcellular localization. Kv3.2 proteins are prominently expressed in patches in somatic and proximal dendritic membrane as well as in axons and presynaptic terminals of GABAergic interneurons. Kv3.2 subunits are found in all PV-containing neurons in deep cortical layers where they probably form heteromultimeric channels with Kv3.1 subunits. In contrast, in superficial layer PV-positive neurons Kv3.2 immunoreactivity is low, but Kv3.1 is still prominently expressed. Because Kv3.1 and Kv3.2 channels are differentially modulated by protein kinases, these results raise the possibility that the fast-spiking properties of superficial- and deep-layer PV neurons are differentially regulated by neuromodulators. Interestingly, Kv3. 2 but not Kv3.1 proteins are also prominent in a subset of seemingly non-fast-spiking, somatostatin- and calbindin-containing interneurons, suggesting that the Kv3.1-Kv3.2 current type can have functions other than facilitating high-frequency firing.

  2. Differential modulation of repetitive firing and synchronous network activity in neocortical interneurons by inhibition of A-type K+ channels and Ih

    PubMed Central

    Williams, Sidney B.; Hablitz, John J.

    2015-01-01

    GABAergic interneurons provide the main source of inhibition in the neocortex and are important in regulating neocortical network activity. In the presence 4-aminopyridine (4-AP), CNQX, and D-APV, large amplitude GABAA-receptor mediated depolarizing responses were observed in the neocortex. GABAergic networks are comprised of several types of interneurons, each with its own protein expression pattern, firing properties, and inhibitory role in network activity. Voltage-gated ion channels, especially A-type K+ channels, differentially regulate passive membrane properties, action potential (AP) waveform, and repetitive firing properties in interneurons depending on their composition and localization. HCN channels are known modulators of pyramidal cell intrinsic excitability and excitatory network activity. Little information is available regarding how HCN channels functionally modulate excitability of individual interneurons and inhibitory networks. In this study, we examined the effect of 4-AP on intrinsic excitability of fast-spiking basket cells (FS-BCs) and Martinotti cells (MCs). 4-AP increased the duration of APs in both FS-BCs and MCs. The repetitive firing properties of MCs were differentially affected compared to FS-BCs. We also examined the effect of Ih inhibition on synchronous GABAergic depolarizations and synaptic integration of depolarizing IPSPs. ZD 7288 enhanced the amplitude and area of evoked GABAergic responses in both cell types. Similarly, the frequency and area of spontaneous GABAergic depolarizations in both FS-BCs and MCs were increased in presence of ZD 7288. Synaptic integration of IPSPs in MCs was significantly enhanced, but remained unaltered in FS-BCs. These results indicate that 4-AP differentially alters the firing properties of interneurons, suggesting MCs and FS-BCs may have unique roles in GABAergic network synchronization. Enhancement of GABAergic network synchronization by ZD 7288 suggests that HCN channels attenuate inhibitory

  3. Subcortical origins of human and monkey neocortical interneurons.

    PubMed

    Ma, Tong; Wang, Congmin; Wang, Lei; Zhou, Xing; Tian, Miao; Zhang, Qiangqiang; Zhang, Yue; Li, Jiwen; Liu, Zhidong; Cai, Yuqun; Liu, Fang; You, Yan; Chen, Chao; Campbell, Kenneth; Song, Hongjun; Ma, Lan; Rubenstein, John L; Yang, Zhengang

    2013-11-01

    Cortical GABAergic inhibitory interneurons have crucial roles in the development and function of the cerebral cortex. In rodents, nearly all neocortical interneurons are generated from the subcortical ganglionic eminences. In humans and nonhuman primates, however, the developmental origin of neocortical GABAergic interneurons remains unclear. Here we show that the expression patterns of several key transcription factors in the developing primate telencephalon are very similar to those in rodents, delineating the three main subcortical progenitor domains (the medial, lateral and caudal ganglionic eminences) and the interneurons tangentially migrating from them. On the basis of the continuity of Sox6, COUP-TFII and Sp8 transcription factor expression and evidence from cell migration and cell fate analyses, we propose that the majority of primate neocortical GABAergic interneurons originate from ganglionic eminences of the ventral telencephalon. Our findings reveal that the mammalian neocortex shares basic rules for interneuron development, substantially reshaping our understanding of the origin and classification of primate neocortical interneurons.

  4. Firing regulation of fast-spiking interneurons by autaptic inhibition

    NASA Astrophysics Data System (ADS)

    Guo, Daqing; Chen, Mingming; Perc, Matjaž; Wu, Shengdun; Xia, Chuan; Zhang, Yangsong; Xu, Peng; Xia, Yang; Yao, Dezhong

    2016-05-01

    Fast-spiking (FS) interneurons in the brain are self-innervated by powerful inhibitory GABAergic autaptic connections. By computational modelling, we investigate how autaptic inhibition regulates the firing response of such interneurons. Our results indicate that autaptic inhibition both boosts the current threshold for action potential generation and modulates the input-output gain of FS interneurons. The autaptic transmission delay is identified as a key parameter that controls the firing patterns and determines multistability regions of FS interneurons. Furthermore, we observe that neuronal noise influences the firing regulation of FS interneurons by autaptic inhibition and extends their dynamic range for encoding inputs. Importantly, autaptic inhibition modulates noise-induced irregular firing of FS interneurons, such that coherent firing appears at an optimal autaptic inhibition level. Our results reveal the functional roles of autaptic inhibition in taming the firing dynamics of FS interneurons.

  5. Gamma-range synchronization of fast-spiking interneurons can enhance detection of tactile stimuli

    PubMed Central

    Siegle, Joshua H.; Pritchett, Dominique L.; Moore, Christopher I.

    2014-01-01

    We tested the sensory impact of repeated synchronization of fast-spiking interneurons (FS), an activity pattern thought to underlie neocortical gamma oscillations. We optogenetically drove “FS-gamma” while mice detected naturalistic vibrissal stimuli and found enhanced detection of less salient stimuli and impaired detection of more salient ones. Prior studies have predicted that the benefit of FS-gamma is generated when sensory neocortical excitation arrives in a specific temporal window 20-25 ms after FS synchronization. To systematically test this prediction, we aligned periodic tactile and optogenetic stimulation. We found that the detection of less salient stimuli was improved only when peripheral drive led to the arrival of excitation 20-25 ms after synchronization and that other temporal alignments either had no effects or impaired detection. These results provide causal evidence that FS-gamma can enhance processing of less salient stimuli, those that benefit from the allocation of attention. PMID:25151266

  6. Corticofugal GABAergic projection neurons in the mouse frontal cortex

    PubMed Central

    Tomioka, Ryohei; Sakimura, Kenji; Yanagawa, Yuchio

    2015-01-01

    Cortical projection neurons are classified by hodology in corticocortical, commissural and corticofugal subtypes. Although cortical projection neurons had been regarded as only glutamatergic neurons, recently corticocortical GABAergic projection neurons has been also reported in several species. Here, we demonstrate corticofugal GABAergic projection neurons in the mouse frontal cortex. We employed viral-vector-mediated anterograde tracing, classical retrograde tracing, and immunohistochemistry to characterize neocortical GABAergic projection neurons. Injections of the Cre-dependent adeno-associated virus into glutamate decarboxylase 67 (GAD67)-Cre knock-in mice revealed neocortical GABAergic projections widely to the forebrain, including the cerebral cortices, caudate putamen (CPu), ventral pallidum (VP), lateral globus pallidus (LGP), nucleus accumbens, and olfactory tubercle (Tu). Minor GABAergic projections were also found in the mediodorsal thalamic nucleus, diagonal band of Broca, medial globus pallidus, substantial nigra, and dorsal raphe nucleus. Retrograde tracing studies also demonstrated corticofugal GABAergic projection neurons in the mouse frontal cortex. Further immunohistochemical screening with neurochemical markers revealed the majority of corticostriatal GABAergic projection neurons were positive for somatostatin (SS)-immunoreactivity. In contrast, corticothalamic GABAergic projection neurons were not identified by representative neurochemical markers for GABAergic neurons. These findings suggest that corticofugal GABAergic projection neurons are heterogeneous in terms of their neurochemical properties and target nuclei, and provide axonal innervations mainly to the nuclei in the basal ganglia. PMID:26578895

  7. Mature BDNF, but not proBDNF, reduces excitability of fast-spiking interneurons in mouse dentate gyrus.

    PubMed

    Holm, Mai Marie; Nieto-Gonzalez, Jose Luis; Vardya, Irina; Vaegter, Christian Bjerggaard; Nykjaer, Anders; Jensen, Kimmo

    2009-10-07

    Mature BDNF and its precursor proBDNF may both be secreted to exert opposite effects on synaptic plasticity in the hippocampus. However, it is unknown how proBDNF and mature BDNF affect the excitability of GABAergic interneurons and thereby regulate GABAergic inhibition. We made recordings of GABAergic spontaneous IPSCs (sIPSCs) in mouse dentate gyrus granule cells and found that chronic or acute BDNF reductions led to large increases in the sIPSC frequencies, which were TTX (tetrodotoxin) sensitive and therefore action-potential driven. Conversely, addition of mature BDNF, but not proBDNF, within minutes led to a decrease in the sIPSC frequency to 44%. Direct recordings from fast-spiking GABAergic interneurons revealed that mature BDNF reduced their excitability and depressed their action potential firing, whereas proBDNF had no effect. Using the TrkB inhibitor K-252a, or mice deficient for the common neurotrophin receptor p75(NTR), the regulation of GABAergic activity was shown specifically to be mediated by BDNF binding to the neurotrophin receptor TrkB. In agreement, immunohistochemistry demonstrated that TrkB, but not p75(NTR), was expressed in parvalbumin-positive interneurons. Our results suggest that mature BDNF decreases the excitability of GABAergic interneurons via activation of TrkB, while proBDNF does not impact on GABAergic activity. Thus, by affecting the firing of GABAergic interneurons, mature BDNF may play an important role in regulating network oscillations in the hippocampus.

  8. Dopaminergic modulation of short-term synaptic plasticity in fast-spiking interneurons of primate dorsolateral prefrontal cortex.

    PubMed

    Gonzalez-Burgos, G; Kroener, S; Seamans, J K; Lewis, D A; Barrionuevo, G

    2005-12-01

    Dopaminergic regulation of primate dorsolateral prefrontal cortex (PFC) activity is essential for cognitive functions such as working memory. However, the cellular mechanisms of dopamine neuromodulation in PFC are not well understood. We have studied the effects of dopamine receptor activation during persistent stimulation of excitatory inputs onto fast-spiking GABAergic interneurons in monkey PFC. Stimulation at 20 Hz induced short-term excitatory postsynaptic potential (EPSP) depression. The D1 receptor agonist SKF81297 (5 microM) significantly reduced the amplitude of the first EPSP but not of subsequent responses in EPSP trains, which still displayed significant depression. Dopamine (DA; 10 microM) effects were similar to those of SKF81297 and were abolished by the D1 antagonist SCH23390 (5 microM), indicating a D1 receptor-mediated effect. DA did not alter miniature excitatory postsynaptic currents, suggesting that its effects were activity dependent and presynaptic action potential dependent. In contrast to previous findings in pyramidal neurons, in fast-spiking cells, contribution of N-methyl-D-aspartate receptors to EPSPs at subthreshold potentials was not significant and fast-spiking cell depolarization decreased EPSP duration. In addition, DA had no significant effects on temporal summation. The selective decrease in the amplitude of the first EPSP in trains delivered every 10 s suggests that in fast-spiking neurons, DA reduces the amplitude of EPSPs evoked at low frequency but not of EPSPs evoked by repetitive stimulation. DA may therefore improve detection of EPSP bursts above background synaptic activity. EPSP bursts displaying short-term depression may transmit spike-timing-dependent temporal codes contained in presynaptic spike trains. Thus DA neuromodulation may increase the signal-to-noise ratio at fast-spiking cell inputs.

  9. Neuroligin-2 deletion selectively decreases inhibitory synaptic transmission originating from fast-spiking, but not from somatostatin-positive interneurons

    PubMed Central

    Gibson, Jay R.; Huber, Kimberly M.; Südhof, Thomas C.

    2009-01-01

    Neuroligins are cell-adhesion molecules involved in synapse formation and/or function. Neurons express four neuroligins (NL1–NL4), of which NL1 is specific to excitatory, and NL2 to inhibitory synapses. Excitatory and inhibitory synapses include numerous subtypes. However, it is unknown whether NL1 performs similar functions in all excitatory and NL2 in all inhibitory synapses, or whether they regulate the formation and/or function of specific subsets of synapses. To address this central question, we performed paired recordings in primary somatosensory cortex of mice lacking NL1 or NL2. Using this system, we examined neocortical microcircuits formed by reciprocal synapses between excitatory neurons and two subtypes of inhibitory interneurons, namely fast-spiking and somatostatin-positive interneurons. We find that the NL1 deletion had little effect on inhibitory synapses, whereas the NL2 deletion decreased (40–50%) the unitary (cell-to-cell) IPSC amplitude evoked from single fast-spiking interneurons. Strikingly, the NL2 deletion had no effect on IPSC amplitude evoked from single somatostatin-positive inhibitory interneurons. Moreover, the frequency of unitary synaptic connections between individual fast-spiking and somatostatin-positive interneurons and excitatory neurons was unchanged. The decrease in unitary IPSC amplitude originating from fast-spiking interneurons in NL2-deficient mice was due to a multiplicative and uniform down-scaling of the amplitude distribution, which in turn was mediated by a decrease in both synaptic quantal amplitude and quantal content – the latter inferred from an increase in the coefficient of variation. Thus, NL2 is not necessary for establishing unitary inhibitory synaptic connections, but is selectively required for “scaling up” unitary connections originating from a subset of interneurons. PMID:19889999

  10. Involvement of cortical fast-spiking parvalbumin-positive basket cells in epilepsy

    PubMed Central

    Jiang, Xiao; Lachance, Mathieu; Rossignol, Elsa

    2016-01-01

    GABAergic interneurons of the parvalbumin-positive fast-spiking basket cells subtype (PV INs) are important regulators of cortical network excitability and gamma oscillations, involved in signal processing and cognition. Impaired development or function of PV INs has been associated with epilepsy in various animal models of epilepsy, as well as in some genetic forms of epilepsy in humans. In this review, we provide an overview of some of the experimental data linking PV INs dysfunction with epilepsy, focusing on disorders of the specification, migration, maturation, synaptic function or connectivity of PV INs. Furthermore, we reflect on the potential therapeutic use of cell-type specific stimulation of PV INs within active networks and on the transplantation of PV INs precursors in the treatment of epilepsy and its co-morbidities. PMID:27323940

  11. Classification of NPY-Expressing Neocortical Interneurons

    PubMed Central

    Karagiannis, Anastassios; Gallopin, Thierry; Dávid, Csaba; Battaglia, Demian; Geoffroy, Hélène; Rossier, Jean; Hillman, Elizabeth M. C.; Staiger, Jochen F.; Cauli, Bruno

    2009-01-01

    Neuropeptide Y (NPY) is an abundant neuropeptide of the neocortex involved in numerous physiological and pathological processes. Because of the large electrophysiological, molecular, and morphological diversity of NPY-expressing neurons their precise identity remains unclear. To define distinct populations of NPY neurons we characterized, in acute slices of rat barrel cortex, 200 cortical neurons of layers I–IV by means of whole-cell patch-clamp recordings, biocytin labeling, and single-cell reverse transcriptase-PCR designed to probe for the expression of well established molecular markers for cortical neurons. To classify reliably cortical NPY neurons, we used and compared different unsupervised clustering algorithms based on laminar location and electrophysiological and molecular properties. These classification schemes confirmed that NPY neurons are nearly exclusively GABAergic and consistently disclosed three main types of NPY-expressing interneurons. (1) Neurogliaform-like neurons exhibiting a dense axonal arbor, were the most frequent and superficial, and substantially expressed the neuronal isoform of nitric oxide synthase. (2) Martinotti-like cells characterized by an ascending axon ramifying in layer I coexpressed somatostatin and were the most excitable type. (3) Among fast-spiking and parvalbumin-positive basket cells, NPY expression was correlated with pronounced spike latency. By clarifying the diversity of cortical NPY neurons, this study establishes a basis for future investigations aiming at elucidating their physiological roles. PMID:19295167

  12. Heterogeneity and Diversity of Striatal GABAergic Interneurons

    PubMed Central

    Tepper, James M.; Tecuapetla, Fatuel; Koós, Tibor; Ibáñez-Sandoval, Osvaldo

    2010-01-01

    The canonical view of striatal GABAergic interneurons has evolved over several decades of neuroanatomical/neurochemical and electrophysiological studies. From the anatomical studies, three distinct GABAergic interneuronal subtypes are generally recognized. The best-studied subtype expresses the calcium-binding protein, parvalbumin. The second best known interneuron type expresses a number of neuropeptides and enzymes, including neuropeptide Y, somatostatin, and nitric oxide synthase. The last GABAergic interneuron subtype expresses the calcium binding protein, calretinin. There is no overlap or co-localization of these three different sets of markers. The parvalbumin-immunoreactive GABAergic interneurons have been recorded in vitro and shown to exhibit a fast-spiking phenotype characterized by short duration action potentials with large and rapid spike AHPs. They often fire in a stuttering pattern of high frequency firing interrupted by periods of silence. They are capable of sustained firing rates of over 200 Hz. The NPY/SOM/NOS interneurons have been identified as PLTS cells, exhibiting very high input resistances, low threshold spike and prolonged plateau potentials in response to intracellular depolarization or excitatory synaptic stimulation. Thus far, no recordings from identified CR interneurons have been obtained. Recent advances in technological approaches, most notably the generation of several BAC transgenic mouse strains which express a fluorescent marker, enhanced green fluorescent protein, specifically and selectively only in neurons of a certain genetic makeup (e.g., parvalbumin-, neuropeptide Y-, or tyrosine hydroxylase-expressing neurons etc.) have led to the ability of electrophysiologists to visualize and patch specific neuron types in brain slices with epifluorescence illumination. This has led to a rapid expansion of the number of neurochemically and/or electrophysiologically identified interneuronal cell types in the striatum and elsewhere

  13. Sugarcoated Perineuronal Nets Regulate "GABAergic" Transmission: Bittersweet Hypothesis in Autism Spectrum Disorder.

    PubMed

    Burket, Jessica A; Urbano, Maria R; Deutsch, Stephen I

    2017-03-09

    Fast-spiking, parvalbumin-expressing "GABAergic" interneurons regulate synchronous oscillatory output of pyramidal neurons. Metabolic demands of these GABAergic projections are great because local ion concentrations must be optimally maintained; in addition, high rates of mitochondrial respiration necessitate exquisite redox regulation. Interestingly, only fast-spiking, parvalbumin-expressing basket cells coexpressing 3 metalloproteinases seem to be preferentially enwrapped in perineuronal nets (PNNs), a specialized lattice-like structure of the extracellular matrix. The PNNs maintain optimal local concentrations of ions, protect against oxidative stress, and concentrate transcription factors and chemorepulsive axon guidance cues. The PNNs mediate opening and closing of periods of heightened plasticity. Therapeutic strategies in autism spectrum disorders include promoting both maintenance and deliberate disruption of PNNs to promote new learning and cognitive flexibility.

  14. Dopamine-deprived striatal GABAergic interneurons burst and generate repetitive gigantic IPSCs in medium spiny neurons.

    PubMed

    Dehorter, Nathalie; Guigoni, Celine; Lopez, Catherine; Hirsch, June; Eusebio, Alexandre; Ben-Ari, Yehezkel; Hammond, Constance

    2009-06-17

    Striatal GABAergic microcircuits modulate cortical responses and movement execution in part by controlling the activity of medium spiny neurons (MSNs). How this is altered by chronic dopamine depletion, such as in Parkinson's disease, is not presently understood. We now report that, in dopamine-depleted slices of the striatum, MSNs generate giant spontaneous postsynaptic GABAergic currents (single or in bursts at 60 Hz) interspersed with silent episodes, rather than the continuous, low-frequency GABAergic drive (5 Hz) observed in control MSNs. This shift was observed in one-half of the MSN population, including both "D(1)-negative" and "D(1)-positive" MSNs. Single GABA and NMDA channel recordings revealed that the resting membrane potential and reversal potential of GABA were similar in control and dopamine-depleted MSNs, and depolarizing, but not excitatory, actions of GABA were observed. Glutamatergic and cholinergic antagonists did not block the GABAergic oscillations, suggesting that they were generated by GABAergic neurons. In support of this, cell-attached recordings revealed that a subpopulation of intrastriatal GABAergic interneurons generated bursts of spikes in dopamine-deprived conditions. This subpopulation included low-threshold spike interneurons but not fast-spiking interneurons, cholinergic interneurons, or MSNs. Therefore, a population of local GABAergic interneurons shifts from tonic to oscillatory mode when dopamine deprived and gives rise to spontaneous repetitive giant GABAergic currents in one-half the MSNs. We suggest that this may in turn alter integration of cortical signals by MSNs.

  15. State-Dependent Function of Neocortical Chandelier Cells

    PubMed Central

    Woodruff, Alan R.; McGarry, Laura M.; Vogels, Tim P.; Inan, Melis; Anderson, Stewart A.; Yuste, Rafael

    2013-01-01

    Chandelier (axoaxonic) cells (ChCs) are a distinct group of GABAergic interneurons that innervate the axon initial segments of pyramidal cells. However, their circuit role and the function of their clearly defined anatomical specificity remain unclear. Recent work has demonstrated that chandelier cells can produce depolarizing GABAergic PSPs, occasionally driving postsynaptic targets to spike. On the other hand, other work suggests that ChCs are hyperpolarizing and may have an inhibitory role. These disparate functional effects may reflect heterogeneity among ChCs. Here, using brain slices from transgenic mouse strains, we first demonstrate that, across different neocortical areas and genetic backgrounds, upper Layer 2/3 ChCs belong to a single electrophysiologically and morphologically defined population, extensively sampling Layer 1 inputs with asymmetric dendrites. Consistent with being a single cell type, we find electrical coupling between ChCs. We then investigate the effect of chandelier cell activation on pyramidal neuron spiking in several conditions, ranging from the resting membrane potential to stimuli designed to approximate in vivo membrane potential dynamics. We find that under quiescent conditions, chandelier cells are capable of both promoting and inhibiting spike generation, depending on the postsynaptic membrane potential. However, during in vivo-like membrane potential fluctuations, the dominant postsynaptic effect was a strong inhibition. Thus, neocortical chandelier cells, even from within a homogeneous population, appear to play a dual role in the circuit, helping to activate quiescent pyramidal neurons, while at the same time inhibiting active ones. PMID:22159102

  16. Firing Frequency Maxima of Fast-Spiking Neurons in Human, Monkey, and Mouse Neocortex

    PubMed Central

    Wang, Bo; Ke, Wei; Guang, Jing; Chen, Guang; Yin, Luping; Deng, Suixin; He, Quansheng; Liu, Yaping; He, Ting; Zheng, Rui; Jiang, Yanbo; Zhang, Xiaoxue; Li, Tianfu; Luan, Guoming; Lu, Haidong D.; Zhang, Mingsha; Zhang, Xiaohui; Shu, Yousheng

    2016-01-01

    Cortical fast-spiking (FS) neurons generate high-frequency action potentials (APs) without apparent frequency accommodation, thus providing fast and precise inhibition. However, the maximal firing frequency that they can reach, particularly in primate neocortex, remains unclear. Here, by recording in human, monkey, and mouse neocortical slices, we revealed that FS neurons in human association cortices (mostly temporal) could generate APs at a maximal mean frequency (Fmean) of 338 Hz and a maximal instantaneous frequency (Finst) of 453 Hz, and they increase with age. The maximal firing frequency of FS neurons in the association cortices (frontal and temporal) of monkey was even higher (Fmean 450 Hz, Finst 611 Hz), whereas in the association cortex (entorhinal) of mouse it was much lower (Fmean 215 Hz, Finst 342 Hz). Moreover, FS neurons in mouse primary visual cortex (V1) could fire at higher frequencies (Fmean 415 Hz, Finst 582 Hz) than those in association cortex. We further validated our in vitro data by examining spikes of putative FS neurons in behaving monkey and mouse. Together, our results demonstrate that the maximal firing frequency of FS neurons varies between species and cortical areas. PMID:27803650

  17. Firing Frequency Maxima of Fast-Spiking Neurons in Human, Monkey, and Mouse Neocortex.

    PubMed

    Wang, Bo; Ke, Wei; Guang, Jing; Chen, Guang; Yin, Luping; Deng, Suixin; He, Quansheng; Liu, Yaping; He, Ting; Zheng, Rui; Jiang, Yanbo; Zhang, Xiaoxue; Li, Tianfu; Luan, Guoming; Lu, Haidong D; Zhang, Mingsha; Zhang, Xiaohui; Shu, Yousheng

    2016-01-01

    Cortical fast-spiking (FS) neurons generate high-frequency action potentials (APs) without apparent frequency accommodation, thus providing fast and precise inhibition. However, the maximal firing frequency that they can reach, particularly in primate neocortex, remains unclear. Here, by recording in human, monkey, and mouse neocortical slices, we revealed that FS neurons in human association cortices (mostly temporal) could generate APs at a maximal mean frequency (Fmean) of 338 Hz and a maximal instantaneous frequency (Finst) of 453 Hz, and they increase with age. The maximal firing frequency of FS neurons in the association cortices (frontal and temporal) of monkey was even higher (Fmean 450 Hz, Finst 611 Hz), whereas in the association cortex (entorhinal) of mouse it was much lower (Fmean 215 Hz, Finst 342 Hz). Moreover, FS neurons in mouse primary visual cortex (V1) could fire at higher frequencies (Fmean 415 Hz, Finst 582 Hz) than those in association cortex. We further validated our in vitro data by examining spikes of putative FS neurons in behaving monkey and mouse. Together, our results demonstrate that the maximal firing frequency of FS neurons varies between species and cortical areas.

  18. Neocortical focus: experimental view.

    PubMed

    Timofeev, Igor; Chauvette, Sylvain; Soltani, Sara

    2014-01-01

    All brain normal or pathological activities occur in one of the states of vigilance: wake, slow-wave sleep, or REM sleep. Neocortical seizures preferentially occur during slow-wave sleep. We provide a description of neuronal behavior and mechanisms mediating such a behavior within neocortex taking place in natural states of vigilance as well as during seizures pointing to similarities and differences exhibited during sleep and seizures. A concept of epileptic focus is described using a model of cortical undercut, because in that model, the borders of the focus are well defined. In this model, as in other models of acquired epilepsy, the main factor altering excitability is deafferentation, which upregulates neuronal excitability that promotes generation of seizures. Periods of disfacilitation recorded during slow-wave sleep further upregulate neuronal excitability. It appears that the state of neurons and neuronal network in the epileptic focus produced by deafferentation are such that seizures cannot be generated there. Instead, seizures always start around the perimeter of the undercut cortex. Therefore, we define these areas as the seizure focus. In this zone, neuronal connectivity and excitability are moderately enhanced, lowering the threshold for seizure generation.

  19. Rapid developmental maturation of neocortical FS cell intrinsic excitability.

    PubMed

    Goldberg, Ethan M; Jeong, Hyo-Young; Kruglikov, Ilya; Tremblay, Robin; Lazarenko, Roman M; Rudy, Bernardo

    2011-03-01

    Fast-spiking (FS) cells are a prominent subtype of neocortical γ-aminobutyric acidergic interneurons that mediate feed-forward inhibition and the temporal sculpting of information transfer in neural circuits, maintain excitation/inhibition balance, and contribute to network oscillations. FS cell dysfunction may be involved in the pathogenesis of disorders such as epilepsy, autism, and schizophrenia. Mature FS cells exhibit coordinated molecular and cellular specializations that facilitate rapid responsiveness, including brief spikes and sustained high-frequency discharge. We show that these features appear during the second and third postnatal weeks driven by upregulation of K(+) channel subunits of the Kv3 subfamily. The low membrane resistance and fast time constant characteristic of FS cells also appears during this time, driven by expression of a K(+) leak current mediated by K(ir)2 subfamily inward rectifier K(+) channels and TASK subfamily 2-pore K(+) channels. Blockade of this leak produces dramatic depolarization of FS cells suggesting the possibility for potent neuromodulation. Finally, the frequency of FS cell membrane potential oscillations increases during development and is markedly slower in TASK-1/3 knockout mice, suggesting that TASK channels regulate FS cell rhythmogenesis. Our findings imply that some of the effects of acidosis and/or anesthetics on brain function may be due to blockade of TASK channels in FS cells.

  20. Rapid Developmental Maturation of Neocortical FS Cell Intrinsic Excitability

    PubMed Central

    Jeong, Hyo-Young; Kruglikov, Ilya; Tremblay, Robin; Lazarenko, Roman M.

    2011-01-01

    Fast-spiking (FS) cells are a prominent subtype of neocortical γ-aminobutyric acidergic interneurons that mediate feed-forward inhibition and the temporal sculpting of information transfer in neural circuits, maintain excitation/inhibition balance, and contribute to network oscillations. FS cell dysfunction may be involved in the pathogenesis of disorders such as epilepsy, autism, and schizophrenia. Mature FS cells exhibit coordinated molecular and cellular specializations that facilitate rapid responsiveness, including brief spikes and sustained high-frequency discharge. We show that these features appear during the second and third postnatal weeks driven by upregulation of K+ channel subunits of the Kv3 subfamily. The low membrane resistance and fast time constant characteristic of FS cells also appears during this time, driven by expression of a K+ leak current mediated by Kir2 subfamily inward rectifier K+ channels and TASK subfamily 2-pore K+ channels. Blockade of this leak produces dramatic depolarization of FS cells suggesting the possibility for potent neuromodulation. Finally, the frequency of FS cell membrane potential oscillations increases during development and is markedly slower in TASK-1/3 knockout mice, suggesting that TASK channels regulate FS cell rhythmogenesis. Our findings imply that some of the effects of acidosis and/or anesthetics on brain function may be due to blockade of TASK channels in FS cells. PMID:20705896

  1. Perineuronal Nets Enhance the Excitability of Fast-Spiking Neurons

    PubMed Central

    2016-01-01

    Perineuronal nets (PNNs) are specialized complexes of extracellular matrix molecules that surround the somata of fast-spiking neurons throughout the vertebrate brain. PNNs are particularly prevalent throughout the auditory brainstem, which transmits signals with high speed and precision. It is unknown whether PNNs contribute to the fast-spiking ability of the neurons they surround. Whole-cell recordings were made from medial nucleus of the trapezoid body (MNTB) principal neurons in acute brain slices from postnatal day 21 (P21) to P27 mice. PNNs were degraded by incubating slices in chondroitinase ABC (ChABC) and were compared to slices that were treated with a control enzyme (penicillinase). ChABC treatment did not affect the ability of MNTB neurons to fire at up to 1000 Hz when driven by current pulses. However, f–I (frequency–intensity) curves constructed by injecting Gaussian white noise currents superimposed on DC current steps showed that ChABC treatment reduced the gain of spike output. An increase in spike threshold may have contributed to this effect, which is consistent with the observation that spikes in ChABC-treated cells were delayed relative to control-treated cells. In addition, parvalbumin-expressing fast-spiking cortical neurons in >P70 slices that were treated with ChABC also had reduced excitability and gain. The development of PNNs around somata of fast-spiking neurons may be essential for fast and precise sensory transmission and synaptic inhibition in the brain. PMID:27570824

  2. Dopamine modulation of GABAergic function enables network stability and input selectivity for sustaining working memory in a computational model of the prefrontal cortex.

    PubMed

    Lew, Sergio E; Tseng, Kuei Y

    2014-12-01

    Dopamine modulation of GABAergic transmission in the prefrontal cortex (PFC) is thought to be critical for sustaining cognitive processes such as working memory and decision-making. Here, we developed a neurocomputational model of the PFC that includes physiological features of the facilitatory action of dopamine on fast-spiking interneurons to assess how a GABAergic dysregulation impacts on the prefrontal network stability and working memory. We found that a particular non-linear relationship between dopamine transmission and GABA function is required to enable input selectivity in the PFC for the formation and retention of working memory. Either degradation of the dopamine signal or the GABAergic function is sufficient to elicit hyperexcitability in pyramidal neurons and working memory impairments. The simulations also revealed an inverted U-shape relationship between working memory and dopamine, a function that is maintained even at high levels of GABA degradation. In fact, the working memory deficits resulting from reduced GABAergic transmission can be rescued by increasing dopamine tone and vice versa. We also examined the role of this dopamine-GABA interaction for the termination of working memory and found that the extent of GABAergic excitation needed to reset the PFC network begins to occur when the activity of fast-spiking interneurons surpasses 40 Hz. Together, these results indicate that the capability of the PFC to sustain working memory and network stability depends on a robust interplay of compensatory mechanisms between dopamine tone and the activity of local GABAergic interneurons.

  3. Dopamine Modulation of GABAergic Function Enables Network Stability and Input Selectivity for Sustaining Working Memory in a Computational Model of the Prefrontal Cortex

    PubMed Central

    Lew, Sergio E; Tseng, Kuei Y

    2014-01-01

    Dopamine modulation of GABAergic transmission in the prefrontal cortex (PFC) is thought to be critical for sustaining cognitive processes such as working memory and decision-making. Here, we developed a neurocomputational model of the PFC that includes physiological features of the facilitatory action of dopamine on fast-spiking interneurons to assess how a GABAergic dysregulation impacts on the prefrontal network stability and working memory. We found that a particular non-linear relationship between dopamine transmission and GABA function is required to enable input selectivity in the PFC for the formation and retention of working memory. Either degradation of the dopamine signal or the GABAergic function is sufficient to elicit hyperexcitability in pyramidal neurons and working memory impairments. The simulations also revealed an inverted U-shape relationship between working memory and dopamine, a function that is maintained even at high levels of GABA degradation. In fact, the working memory deficits resulting from reduced GABAergic transmission can be rescued by increasing dopamine tone and vice versa. We also examined the role of this dopamine–GABA interaction for the termination of working memory and found that the extent of GABAergic excitation needed to reset the PFC network begins to occur when the activity of fast-spiking interneurons surpasses 40 Hz. Together, these results indicate that the capability of the PFC to sustain working memory and network stability depends on a robust interplay of compensatory mechanisms between dopamine tone and the activity of local GABAergic interneurons. PMID:24975022

  4. Repeated cocaine exposure increases fast-spiking interneuron excitability in the rat medial prefrontal cortex.

    PubMed

    Campanac, Emilie; Hoffman, Dax A

    2013-06-01

    The medial prefrontal cortex plays a key role in cocaine addiction. However, how chronic cocaine exposure affects cortical networks remains unclear. Most studies have focused on layer 5 pyramidal neurons (the circuit output), while the response of local GABAergic interneurons to cocaine remains poorly understood. Here, we recorded from fast-spiking interneurons (FS-IN) after repeated cocaine exposure and found altered membrane excitability. After cocaine withdrawal, FS-IN showed an increase in the number of spikes evoked by positive current injection, increased input resistance, and decreased hyperpolarization-activated current. We also observed a reduction in miniature excitatory postsynaptic currents, whereas miniature inhibitory postsynaptic current activity was unaffected. We show that, in animals with cocaine history, dopamine receptor D(2) activation is less effective in increasing FS-IN intrinsic excitability. Interestingly, these alterations are only observed 1 wk or more after the last cocaine exposure. This suggests that the dampening of D(2)-receptor-mediated response may be a compensatory mechanism to rein down the excitability of FS-IN.

  5. Repeated cocaine exposure increases fast-spiking interneuron excitability in the rat medial prefrontal cortex

    PubMed Central

    Hoffman, Dax A.

    2013-01-01

    The medial prefrontal cortex plays a key role in cocaine addiction. However, how chronic cocaine exposure affects cortical networks remains unclear. Most studies have focused on layer 5 pyramidal neurons (the circuit output), while the response of local GABAergic interneurons to cocaine remains poorly understood. Here, we recorded from fast-spiking interneurons (FS-IN) after repeated cocaine exposure and found altered membrane excitability. After cocaine withdrawal, FS-IN showed an increase in the number of spikes evoked by positive current injection, increased input resistance, and decreased hyperpolarization-activated current. We also observed a reduction in miniature excitatory postsynaptic currents, whereas miniature inhibitory postsynaptic current activity was unaffected. We show that, in animals with cocaine history, dopamine receptor D2 activation is less effective in increasing FS-IN intrinsic excitability. Interestingly, these alterations are only observed 1 wk or more after the last cocaine exposure. This suggests that the dampening of D2-receptor-mediated response may be a compensatory mechanism to rein down the excitability of FS-IN. PMID:23486201

  6. Functional diversity of supragranular GABAergic neurons in the barrel cortex

    PubMed Central

    Gentet, Luc J.

    2012-01-01

    Although the neocortex forms a distributed system comprised of several functional areas, its vertical columnar organization is largely conserved across areas and species, suggesting the existence of a canonical neocortical microcircuit. In order to elucidate the principles governing the organization of such a cortical diagram, a detailed understanding of the dynamics binding different types of cortical neurons into a coherent algorithm is essential. Within this complex circuitry, GABAergic interneurons, while forming approximately only 15–20% of all cortical neurons, appear critical in maintaining a dynamic balance between excitation and inhibition. Despite their importance, cortical GABAergic neurons have not been extensively studied in vivo and their precise role in shaping the local microcircuit sensory response still remains to be determined. Their paucity, combined with their molecular, anatomical, and physiological diversity, has made it difficult to even establish a consensual nomenclature. However, recent technological advances in microscopy and mouse genetics have fostered a renewed interest in neocortical interneurons by putting them within “visible” reach of experimenters. The anatomically well-defined whisker-to-barrel pathway of the rodent is particularly amenable to studies attempting to link cortical circuit dynamics to behavior. To each whisker corresponds a discrete cortical unit equivalent to a single column, specialized in the encoding and processing of the sensory information it receives. In this review, we will focus on the functional role that each subtype of supragranular GABAergic neuron embedded within such a single neocortical unit may play in shaping the dynamics of the local circuit during somatosensory integration. PMID:22912602

  7. Identified Cellular Correlates of Neocortical Ripple and High-Gamma Oscillations during Spindles of Natural Sleep.

    PubMed

    Averkin, Robert G; Szemenyei, Viktor; Bordé, Sándor; Tamás, Gábor

    2016-11-23

    Ultra-high-frequency network events in the hippocampus are instrumental in a dialogue with the neocortex during memory formation, but the existence of transient ∼200 Hz network events in the neocortex is not clear. Our recordings from neocortical layer II/III of freely behaving rats revealed field potential events at ripple and high-gamma frequencies repeatedly occurring at troughs of spindle oscillations during sleep. Juxtacellular recordings identified subpopulations of fast-spiking, parvalbumin-containing basket cells with epochs of firing at ripple (∼200 Hz) and high-gamma (∼120 Hz) frequencies detected during spindles and centered with millisecond precision at the trough of spindle waves in phase with field potential events but phase shifted relative to pyramidal cell firing. The results suggest that basket cell subpopulations are involved in spindle-nested, high-frequency network events that hypothetically provide repeatedly occurring neocortical temporal reference states potentially involved in mnemonic processes.

  8. Revisiting the Lamotrigine-Mediated Effect on Hippocampal GABAergic Transmission

    PubMed Central

    Huang, Yu-Yin; Liu, Yu-Chao; Lee, Cheng-Ta; Lin, Yen-Chu; Wang, Mong-Lien; Yang, Yi-Ping; Chang, Kaung-Yi; Chiou, Shih-Hwa

    2016-01-01

    Lamotrigine (LTG) is generally considered as a voltage-gated sodium (Nav) channel blocker. However, recent studies suggest that LTG can also serve as a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel enhancer and can increase the excitability of GABAergic interneurons (INs). Perisomatic inhibitory INs, predominantly fast-spiking basket cells (BCs), powerfully inhibit granule cells (GCs) in the hippocampal dentate gyrus. Notably, BCs express abundant Nav channels and HCN channels, both of which are able to support sustained action potential generation. Using whole-cell recording in rat hippocampal slices, we investigated the net LTG effect on BC output. We showed that bath application of LTG significantly decreased the amplitude of evoked compound inhibitory postsynaptic currents (IPSCs) in GCs. In contrast, simultaneous paired recordings from BCs to GCs showed that LTG had no effect on both the amplitude and the paired-pulse ratio of the unitary IPSCs, suggesting that LTG did not affect GABA release, though it suppressed cell excitability. In line with this, LTG decreased spontaneous IPSC (sIPSC) frequency, but not miniature IPSC frequency. When re-examining the LTG effect on GABAergic transmission in the cornus ammonis region 1 (CA1) area, we found that LTG markedly inhibits both the excitability of dendrite-targeting INs in the stratum oriens and the concurrent sIPSCs recorded on their targeting pyramidal cells (PCs) without significant hyperpolarization-activated current (Ih) enhancement. In summary, LTG has no effect on augmenting Ih in GABAergic INs and does not promote GABAergic inhibitory output. The antiepileptic effect of LTG is likely through Nav channel inhibition and the suppression of global neuronal network activity. PMID:27455251

  9. GABAergic Neuron-Specific Loss of Ube3a Causes Angelman Syndrome-Like EEG Abnormalities and Enhances Seizure Susceptibility.

    PubMed

    Judson, Matthew C; Wallace, Michael L; Sidorov, Michael S; Burette, Alain C; Gu, Bin; van Woerden, Geeske M; King, Ian F; Han, Ji Eun; Zylka, Mark J; Elgersma, Ype; Weinberg, Richard J; Philpot, Benjamin D

    2016-04-06

    Loss of maternal UBE3A causes Angelman syndrome (AS), a neurodevelopmental disorder associated with severe epilepsy. We previously implicated GABAergic deficits onto layer (L) 2/3 pyramidal neurons in the pathogenesis of neocortical hyperexcitability, and perhaps epilepsy, in AS model mice. Here we investigate consequences of selective Ube3a loss from either GABAergic or glutamatergic neurons, focusing on the development of hyperexcitability within L2/3 neocortex and in broader circuit and behavioral contexts. We find that GABAergic Ube3a loss causes AS-like increases in neocortical EEG delta power, enhances seizure susceptibility, and leads to presynaptic accumulation of clathrin-coated vesicles (CCVs)-all without decreasing GABAergic inhibition onto L2/3 pyramidal neurons. Conversely, glutamatergic Ube3a loss fails to yield EEG abnormalities, seizures, or associated CCV phenotypes, despite impairing tonic inhibition onto L2/3 pyramidal neurons. These results substantiate GABAergic Ube3a loss as the principal cause of circuit hyperexcitability in AS mice, lending insight into ictogenic mechanisms in AS.

  10. Glutamatergic Nonpyramidal Neurons From Neocortical Layer VI and Their Comparison With Pyramidal and Spiny Stellate Neurons

    PubMed Central

    Andjelic, Sofija; Gallopin, Thierry; Cauli, Bruno; Hill, Elisa L.; Roux, Lisa; Badr, Sammy; Hu, Emilie; Tamás, Gábor; Lambolez, Bertrand

    2009-01-01

    The deeper part of neocortical layer VI is dominated by nonpyramidal neurons, which lack a prominent vertically ascending dendrite and predominantly establish corticocortical connections. These neurons were studied in rat neocortical slices using patch-clamp, single-cell reverse transcription–polymerase chain reaction, and biocytin labeling. The majority of these neurons expressed the vesicular glutamate transporter but not glutamic acid decarboxylase, suggesting that a high proportion of layer VI nonpyramidal neurons are glutamatergic. Indeed, they exhibited numerous dendritic spines and established asymmetrical synapses. Our sample of glutamatergic nonpyramidal neurons displayed a wide variety of somatodendritic morphologies and a subset of these cells expressed the Nurr1 mRNA, a marker for ipsilateral, but not commissural corticocortical projection neurons in layer VI. Comparison with spiny stellate and pyramidal neurons from other layers showed that glutamatergic neurons consistently exhibited a low occurrence of GABAergic interneuron markers and regular spiking firing patterns. Analysis of electrophysiological diversity using unsupervised clustering disclosed three groups of cells. Layer V pyramidal neurons were segregated into a first group, whereas a second group consisted of a subpopulation of layer VI neurons exhibiting tonic firing. A third heterogeneous cluster comprised spiny stellate, layer II/III pyramidal, and layer VI neurons exhibiting adaptive firing. The segregation of layer VI neurons in two different clusters did not correlate either with their somatodendritic morphologies or with Nurr1 expression. Our results suggest that electrophysiological similarities between neocortical glutamatergic neurons extend beyond layer positioning, somatodendritic morphology, and projection specificity. PMID:19052106

  11. Glutamatergic nonpyramidal neurons from neocortical layer VI and their comparison with pyramidal and spiny stellate neurons.

    PubMed

    Andjelic, Sofija; Gallopin, Thierry; Cauli, Bruno; Hill, Elisa L; Roux, Lisa; Badr, Sammy; Hu, Emilie; Tamás, Gábor; Lambolez, Bertrand

    2009-02-01

    The deeper part of neocortical layer VI is dominated by nonpyramidal neurons, which lack a prominent vertically ascending dendrite and predominantly establish corticocortical connections. These neurons were studied in rat neocortical slices using patch-clamp, single-cell reverse transcription-polymerase chain reaction, and biocytin labeling. The majority of these neurons expressed the vesicular glutamate transporter but not glutamic acid decarboxylase, suggesting that a high proportion of layer VI nonpyramidal neurons are glutamatergic. Indeed, they exhibited numerous dendritic spines and established asymmetrical synapses. Our sample of glutamatergic nonpyramidal neurons displayed a wide variety of somatodendritic morphologies and a subset of these cells expressed the Nurr1 mRNA, a marker for ipsilateral, but not commissural corticocortical projection neurons in layer VI. Comparison with spiny stellate and pyramidal neurons from other layers showed that glutamatergic neurons consistently exhibited a low occurrence of GABAergic interneuron markers and regular spiking firing patterns. Analysis of electrophysiological diversity using unsupervised clustering disclosed three groups of cells. Layer V pyramidal neurons were segregated into a first group, whereas a second group consisted of a subpopulation of layer VI neurons exhibiting tonic firing. A third heterogeneous cluster comprised spiny stellate, layer II/III pyramidal, and layer VI neurons exhibiting adaptive firing. The segregation of layer VI neurons in two different clusters did not correlate either with their somatodendritic morphologies or with Nurr1 expression. Our results suggest that electrophysiological similarities between neocortical glutamatergic neurons extend beyond layer positioning, somatodendritic morphology, and projection specificity.

  12. 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

  13. GABAergic projections from the medial septum selectively inhibit interneurons in the medial entorhinal cortex.

    PubMed

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

    2014-12-10

    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.

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

    PubMed

    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.

  15. Quantifying noise-induced stability of a cortical fast-spiking cell model with Kv3-channel-like current.

    PubMed

    Tateno, T; Robinson, H P C

    2007-01-01

    Population oscillations in neural activity in the gamma (>30 Hz) and higher frequency ranges are found over wide areas of the mammalian cortex. Recently, in the somatosensory cortex, the details of neural connections formed by several types of GABAergic interneurons have become apparent, and they are believed to play a significant role in generating these oscillations through synaptic and gap-junctional interactions. However, little is known about the mechanism of how such oscillations are maintained stably by particular interneurons and by their local networks, in a noisy environment with abundant synaptic inputs. To obtain more insight into this, we studied a fast-spiking (FS)-cell model including Kv3-channel-like current, which is a distinctive feature of these cells, from the viewpoint of nonlinear dynamical systems. To examine the specific role of the Kv3-channel in determining oscillation properties, we analyzed basic properties of the FS-cell model, such as the bifurcation structure and phase resetting curves (PRCs). Furthermore, to quantitatively characterize the oscillation stability under noisy fluctuations mimicking small fast synaptic inputs, we applied a recently developed method from random dynamical system theory to estimate Lyapunov exponents, both for the original four-dimensional dynamics and for a reduced one-dimensional phase-equation on the circle. The results indicated that the presence of the Kv3-channel-like current helps to regulate the stability of noisy neural oscillations and a transient-period length to stochastic attractors.

  16. Brain-derived neurotrophic factor mediates activity-dependent dendritic growth in nonpyramidal neocortical interneurons in developing organotypic cultures.

    PubMed

    Jin, Xiaoming; Hu, Hang; Mathers, Peter H; Agmon, Ariel

    2003-07-02

    Brain-derived neurotrophic factor (BDNF) promotes postnatal maturation of GABAergic inhibition in the cerebral and cerebellar cortices, and its expression and release are enhanced by neuronal activity, suggesting that it acts in a feedback manner to maintain a balance between excitation and inhibition during development. BDNF promotes differentiation of cerebellar, hippocampal, and neostriatal inhibitory neurons, but its effects on the dendritic development of neocortical inhibitory interneurons remain unknown. Here, we show that BDNF mediates depolarization-induced dendritic growth and branching in neocortical interneurons. To visualize inhibitory interneurons, we biolistically transfected organotypic cortical slice cultures from neonatal mice with green fluorescent protein (GFP) driven by the glutamic acid decarboxylase (GAD)67 promoter. Nearly all GAD67-GFP-expressing neurons were nonpyramidal, many contained GABA, and some expressed markers of neurochemically defined GABAergic subtypes, indicating that GAD67-GFP-expressing neurons were GABAergic. We traced dendritic trees from confocal images of the same GAD67-GFP-expressing neurons before and after a 5 d growth period, and quantified the change in total dendritic length (TDL) and total dendritic branch points (TDBPs) for each neuron. GAD67-GFP-expressing neurons growing in control medium exhibited a 20% increase in TDL, but in 200 ng/ml BDNF or 10 mm KCl, this increase nearly doubled and was accompanied by a significant increase in TDBPs. Blocking action potentials with TTX did not prevent the BDNF-induced growth, but antibodies against BDNF blocked the growth-promoting effect of KCl. We conclude that BDNF, released by neocortical pyramidal neurons in response to depolarization, enhances dendritic growth and branching in nearby inhibitory interneurons.

  17. Functional properties and short-term dynamics of unidirectional and reciprocal synaptic connections between layer 2/3 pyramidal cells and fast-spiking interneurons in juvenile rat prefrontal cortex.

    PubMed

    Zaitsev, A V; Lewis, D A

    2013-10-01

    The interactions between inhibitory fast-spiking (FS) interneurons and excitatory pyramidal neurons contribute to the fundamental properties of cortical networks. An important role for FS interneurons in mediating rapid inhibition in local sensory and motor cortex microcircuits and processing thalamic inputs to the cortex has been shown in multiple reports; however, studies in the prefrontal cortex, a key neocortical region supporting working memory, are less numerous. In the present work, connections between layer 2/3 pyramidal cells and FS interneurons were studied with paired whole-cell recordings in acute neocortical slices of the medial prefrontal cortex from juvenile rats. The connection rate between FS interneurons and pyramidal neurons was about 40% in each direction with 16% of pairs connected reciprocally. Excitatory and inhibitory connections had a high efficacy and a low neurotransmission failure rate. Sustained presynaptic activity decreased the amplitude of responses and increased the failure rate more in excitatory connections than in inhibitory connections. In the reciprocal connections between the FS and pyramidal neurons, inhibitory and excitatory neurotransmission was more efficient and had a lower failure rate than in the unidirectional connections; the differences increased during the train stimulation. These results suggest the presence of distinct preferential subnetworks between FS interneurons and pyramidal cells in the rat prefrontal cortex that might be specific for this cortical area.

  18. Several posttranslational modifications act in concert to regulate gephyrin scaffolding and GABAergic transmission

    PubMed Central

    Ghosh, Himanish; Auguadri, Luca; Battaglia, Sereina; Simone Thirouin, Zahra; Zemoura, Khaled; Messner, Simon; Acuña, Mario A.; Wildner, Hendrik; Yévenes, Gonzalo E.; Dieter, Andrea; Kawasaki, Hiroshi; O. Hottiger, Michael; Zeilhofer, Hanns Ulrich; Fritschy, Jean-Marc; Tyagarajan, Shiva K.

    2016-01-01

    GABAA receptors (GABAARs) mediate the majority of fast inhibitory neurotransmission in the brain via synergistic association with the postsynaptic scaffolding protein gephyrin and its interaction partners. However, unlike their counterparts at glutamatergic synapses, gephyrin and its binding partners lack canonical protein interaction motifs; hence, the molecular basis for gephyrin scaffolding has remained unclear. In this study, we identify and characterize two new posttranslational modifications of gephyrin, SUMOylation and acetylation. We demonstrate that crosstalk between SUMOylation, acetylation and phosphorylation pathways regulates gephyrin scaffolding. Pharmacological intervention of SUMO pathway or transgenic expression of SUMOylation-deficient gephyrin variants rescued gephyrin clustering in CA1 or neocortical neurons of Gabra2-null mice, which otherwise lack gephyrin clusters, indicating that gephyrin SUMO modification is an essential determinant for scaffolding at GABAergic synapses. Together, our results demonstrate that concerted modifications on a protein scaffold by evolutionarily conserved yet functionally diverse signalling pathways facilitate GABAergic transmission. PMID:27819299

  19. Strength and duration of perisomatic GABAergic inhibition depend on distance between synaptically connected cells

    PubMed Central

    Strüber, Michael; Jonas, Peter; Bartos, Marlene

    2015-01-01

    GABAergic perisoma-inhibiting fast-spiking interneurons (PIIs) effectively control the activity of large neuron populations by their wide axonal arborizations. It is generally assumed that the output of one PII to its target cells is strong and rapid. Here, we show that, unexpectedly, both strength and time course of PII-mediated perisomatic inhibition change with distance between synaptically connected partners in the rodent hippocampus. Synaptic signals become weaker due to lower contact numbers and decay more slowly with distance, very likely resulting from changes in GABAA receptor subunit composition. When distance-dependent synaptic inhibition is introduced to a rhythmically active neuronal network model, randomly driven principal cell assemblies are strongly synchronized by the PIIs, leading to higher precision in principal cell spike times than in a network with uniform synaptic inhibition. PMID:25583495

  20. Dense, unspecific connectivity of neocortical parvalbumin-positive interneurons: a canonical microcircuit for inhibition?

    PubMed

    Packer, Adam M; Yuste, Rafael

    2011-09-14

    GABAergic interneurons play a major role in the function of the mammalian neocortex, but their circuit connectivity is still poorly understood. We used two-photon RuBi-Glutamate uncaging to optically map how the largest population of cortical interneurons, the parvalbumin-positive cells (PV+), are connected to pyramidal cells (PCs) in mouse neocortex. We found locally dense connectivity from PV+ interneurons onto PCs across cortical areas and layers. In many experiments, all nearby PV+ cells were connected to every local PC sampled. In agreement with this, we found no evidence for connection specificity, as PV+ interneurons contacted PC pairs similarly regardless of whether they were synaptically connected or not. We conclude that the microcircuit architecture for PV+ interneurons, and probably neocortical inhibition in general, is an unspecific, densely homogenous matrix covering all nearby pyramidal cells.

  1. Taurine activates GABAergic networks in the neocortex of immature mice

    PubMed Central

    Sava, Bogdan A.; Chen, Rongqing; Sun, Haiyan; Luhmann, Heiko J.; Kilb, Werner

    2014-01-01

    Although it has been suggested that taurine is the main endogenous neurotransmitter acting on glycine receptors, the implications of glycine receptor-mediated taurine actions on immature neocortical networks have not been addressed yet. To investigate the influence of taurine on the excitability of neuronal networks in the immature neocortex, we performed whole-cell patch-clamp recordings from visually identified pyramidal neurons and interneurons in coronal slices from C57Bl/6 and GAD67-green fluorescent protein (GFP) transgenic mice (postnatal days 2–4). In 46% of the pyramidal neurons bath-application of taurine at concentrations ≥ 300 μM significantly enhanced the frequency of postsynaptic currents (PSCs) by 744.3 ± 93.8% (n = 120 cells). This taurine-induced increase of PSC frequency was abolished by 0.2 μM tetrodotoxin (TTX), 1 μM strychnine or 3 μM gabazine, but was unaffected by the glutamatergic antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and (±) R(-)-3-(2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid (CPP), suggesting that taurine specifically activates GABAergic network activity projecting to pyramidal neurons. Cell-attached recordings revealed that taurine enhanced the frequency of action potentials (APs) in pyramidal neurons, indicating an excitatory action of the GABAergic PSCs. In order to identify the presynaptic targets of taurine we demonstrate that bath application of taurine induced in GAD67-GFP labeled interneurons an inward current that is mainly mediated by glycine receptors and can generate APs in these cells. We conclude from these results that taurine can enhance network excitability in the immature neocortex by selectively activating GABAergic interneurons via interactions with glycine receptors. PMID:24550782

  2. GABA-A receptors regulate neocortical neuronal migration in vitro and in vivo.

    PubMed

    Heck, Nicolas; Kilb, Werner; Reiprich, Petra; Kubota, Hisahiko; Furukawa, Tomonori; Fukuda, Atsuo; Luhmann, Heiko J

    2007-01-01

    The cortical migration process depends on a number of trophic factors and on the activation of different voltage- and ligand-gated channels. We investigated the role of gamma-aminobutyric acid (GABA) type A receptors in the neuronal migration process of the newborn rat parietal cortex in vivo and in vitro. Local in vivo application of the GABA-A antagonist bicuculline methiodide (BMI) or the agonist muscimol via cortical surface Elvax implants induced prominent alterations in the cortical architecture when compared with untreated or sham-operated controls. BMI- and muscimol-treated animals revealed heterotopic cell clusters in the upper layers and a complete loss of the cortical lamination in the region underlying the Elvax implant. Immunocytochemical staining for glial fibrillary acidic protein, N-methyl-D-aspartate receptors, and GABA demonstrated that heterotopia was not provoked by glial proliferation and confirmed the presence of both glutamatergic and GABAergic neurons. In organotypic neocortical slices from embryonic day 18-19 embryos, application of BMI and to a lesser extent also muscimol induced an increase in the migration speed and an accumulation of neurons in the upper cortical layers. Spontaneous intracellular calcium ([Ca2+]i) oscillations in neocortical slices from newborn rats were abolished by BMI (5 and 20 microM) and muscimol (1 and 10 microM), indicating that both compounds interfere with [Ca2+]i signaling required for normal neuronal migration. Electrophysiological recordings from migrating neurons in newborn rat neocortical slices indicate that long-term application of muscimol causes a pronounced reduction (1 microM muscimol) or blockade (10 microM) in the responsiveness of postsynaptic GABA-A receptors due to a pronounced receptor desensitization. Our results indicate that modulation of GABA-A receptors by compounds acting as agonists or antagonists may profoundly influence the neuronal migration process in the developing cerebral cortex.

  3. GABAergic transmission in hepatic encephalopathy.

    PubMed

    Sergeeva, Olga A

    2013-08-15

    Hepatic encephalopathy (HE)(1) is a neuropsychiatric disorder caused by chronic or acute liver failure. Nearly thirty years ago a hypothesis was formulated explaining the neuropathology of HE by increased GABAergic tone. Recent progress in the GABAA-receptor (GABAAR) molecular pharmacology and biochemistry as well as the physiology of GABAergic transmission provided better understanding of GABA's role in health and disease. A detailed analysis of neuronal populations and their GABAergic afferents affected in HE is still missing. The slow progress in understanding the pathology of GABAergic transmission in HE is due to the high complexity of brain circuitries controlled by multiple types of GABAergic interneurons and the large variety of GABAAR, which are differently affected by pathological conditions and not yet fully identified. The mechanisms of action of the GABAAR agonist taurine, allosteric positive modulators (inhibitory neurosteroids, anaesthetics, benzodiazepines and histamine) and inhibitors of the GABAAR (excitatory neurosteroids, Ro15-4513) are discussed with respect to HE pathophysiology. Perspectives for GABAergic drugs in the symptomatic treatment of HE are suggested.

  4. 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

  5. Quantification of neocortical ratios in stem primates.

    PubMed

    Long, Adam; Bloch, Jonathan I; Silcox, Mary T

    2015-07-01

    Extant euprimates (=crown primates) have a characteristically expanded neocortical region of the brain relative to that of other mammals, but the timing of that expansion in their evolutionary history is poorly resolved. Examination of anatomical landmarks on fossil endocasts of Eocene euprimates suggests that significant neocortical expansion relative to contemporaneous mammals was already underway. Here, we provide quantitative estimates of neocorticalization in stem primates (plesiadapiforms) relevant to the question of whether relative neocortical expansion was uniquely characteristic of the crown primate radiation. Ratios of neocortex to endocast surface areas were calculated for plesiadapiforms using measurements from virtual endocasts of the paromomyid Ignacius graybullianus (early Eocene, Wyoming) and the microsyopid Microsyops annectens (middle Eocene, Wyoming). These data are similar to a published estimate for the plesiadapid, Plesiadapis tricuspidens, but contrast with those calculated for early Tertiary euprimates in being within the 95% confidence intervals for archaic mammals generally. Interpretation of these values is complicated by the paucity of sampled endocasts for older stem primates and euarchontogliran outgroups, as well as by a combination of effects related to temporal trends, allometry, and taxon-unique specializations. Regardless, these results are consistent with the hypothesis that a shift in brain organization occurred in the first euprimates, likely in association with elaborations to the visual system.

  6. Distinct Defects in Synaptic Differentiation of Neocortical Neurons in Response to Prenatal Valproate Exposure

    PubMed Central

    Iijima, Yoko; Behr, Katharina; Iijima, Takatoshi; Biemans, Barbara; Bischofberger, Josef; Scheiffele, Peter

    2016-01-01

    Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders characterized by impairments in social interactions and stereotyped behaviors. Valproic acid (VPA) is frequently used to treat epilepsy and bipolar disorders. When taken during pregnancy, VPA increases the risk of the unborn child to develop an ASD. In rodents, in utero VPA exposure can precipitate behavioral phenotypes related to ASD in the offspring. Therefore, such rodent models may allow for identification of synaptic pathophysiology underlying ASD risk. Here, we systematically probed alterations in synaptic proteins that might contribute to autism-related behavior in the offspring of in utero VPA-exposed mice. Moreover, we tested whether direct VPA exposure of cultured neocortical neurons may recapitulate the molecular alterations seen in vivo. VPA-exposed neurons in culture exhibit a significant increase in the number of glutamatergic synapses accompanied by a significant decrease in the number of GABAergic synapses. This shift in excitatory/inhibitory balance results in substantially increased spontaneous activity in neuronal networks arising from VPA-exposed neurons. Pharmacological experiments demonstrate that the alterations in GABAergic and glutamatergic synaptic proteins and structures are largely caused by inhibition of histone deacetylases. Therefore, our study highlights an epigenetic mechanism underlying the synaptic pathophysiology in this ASD model. PMID:27264355

  7. The Progenitor Zone of the Ventral MGE Requires Nkx2-1 to Generate Most of the Globus Pallidus but Few Neocortical Interneurons

    PubMed Central

    Flandin, Pierre; Kimura, Shioko; Rubenstein, John L. R.

    2010-01-01

    We show that most globus pallidus neurons, but very few neocortical interneurons, are generated from the ventral MGE and dorsal POA based on fate mapping using a Shh-Cre allele. The Shh-expressing subpallial lineage produces parvalbumin+ GABAergic neurons, ChAT+ cholinergic neurons, and oligodendrocytes. Loss of Nkx2-1 function from the Shh-expressing domain eliminated most globus pallidus neurons, whereas most cortical and striatal interneurons continued to be generated, except for striatal cholinergic neurons. Finally, our analysis provided evidence for a novel cellular component (Nkx2-1−;Npas1+) of the globus pallidus. PMID:20181579

  8. Hypocretin (orexin) regulates glutamate input to fast-spiking interneurons in layer V of the Fr2 region of the murine prefrontal cortex.

    PubMed

    Aracri, Patrizia; Banfi, Daniele; Pasini, Maria Enrica; Amadeo, Alida; Becchetti, Andrea

    2015-05-01

    We studied the effect of hypocretin 1 (orexin A) in the frontal area 2 (Fr2) of the murine neocortex, implicated in the motivation-dependent goal-directed tasks. In layer V, hypocretin stimulated the spontaneous excitatory postsynaptic currents (EPSCs) on fast-spiking (FS) interneurons. The effect was accompanied by increased frequency of miniature EPSCs, indicating that hypocretin can target the glutamatergic terminals. Moreover, hypocretin stimulated the spontaneous inhibitory postsynaptic currents (IPSCs) on pyramidal neurons, with no effect on miniature IPSCs. This action was prevented by blocking 1) the ionotropic glutamatergic receptors; 2) the hypocretin receptor type 1 (HCRTR-1), with SB-334867. Finally, hypocretin increased the firing frequency in FS cells, and the effect was blocked when the ionotropic glutamate transmission was inhibited. Immunolocalization confirmed that HCRTR-1 is highly expressed in Fr2, particularly in layer V-VI. Conspicuous labeling was observed in pyramidal neuron somata and in VGLUT1+ glutamatergic terminals, but not in VGLUT2+ fibers (mainly thalamocortical afferents). The expression of HCRTR-1 in GABAergic structures was scarce. We conclude that 1) hypocretin regulates glutamate release in Fr2; 2) the effect presents a presynaptic component; 3) the peptide control of FS cells is indirect, and probably mediated by the regulation of glutamatergic input onto these cells.

  9. Hypocretin (Orexin) Regulates Glutamate Input to Fast-Spiking Interneurons in Layer V of the Fr2 Region of the Murine Prefrontal Cortex

    PubMed Central

    Aracri, Patrizia; Banfi, Daniele; Pasini, Maria Enrica; Amadeo, Alida; Becchetti, Andrea

    2015-01-01

    We studied the effect of hypocretin 1 (orexin A) in the frontal area 2 (Fr2) of the murine neocortex, implicated in the motivation-dependent goal-directed tasks. In layer V, hypocretin stimulated the spontaneous excitatory postsynaptic currents (EPSCs) on fast-spiking (FS) interneurons. The effect was accompanied by increased frequency of miniature EPSCs, indicating that hypocretin can target the glutamatergic terminals. Moreover, hypocretin stimulated the spontaneous inhibitory postsynaptic currents (IPSCs) on pyramidal neurons, with no effect on miniature IPSCs. This action was prevented by blocking 1) the ionotropic glutamatergic receptors; 2) the hypocretin receptor type 1 (HCRTR-1), with SB-334867. Finally, hypocretin increased the firing frequency in FS cells, and the effect was blocked when the ionotropic glutamate transmission was inhibited. Immunolocalization confirmed that HCRTR-1 is highly expressed in Fr2, particularly in layer V–VI. Conspicuous labeling was observed in pyramidal neuron somata and in VGLUT1+ glutamatergic terminals, but not in VGLUT2+ fibers (mainly thalamocortical afferents). The expression of HCRTR-1 in GABAergic structures was scarce. We conclude that 1) hypocretin regulates glutamate release in Fr2; 2) the effect presents a presynaptic component; 3) the peptide control of FS cells is indirect, and probably mediated by the regulation of glutamatergic input onto these cells. PMID:24297328

  10. Selective suppression of excitatory synapses on GABAergic interneurons by norepinephrine in juvenile rat prefrontal cortical microcircuitry.

    PubMed

    Wang, H-X; Waterhouse, B D; Gao, W-J

    2013-08-29

    The noradrenergic system of the brain is thought to facilitate neuronal processes that promote behavioral activation, alertness, and attention. It is known that norepinephrine (NE) can be significantly elevated in the prefrontal cortex under normal conditions such as arousal and attention, and following the administration of psychostimulants and various other drugs prescribed for psychiatric disorders. However, how NE modulates neuronal activity and synapses in the local prefrontal circuitry remains elusive. In this study, we characterized the actions of NE on individual monosynaptic connections among layer V pyramidal neurons (P) and fast-spiking (FS) GABAergic interneurons in the juvenile (postnatal days 20-23) rat prefrontal local circuitry. We found that NE selectively depresses excitatory synaptic transmission in P-FS connections but has no detectable effect on the excitatory synapses in P-P connections and the inhibitory synapses in FS-P connections. NE apparently exerts distinctly different modulatory actions on identified synapses that target GABAergic interneurons but has no effect on those in the pyramidal neurons in this specific developmental period. These results indicate that, depending on the postsynaptic targets, the effects of NE in prefrontal cortex are synapse-specific, at least in the juvenile animals.

  11. High-Frequency Oscillations and Seizure Generation in Neocortical Epilepsy

    ERIC Educational Resources Information Center

    Worrell, Greg A.; Parish, Landi; Cranstoun, Stephen D.; Jonas, Rachel; Baltuch, Gordon; Litt, Brian

    2004-01-01

    Neocortical seizures are often poorly localized, explosive and widespread at onset, making them poorly amenable to epilepsy surgery in the absence of associated focal brain lesions. We describe, for the first time in an unselected group of patients with neocortical epilepsy, the finding that high-frequency (60--100 Hz) epileptiform oscillations…

  12. EXTRACELLULAR Ca2+ FLUCTUATIONS IN VIVO AFFECT AFTERHYPERPOLARIZATION POTENTIAL AND MODIFY FIRING PATTERNS OF NEOCORTICAL NEURONS

    PubMed Central

    Sofiane, Boucetta; Sylvain, Crochet; Sylvain, Chauvette; Josée, Seigneur; Igor, Timofeev

    2012-01-01

    Neocortical neurons can be classified in four major electrophysiological types according to their pattern of discharge: Regular-Spiking (RS), Intrinsically-Bursting (IB), Fast-Rhythmic-Bursting (FRB), and Fast-Spiking (FS). Previously, we have shown that these firing patterns are not fixed and can change as a function of membrane potential and states of vigilance. Other studies have reported that extracellular calcium concentration ([Ca2+]o) fluctuates as a function of the phase of the cortical slow oscillation. In the present study we investigated how spontaneous and induced changes in [Ca2+]o affect the properties of action potentials (APs) and firing patterns in cortical neurons in vivo. Intracellular recordings were performed in cats anesthetized with ketamine-xylazine during spontaneous [Ca2+]o fluctuation and while changing [Ca2+]o with reverse microdialysis. When [Ca2+]o fluctuated spontaneously according to the phase of the slow oscillation, we found an increase of the firing threshold and a decrease of the afterhyperpolarization (AHP) amplitude during the depolarizing (active, up) phase of the slow oscillation and some neurons also changed their firing pattern as compared with the hyperpolarizing (silent, down) phase. Induced changes in [Ca2+]o significantly affected the AP properties in all neurons. The AHP amplitude was increased in high calcium conditions and decreased in low calcium conditions, in particular the earliest components. Modulation of spike AHP resulted in notable modulation of intrinsic firing pattern and some RS neurons revealed burst firing when [Ca2+]o was decreased. We also found an increase in AHP amplitude in high [Ca2+]o with in vitro preparation. We suggest that during spontaneous network oscillations in vivo, the dynamic changes of firing patterns depend partially on fluctuations of the [Ca2+]o. PMID:23262121

  13. Independent controls for neocortical neuron production and histogenetic cell death

    NASA Technical Reports Server (NTRS)

    Verney, C.; Takahashi, T.; Bhide, P. G.; Nowakowski, R. S.; Caviness, V. S. Jr

    2000-01-01

    We estimated the proportion of cells eliminated by histogenetic cell death during the first 2 postnatal weeks in areas 1, 3 and 40 of the mouse parietal neocortex. For each layer and for the subcortical white matter in each neocortical area, the number of dying cells per mm(2) was calculated and the proportionate cell death for each day of the 2-week interval was estimated. The data show that cell death proceeds essentially uniformly across the neocortical areas and layers and that it does not follow either the spatiotemporal gradient of cell cycle progression in the pseudostratified ventricular epithelium of the cerebral wall, the source of neocortical neurons, or the 'inside-out' neocortical neuronogenetic sequence. Therefore, we infer that the control mechanisms of neocortical histogenetic cell death are independent of mechanisms controlling neuronogenesis or neuronal migration but may be associated with the ingrowth, expansion and a system-wide matching of neuronal connectivity. Copyright 2000 S. Karger AG, Basel.

  14. 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

  15. Cl− uptake promoting depolarizing GABA actions in immature rat neocortical neurones is mediated by NKCC1

    PubMed Central

    Yamada, Junko; Okabe, Akihito; Toyoda, Hiroki; Kilb, Werner; Luhmann, Heiko J; Fukuda, Atsuo

    2004-01-01

    GABA is the principal inhibitory neurotransmitter in the mature brain, but during early postnatal development the elevated [Cl−]i in immature neocortical neurones causes GABAA receptor activation to be depolarizing. The molecular mechanisms underlying this intracellular Cl− accumulation remain controversial. Therefore, the GABA reversal potential (EGABA) or [Cl−]i in early postnatal rat neocortical neurones was measured by the gramicidin-perforated patch-clamp method, and the relative expression levels of the cation−Cl− cotransporter mRNAs (in the same cells) were examined by semiquantitative single-cell multiplex RT-PCR to look for statistical correlations with [Cl−]i. The mRNA expression levels were positively (the Cl− accumulating Na+,K+−2Cl− cotransporter NKCC1) or negatively (the Cl− extruding K+−Cl− cotransporter KCC2) correlated with [Cl−]i. NKCC1 mRNA expression was high in early postnatal days, but decreased during postnatal development, whereas KCC2 mRNA expression displayed the opposite pattern. [Cl−]i and NKCC1 mRNA expression were each higher in cortical plate (CP) neurones than in the presumably older layer V/VI pyramidal neurones in a given slice. The pharmacological effects of bumetanide on EGABA were consistent with the different expression levels of NKCC1 mRNA. These data suggest that NKCC1 may play a pivotal role in the generation of GABA-mediated depolarization in immature CP cells, while KCC2 promotes the later maturation of GABAergic inhibition in the rat neocortex. PMID:15090604

  16. Regulation of Fast-Spiking Basket Cell Synapses by the Chloride Channel ClC–2

    PubMed Central

    Földy, Csaba; Lee, Sang-Hun; Morgan, Robert J.; Soltesz, Ivan

    2010-01-01

    Parvalbumin-expressing, fast-spiking basket cells play key roles in the generation of synchronous, rhythmic population activities in the hippocampus. Here we show that GABAA receptor-mediated synaptic inputs from murine parvalbumin-expressing basket cells are selectively modulated by the membrane voltage- and intracellular chloride-dependent chloride channel ClC–2. These data demonstrate a novel cell type-specific regulation of intracellular chloride homeostasis in the perisomatic region of hippocampal pyramidal neurons. PMID:20676104

  17. Oxytocin enhances hippocampal spike transmission by modulating fast-spiking interneurons.

    PubMed

    Owen, Scott F; Tuncdemir, Sebnem N; Bader, Patrick L; Tirko, Natasha N; Fishell, Gord; Tsien, Richard W

    2013-08-22

    Neuromodulatory control by oxytocin is essential to a wide range of social, parental and stress-related behaviours. Autism spectrum disorders (ASD) are associated with deficiencies in oxytocin levels and with genetic alterations of the oxytocin receptor (OXTR). Thirty years ago, Mühlethaler et al. found that oxytocin increases the firing of inhibitory hippocampal neurons, but it remains unclear how elevated inhibition could account for the ability of oxytocin to improve information processing in the brain. Here we describe in mammalian hippocampus a simple yet powerful mechanism by which oxytocin enhances cortical information transfer while simultaneously lowering background activity, thus greatly improving the signal-to-noise ratio. Increased fast-spiking interneuron activity not only suppresses spontaneous pyramidal cell firing, but also enhances the fidelity of spike transmission and sharpens spike timing. Use-dependent depression at the fast-spiking interneuron-pyramidal cell synapse is both necessary and sufficient for the enhanced spike throughput. We show the generality of this novel circuit mechanism by activation of fast-spiking interneurons with cholecystokinin or channelrhodopsin-2. This provides insight into how a diffusely delivered neuromodulator can improve the performance of neural circuitry that requires synapse specificity and millisecond precision.

  18. Reliability of Spike Timing in Neocortical Neurons

    NASA Astrophysics Data System (ADS)

    Mainen, Zachary F.; Sejnowski, Terrence J.

    1995-06-01

    It is not known whether the variability of neural activity in the cerebral cortex carries information or reflects noisy underlying mechanisms. In an examination of the reliability of spike generation using recordings from neurons in rat neocortical slices, the precision of spike timing was found to depend on stimulus transients. Constant stimuli led to imprecise spike trains, whereas stimuli with fluctuations resembling synaptic activity produced spike trains with timing reproducible to less than 1 millisecond. These data suggest a low intrinsic noise level in spike generation, which could allow cortical neurons to accurately transform synaptic input into spike sequences, supporting a possible role for spike timing in the processing of cortical information by the neocortex.

  19. Wilson-Cowan Equations for Neocortical Dynamics.

    PubMed

    Cowan, Jack D; Neuman, Jeremy; van Drongelen, Wim

    2016-12-01

    In 1972-1973 Wilson and Cowan introduced a mathematical model of the population dynamics of synaptically coupled excitatory and inhibitory neurons in the neocortex. The model dealt only with the mean numbers of activated and quiescent excitatory and inhibitory neurons, and said nothing about fluctuations and correlations of such activity. However, in 1997 Ohira and Cowan, and then in 2007-2009 Buice and Cowan introduced Markov models of such activity that included fluctuation and correlation effects. Here we show how both models can be used to provide a quantitative account of the population dynamics of neocortical activity.We first describe how the Markov models account for many recent measurements of the resting or spontaneous activity of the neocortex. In particular we show that the power spectrum of large-scale neocortical activity has a Brownian motion baseline, and that the statistical structure of the random bursts of spiking activity found near the resting state indicates that such a state can be represented as a percolation process on a random graph, called directed percolation.Other data indicate that resting cortex exhibits pair correlations between neighboring populations of cells, the amplitudes of which decay slowly with distance, whereas stimulated cortex exhibits pair correlations which decay rapidly with distance. Here we show how the Markov model can account for the behavior of the pair correlations.Finally we show how the 1972-1973 Wilson-Cowan equations can account for recent data which indicates that there are at least two distinct modes of cortical responses to stimuli. In mode 1 a low intensity stimulus triggers a wave that propagates at a velocity of about 0.3 m/s, with an amplitude that decays exponentially. In mode 2 a high intensity stimulus triggers a larger response that remains local and does not propagate to neighboring regions.

  20. Distribution and Intrinsic Membrane Properties of Basal Forebrain GABAergic and Parvalbumin Neurons in the Mouse

    PubMed Central

    McKenna, James T.; Yang, Chun; Franciosi, Serena; Winston, Stuart; Abarr, Kathleen K.; Rigby, Matthew S.; Yanagawa, Yuchio; McCarley, Robert W.; Brown, Ritchie E.

    2013-01-01

    The basal forebrain (BF) strongly regulates cortical activation, sleep homeostasis, and attention. Many BF neurons involved in these processes are GABAergic, including a subpopulation of projection neurons containing the calcium-binding protein, parvalbumin (PV). However, technical difficulties in identification have prevented a precise mapping of the distribution of GABAergic and GABA/PV+ neurons in the mouse or a determination of their intrinsic membrane properties. Here we used mice expressing fluorescent proteins in GABAergic (GAD67-GFP knock-in mice) or PV+ neurons (PV-Tomato mice) to study these neurons. Immunohistochemical staining for GABA in GAD67-GFP mice confirmed that GFP selectively labeled BF GABAergic neurons. GFP+ neurons and fibers were distributed throughout the BF, with the highest density in the magnocellular preoptic area (MCPO). Immunohistochemistry for PV indicated that the majority of PV+ neurons in the BF were large (>20 μm) or medium-sized (15–20 μm) GFP+ neurons. Most medium and large-sized BF GFP+ neurons, including those retrogradely labeled from the neocortex, were fast-firing and spontaneously active in vitro. They exhibited prominent hyperpolarization-activated inward currents and subthreshold “spikelets,” suggestive of electrical coupling. PV+ neurons recorded in PV-Tomato mice had similar properties but had significantly narrower action potentials and a higher maximal firing frequency. Another population of smaller GFP+ neurons had properties similar to striatal projection neurons. The fast firing and electrical coupling of BF GABA/PV+ neurons, together with their projections to cortical interneurons and the thalamic reticular nucleus, suggest a strong and synchronous control of the neocortical fast rhythms typical of wakefulness and REM sleep. PMID:23254904

  1. Robust tonic GABA currents can inhibit cell firing in mouse newborn neocortical pyramidal cells

    PubMed Central

    Sebe, Joy Y.; Looke-Stewart, Elizabeth C.; Estrada, Rosanne C.; Baraban, Scott C.

    2010-01-01

    Within the hippocampus and neocortex, GABA is considered excitatory in early development due to a relatively depolarized Cl- reversal potential. Although the depolarizing nature of synaptic GABAergic events has been well established, it is unknown whether cortical tonic currents mediated by extrasynaptically located GABAA receptors (GABAARs) are also excitatory. Here we examined the development of tonic currents in the neocortex and their effect on neuronal excitability. We found that mean tonic current, recorded from Layer 5 pyramidal cells of the mouse somatosensory cortex, is robust in newborns (P2-4) then decreases dramatically by the second postnatal week (P7-10 and P30-40). Pharmacological studies, in combination with Western blot analysis, show that neonatal tonic currents are partially mediated by the GABAAR α5, and likely the δ, subunit. In newborns, the charge due to tonic current accounts for nearly 100% of total GABA charge, a contribution that decreases to less than 50% in mature tissue. Current clamp recordings reveal that tonic current contributes to large fluctuations in the membrane potential that may disrupt its stability. Bath application of 5 μM GABA, to induce tonic currents, markedly decreased cell firing frequency in most recorded cells while increasing it in others. Gramicidin perforated patch recordings reveal heterogeneity in ECl recorded from P2-5 Layer 5 pyramidal cells. Taken together, these findings demonstrate that tonic currents activated by low GABA concentrations can dominate GABAergic transmission in newborn neocortical pyramidal cells and that tonic currents can exert heterogeneous effects on neuronal excitability. PMID:20846324

  2. Quantitative Classification of Somatostatin-Positive Neocortical Interneurons Identifies Three Interneuron Subtypes

    PubMed Central

    McGarry, Laura M.; Packer, Adam M.; Fino, Elodie; Nikolenko, Volodymyr; Sippy, Tanya; Yuste, Rafael

    2010-01-01

    Deciphering the circuitry of the neocortex requires knowledge of its components, making a systematic classification of neocortical neurons necessary. GABAergic interneurons contribute most of the morphological, electrophysiological and molecular diversity of the cortex, yet interneuron subtypes are still not well defined. To quantitatively identify classes of interneurons, 59 GFP-positive interneurons from a somatostatin-positive mouse line were characterized by whole-cell recordings and anatomical reconstructions. For each neuron, we measured a series of physiological and morphological variables and analyzed these data using unsupervised classification methods. PCA and cluster analysis of morphological variables revealed three groups of cells: one comprised of Martinotti cells, and two other groups of interneurons with short asymmetric axons targeting layers 2/3 and bending medially. PCA and cluster analysis of electrophysiological variables also revealed the existence of these three groups of neurons, particularly with respect to action potential time course. These different morphological and electrophysiological characteristics could make each of these three interneuron subtypes particularly suited for a different function within the cortical circuit. PMID:20617186

  3. Impaired fast-spiking, suppressed cortical inhibition, and increased susceptibility to seizures in mice lacking Kv3.2 K+ channel proteins.

    PubMed

    Lau, D; Vega-Saenz de Miera, E C; Contreras, D; Ozaita, A; Harvey, M; Chow, A; Noebels, J L; Paylor, R; Morgan, J I; Leonard, C S; Rudy, B

    2000-12-15

    Voltage-gated K(+) channels of the Kv3 subfamily have unusual electrophysiological properties, including activation at very depolarized voltages (positive to -10 mV) and very fast deactivation rates, suggesting special roles in neuronal excitability. In the brain, Kv3 channels are prominently expressed in select neuronal populations, which include fast-spiking (FS) GABAergic interneurons of the neocortex, hippocampus, and caudate, as well as other high-frequency firing neurons. Although evidence points to a key role in high-frequency firing, a definitive understanding of the function of these channels has been hampered by a lack of selective pharmacological tools. We therefore generated mouse lines in which one of the Kv3 genes, Kv3.2, was disrupted by gene-targeting methods. Whole-cell electrophysiological recording showed that the ability to fire spikes at high frequencies was impaired in immunocytochemically identified FS interneurons of deep cortical layers (5-6) in which Kv3.2 proteins are normally prominent. No such impairment was found for FS neurons of superficial layers (2-4) in which Kv3.2 proteins are normally only weakly expressed. These data directly support the hypothesis that Kv3 channels are necessary for high-frequency firing. Moreover, we found that Kv3.2 -/- mice showed specific alterations in their cortical EEG patterns and an increased susceptibility to epileptic seizures consistent with an impairment of cortical inhibitory mechanisms. This implies that, rather than producing hyperexcitability of the inhibitory interneurons, Kv3.2 channel elimination suppresses their activity. These data suggest that normal cortical operations depend on the ability of inhibitory interneurons to generate high-frequency firing.

  4. Mitochondrial calcium uptake capacity modulates neocortical excitability

    PubMed Central

    Sanganahalli, Basavaraju G; Herman, Peter; Hyder, Fahmeed; Kannurpatti, Sridhar S

    2013-01-01

    Local calcium (Ca2+) changes regulate central nervous system metabolism and communication integrated by subcellular processes including mitochondrial Ca2+ uptake. Mitochondria take up Ca2+ through the calcium uniporter (mCU) aided by cytoplasmic microdomains of high Ca2+. Known only in vitro, the in vivo impact of mCU activity may reveal Ca2+-mediated roles of mitochondria in brain signaling and metabolism. From in vitro studies of mitochondrial Ca2+ sequestration and cycling in various cell types of the central nervous system, we evaluated ranges of spontaneous and activity-induced Ca2+ distributions in multiple subcellular compartments in vivo. We hypothesized that inhibiting (or enhancing) mCU activity would attenuate (or augment) cortical neuronal activity as well as activity-induced hemodynamic responses in an overall cytoplasmic and mitochondrial Ca2+-dependent manner. Spontaneous and sensory-evoked cortical activities were measured by extracellular electrophysiology complemented with dynamic mapping of blood oxygen level dependence and cerebral blood flow. Calcium uniporter activity was inhibited and enhanced pharmacologically, and its impact on the multimodal measures were analyzed in an integrated manner. Ru360, an mCU inhibitor, reduced all stimulus-evoked responses, whereas Kaempferol, an mCU enhancer, augmented all evoked responses. Collectively, the results confirm aforementioned hypotheses and support the Ca2+ uptake-mediated integrative role of in vivo mitochondria on neocortical activity. PMID:23591650

  5. An Adaptive Threshold in Mammalian Neocortical Evolution

    PubMed Central

    Kalinka, Alex T.; Tomancak, Pavel; Huttner, Wieland B.

    2014-01-01

    Expansion of the neocortex is a hallmark of human evolution. However, determining which adaptive mechanisms facilitated its expansion remains an open question. Here we show, using the gyrencephaly index (GI) and other physiological and life-history data for 102 mammalian species, that gyrencephaly is an ancestral mammalian trait. We find that variation in GI does not evolve linearly across species, but that mammals constitute two principal groups above and below a GI threshold value of 1.5, approximately equal to 109 neurons, which may be characterized by distinct constellations of physiological and life-history traits. By integrating data on neurogenic period, neuroepithelial founder pool size, cell-cycle length, progenitor-type abundances, and cortical neuron number into discrete mathematical models, we identify symmetric proliferative divisions of basal progenitors in the subventricular zone of the developing neocortex as evolutionarily necessary for generating a 14-fold increase in daily prenatal neuron production, traversal of the GI threshold, and thus establishment of two principal groups. We conclude that, despite considerable neuroanatomical differences, changes in the length of the neurogenic period alone, rather than any novel neurogenic progenitor lineage, are sufficient to explain differences in neuron number and neocortical size between species within the same principal group. PMID:25405475

  6. Zbtb20 promotes astrocytogenesis during neocortical development

    PubMed Central

    Nagao, Motoshi; Ogata, Toru; Sawada, Yasuhiro; Gotoh, Yukiko

    2016-01-01

    Multipotent neural precursor cells (NPCs) generate astrocytes at late stages of mammalian neocortical development. Many signalling pathways that regulate astrocytogenesis directly induce the expression of GFAP, a marker of terminally differentiated astrocytes. However, astrocyte specification occurs before GFAP expression and essential factors for the specification step have remained elusive. Here we show that Zbtb20 regulates astrocyte specification in the mouse neocortex. Zbtb20 is highly expressed in late-stage NPCs and their astrocytic progeny. Overexpression and knockdown of Zbtb20 promote and suppress astrocytogenesis, respectively, although Zbtb20 does not directly activate the Gfap promoter. Astrocyte induction by Zbtb20 is suppressed by knockdown of Sox9 or NFIA. Furthermore, in the astrocyte lineage, Zbtb20 directly represses the expression of Brn2, which encodes a protein necessary for upper-layer neuron specification. Zbtb20 is thus a key determinant of astrocytogenesis, in which it collaborates with Sox9 and NFIA, and acts in part through direct repression of Brn2 expression. PMID:27000654

  7. Neocortical activation of the hippocampus during sleep in infant rats.

    PubMed

    Mohns, Ethan J; Blumberg, Mark S

    2010-03-03

    We recently reported that the majority of hippocampal neurons in newborn rats increase their activity in association with myoclonic twitches, which are indicative of active sleep. Because spindle bursts in the developing somatosensory neocortex occur in response to sensory feedback from myoclonic twitching, we hypothesized that the state-dependent activity of the newborn hippocampus arises from sensory feedback that sequentially activates the neocortex and then hippocampus, constituting an early form of neocortical-hippocampal communication. Here, in unanesthetized 5- to 6-d-old rats, we test this hypothesis by recording simultaneously from forelimb and barrel regions of somatosensory neocortex and dorsal hippocampus during periods of spontaneous sleep and wakefulness and in response to peripheral stimulation. Myoclonic twitches were consistently followed by neocortical spindle bursts, which were in turn consistently followed by bursts of hippocampal unit activity; moreover, spindle burst power was positively correlated with hippocampal unit activity. In addition, exogenous stimulation consistently evoked this neocortical-to-hippocampal sequence of activation. Finally, parahippocampal lesions that disrupted functional connections between the neocortex and hippocampus effectively disrupted the transmission of both spontaneous and evoked neocortical activity to the hippocampus. These findings suggest that sleep-related motor activity contributes to the development of neocortical and hippocampal circuits and provides a foundation on which coordinated activity between these two forebrain structures develops.

  8. Endogenous Electric Fields May Guide Neocortical Network Activity

    PubMed Central

    Fröhlich, Flavio; McCormick, David A.

    2011-01-01

    Local field potentials and the underlying endogenous electric fields (EFs) are traditionally considered to be epiphenomena of structured neuronal network activity. Recently, however, externally applied EFs have been shown to modulate pharmacologically evoked network activity in rodent hippocampus. In contrast, very little is known about the role of endogenous EFs during physiological activity states in neocortex. Here we used the neocortical slow oscillation in vitro as a model system to show that weak sinusoidal and naturalistic EFs enhance and entrain physiological neocortical network activity with an amplitude threshold within the range of in vivo endogenous field strengths. Modulation of network activity by positive and negative feedback fields based on the network activity in real-time provide direct evidence for a feedback loop between neuronal activity and endogenous EF. This significant susceptibility of active networks to EFs that only cause small changes in membrane potential in individual neurons suggests that endogenous EFs could guide neocortical network activity. PMID:20624597

  9. 532 nm Low-Power Laser Irradiation Facilitates the Migration of GABAergic Neural Stem/Progenitor Cells in Mouse Neocortex

    PubMed Central

    Fukuzaki, Yumi; Shin, Hyeryun; Kawai, Hideki D.; Yamanoha, Banri; Kogure, Shinichi

    2015-01-01

    Background and Objective Accumulating evidence has shown that low-power laser irradiation (LLI) affects cell proliferation and survival, but little is known about LLI effects on neural stem/progenitor cells (NSPCs). Here we investigate whether transcranial 532 nm LLI affects NSPCs in adult murine neocortex and in neurospheres from embryonic mice. Study Design/Materials and Methods We applied 532 nm LLI (Nd:YVO4, CW, 60 mW) on neocortical surface via cranium in adult mice and on cultured cells from embryonic mouse brains in vitro to investigate the proliferation and migration of NSPCs and Akt expression using immunohistochemical assays and Western blotting techniques. Results In vivo experiments demonstrated that 532 nm LLI significantly facilitated the migration of GABAergic NSPCs that were induced to proliferate in layer 1 by mild ischemia. In vitro experiments using GABAergic NSPCs derived from embryonic day 14 ganglionic eminence demonstrated that 532 nm LLI for 60 min promoted the migration of GAD67-immunopositive NSPCs with a significant increase of Akt expression. Meanwhile, the LLI induced proliferation, but not migration, of NSPCs that give rise to excitatory neurons. Conclusion It is concluded that 532 nm LLI promoted the migration of GABAergic NSPCs into deeper layers of the neocortex in vivo by elevating Akt expression. PMID:25919297

  10. GABAergic cell types in the lizard hippocampus.

    PubMed

    Guirado, S; Dávila, J C

    1999-04-01

    The neurochemical classification of GABAergic cells in the lizard hippocampus resulted in a further division into four major, non-overlapping subtypes. Each GABAergic cell subtype displays specific targets on the principal hippocampal neurons. The synaptic targets of the GABA/neuropeptide subtype are the distal apical dendrites of principal neurons. Calretinin- and parvalbumin-containing GABAergic cells synapse on the cell body and proximal dendrites of principal cells. Calbindin is expressed in a distinct group of interneurons, the synapses of which are directed to the dendrites of principal neurons. Finally, another subtype displays NADPH-diaphorase activity, but its synaptic target has not been established.

  11. Interareal oscillatory synchronization in top-down neocortical processing.

    PubMed

    Bressler, Steven L; Richter, Craig G

    2015-04-01

    Top-down processing in the neocortex underlies important cognitive functions such as predictive coding and attentional set. We review evidence indicating that top-down neocortical processes are carried by interareal synchrony, particularly in the beta frequency band. We hypothesize that top-down neocortical signals in the beta band convey behavioral context to low-level sensory neurons. We further speculate that large-scale distributed networks, self-organized at the highest hierarchical levels, are the source of top-down signals in the neocortex.

  12. Emerging Themes in GABAergic Synapse Development

    PubMed Central

    Kuzirian, Marissa S.

    2011-01-01

    Glutamatergic synapse formation has been rigorously investigated for the past two decadesat both the molecular and cell biological level yet a comparable intensity of investigation into the cellular and molecular mechanisms of GABAergic synapses has been lacking until relatively recently. This review will provide a detailed overview of the current understanding of GABAergic synapse formation with a particular emphasis on assembly of synaptic components, molecular mechanisms of synaptic development, and a subset of human disorders which manifest when GABAergic synapse development is disrupted. An unexpected and emerging theme from these studies is that glutamatergicand GABAergic synapse formation share a number of overlapping molecular and cell biologicalmechanisms that will be emphasized in this review. PMID:21798307

  13. Neocortical networks entrain neuronal circuits in cerebellar cortex

    PubMed Central

    Roš, Hana; Sachdev, Robert N. S.; Yu, Yuguo; Šestan, Nenad; McCormick, David A.

    2011-01-01

    Activity in neocortex is often characterized by synchronized oscillations of neurons and networks, resulting in the generation of a local field potential and electroencephalogram. Do the neuronal networks of the cerebellum also generate synchronized oscillations and are they under the influence of those in the neocortex? Here we show that in the absence of any overt external stimulus, the cerebellar cortex generates a slow oscillation that is correlated with that of the neocortex. Disruption of the neocortical slow oscillation abolishes the cerebellar slow oscillation, whereas blocking cerebellar activity has no overt effect on the neocortex. We provide evidence that the cerebellar slow oscillation results in part from the activation of granule, Golgi, and Purkinje neurons. In particular, we show that granule and Golgi cells discharge trains of single spikes, and Purkinje cells generate complex spikes, during the Up state of the slow oscillation. Purkinje cell simple spiking is weakly related to the cerebellar and neocortical slow oscillation in a minority of cells. Our results indicate that the cerebellum generates rhythmic network activity that can be recorded as an LFP in the anesthetized animal, which is driven by synchronized oscillations of the neocortex. Furthermore, we show that correlations between neocortical and cerebellar LFPs persist in the awake animal, indicating that neocortical circuits modulate cerebellar neurons in a similar fashion in natural behavioral states. Thus, the projection neurons of the neocortex collectively exert a driving and modulatory influence on cerebellar network activity. PMID:19692605

  14. Seizure-induced alterations in fast-spiking basket cell GABA currents modulate frequency and coherence of gamma oscillation in network simulations

    SciTech Connect

    Proddutur, Archana; Yu, Jiandong; Elgammal, Fatima S.; Santhakumar, Vijayalakshmi

    2013-12-15

    Gamma frequency oscillations have been proposed to contribute to memory formation and retrieval. Fast-spiking basket cells (FS-BCs) are known to underlie development of gamma oscillations. Fast, high amplitude GABA synapses and gap junctions have been suggested to contribute to gamma oscillations in FS-BC networks. Recently, we identified that, apart from GABAergic synapses, FS-BCs in the hippocampal dentate gyrus have GABAergic currents mediated by extrasynaptic receptors. Our experimental studies demonstrated two specific changes in FS-BC GABA currents following experimental seizures [Yu et al., J. Neurophysiol. 109, 1746 (2013)]: increase in the magnitude of extrasynaptic (tonic) GABA currents and a depolarizing shift in GABA reversal potential (E{sub GABA}). Here, we use homogeneous networks of a biophysically based model of FS-BCs to examine how the presence of extrasynaptic GABA conductance (g{sub GABA-extra}) and experimentally identified, seizure-induced changes in g{sub GABA-extra} and E{sub GABA} influence network activity. Networks of FS-BCs interconnected by fast GABAergic synapses developed synchronous firing in the dentate gamma frequency range (40–100 Hz). Systematic investigation revealed that the biologically realistic range of 30 to 40 connections between FS-BCs resulted in greater coherence in the gamma frequency range when networks were activated by Poisson-distributed dendritic synaptic inputs rather than by homogeneous somatic current injections, which were balanced for FS-BC firing frequency in unconnected networks. Distance-dependent conduction delay enhanced coherence in networks with 30–40 FS-BC interconnections while inclusion of gap junctional conductance had a modest effect on coherence. In networks activated by somatic current injections resulting in heterogeneous FS-BC firing, increasing g{sub GABA-extra} reduced the frequency and coherence of FS-BC firing when E{sub GABA} was shunting (−74 mV), but failed to alter average

  15. Seizure-induced alterations in fast-spiking basket cell GABA currents modulate frequency and coherence of gamma oscillation in network simulations

    NASA Astrophysics Data System (ADS)

    Proddutur, Archana; Yu, Jiandong; Elgammal, Fatima S.; Santhakumar, Vijayalakshmi

    2013-12-01

    Gamma frequency oscillations have been proposed to contribute to memory formation and retrieval. Fast-spiking basket cells (FS-BCs) are known to underlie development of gamma oscillations. Fast, high amplitude GABA synapses and gap junctions have been suggested to contribute to gamma oscillations in FS-BC networks. Recently, we identified that, apart from GABAergic synapses, FS-BCs in the hippocampal dentate gyrus have GABAergic currents mediated by extrasynaptic receptors. Our experimental studies demonstrated two specific changes in FS-BC GABA currents following experimental seizures [Yu et al., J. Neurophysiol. 109, 1746 (2013)]: increase in the magnitude of extrasynaptic (tonic) GABA currents and a depolarizing shift in GABA reversal potential (EGABA). Here, we use homogeneous networks of a biophysically based model of FS-BCs to examine how the presence of extrasynaptic GABA conductance (gGABA-extra) and experimentally identified, seizure-induced changes in gGABA-extra and EGABA influence network activity. Networks of FS-BCs interconnected by fast GABAergic synapses developed synchronous firing in the dentate gamma frequency range (40-100 Hz). Systematic investigation revealed that the biologically realistic range of 30 to 40 connections between FS-BCs resulted in greater coherence in the gamma frequency range when networks were activated by Poisson-distributed dendritic synaptic inputs rather than by homogeneous somatic current injections, which were balanced for FS-BC firing frequency in unconnected networks. Distance-dependent conduction delay enhanced coherence in networks with 30-40 FS-BC interconnections while inclusion of gap junctional conductance had a modest effect on coherence. In networks activated by somatic current injections resulting in heterogeneous FS-BC firing, increasing gGABA-extra reduced the frequency and coherence of FS-BC firing when EGABA was shunting (-74 mV), but failed to alter average FS-BC frequency when EGABA was depolarizing

  16. Brain region specific modulation of ethanol-induced depression of GABAergic neurons in the brain reward system by the nicotine receptor antagonist mecamylamine.

    PubMed

    Adermark, Louise; Söderpalm, Bo; Burkhardt, John M

    2014-08-01

    The mechanisms underlying ethanol-induced activation of the mesolimbic dopamine system are not fully understood, but increased extracellular dopamine in the nucleus accumbens (nAc) has been shown to involve nicotinic acetylcholine receptors (nAChRs). Basal activity of dopaminergic neurons in the ventral tegmental area (VTA) is under the influence of GABAergic neurotransmission, and the aim of this study was to characterize the involvement of nAChRs in mediating acute ethanol effects on GABAergic activity in subregions of the brain reward system. Multi-electrode in vivo recordings were made in the VTA and nAc of awake and behaving C57BL6/J mice receiving intraperitoneal injections of saline or ethanol (2.0 g/kg), combined with, or without, pre-injection of the non-competitive nAChR antagonist mecamylamine (1.0 mg/kg). Ethanol significantly decreased the activity of quinpirole-insensitive slow-spiking and fast-spiking units in both the VTA and the nAc as compared to saline injection. Pre-treatment with mecamylamine inhibited the rate-inhibiting properties of ethanol in the VTA, but not in the nAc. The data presented here show that ethanol depresses the activity of quinpirole-insensitive, putative GABAergic neurons, in the mesolimbic dopamine system of mice, and that nAChRs contribute to this modulation. This finding, taken together with previous microdialysis studies, supports an involvement of GABAergic neurons and nAChRs in ethanol's interaction with the mesolimbic dopamine system.

  17. Development of Cortical GABAergic Innervation

    PubMed Central

    Jovanovic, Jasmina N.; Thomson, Alex M.

    2011-01-01

    The mature neocortex contains many different classes of GABAergic inhibitory interneurons, distributed, with some degree of selectivity, through six layers, and through many different regions. Some of the events in the early lives of these neurones that may determine their ultimate destination, their maturation and their selective innervation of targets appropriate for each subtype, are discussed. Both time and place of birth influence the class of interneuron that an early post-mitotic interneuronal precursor will become, driven by the selective expression of different combinations of transcription factors in different regions of their birth places in the ganglionic eminence and ventricular zone. The long distance migration of these precursors along tangential routes in marginal, subventricular, and intermediate zones and their final radial movement, into the developing cortex, is regulated by chemical cues, both attractant and repellent. Once they arrive at their final destination, they must integrate into the developing circuitry. As they mature within the cortex, their axons grow and branch in highly specific patterns that may be partially determined by the genetic blueprint for each interneuronal class and partly by the environment in which they find themselves. Finally, as each interneuron class begins to form synapses with only certain postsynaptic targets, cell–cell recognition, most probably via protein–protein interactions across the synaptic cleft, facilitate the formation of appropriate synapses. PMID:21808605

  18. Voltage-dependent membrane potential oscillations of rat striatal fast-spiking interneurons

    PubMed Central

    Bracci, Enrico; Centonze, Diego; Bernardi, Giorgio; Calabresi, Paolo

    2003-01-01

    We used whole-cell recordings to investigate subthreshold membrane potential oscillations and their relationship with intermittent firing in striatal fast-spiking interneurons. During current injections (100–500 pA, 1 s), these cells displayed a highly variable pattern of spike bursts (comprising 1–30 action potentials) interspersed with membrane potential oscillations. The oscillation threshold was −42 ± 10 mV, and coincided with that for action potentials. The oscillation frequency was voltage dependent and ranged between 20 and 100 Hz. Oscillations were unaffected by the calcium channel blockers cadmium and nickel and by blockers of ionotropic glutamate and GABA receptors. Conversely, the sodium channel blocker tetrodotoxin fully abolished the oscillations and the spike bursts. The first spike of a burst appeared to be triggered by an oscillation, since the timing and rate of rise of the membrane potential in the subthreshold voltage region was similar for the two events. Conversely, the second spike (and the subsequent ones) displayed much faster depolarisations in the subthreshold voltage range, indicating that they were generated by a different mechanism. Consistent with these notions, a small pulse of intracellular current delivered during the oscillation was effective in triggering a burst of action potentials that largely outlasted the pulse. We conclude that fast-spiking interneuron oscillations are generated by an intrinsic membrane mechanism that does not require fast synaptic transmission, and which depends on sodium conductance but not calcium conductance, and that such oscillations are responsible for triggering the intermittent spike bursts that are typical of these neurons. PMID:12665602

  19. The GABAergic System and the Gastrointestinal Physiopathology.

    PubMed

    Auteri, Michelangelo; Zizzo, Maria Grazia; Serio, Rosa

    2015-01-01

    Since the first report about the presence of γ-aminobutyric acid (GABA) within the gastrointestinal (GI) tract, accumulating evidence strongly supports the widespread representation of the GABAergic system in the enteric milieu, underlining its potential multifunctional role in the regulation of GI functions in health and disease. GABA and GABA receptors are widely distributed throughout the GI tract, constituting a complex network likely regulating the diverse GI behaviour patterns, cooperating with other major neurotransmitters and mediators for maintaining GI homeostasis in physiologic and pathologic conditions. GABA is involved in the circuitry of the enteric nervous system, controlling GI secretion and motility, as well as in the GI endocrine system, possibly acting as a autocrine/paracrine or hormonal agent. Furthermore, a series of investigations addresses the GABAergic system as a potential powerful modulator of GI visceral pain processing, enteric immune system and carcinogenesis. Although overall such actions may imply the consideration of the GABAergic system as a novel therapeutic target in different GI pathologic states, including GI motor and secretory diseases and different enteric inflammatory- and pain-related pathologies, current clinical applications of GABAergic drugs are scarce. Thus, in an attempt to propel novel scientific efforts addressing the detailed characterization of the GABAergic signaling in the GI tract, and consequently the development of novel strategies for the treatment of different GI disorders, we reviewed and discussed the current evidence about GABA actions in the enteric environment, with a particular focus on their possible therapeutic implications.

  20. GABAergic circuit dysfunctions in neurodevelopmental disorders.

    PubMed

    Chattopadhyaya, Bidisha; Cristo, Graziella Di

    2012-01-01

    GABAergic interneurons control neuronal excitability, integration, and plasticity. Further, they regulate the generation of temporal synchrony and oscillatory behavior among networks of pyramidal neurons. Such oscillations within and across neural systems are believed to serve various complex functions, such as perception, movement initiation, and memory. Alterations in the development of GABAergic circuits have been implicated in various brain diseases with neurodevelopmental origin. Here, we highlight recent studies suggesting a role for alterations of GABA transmission in the pathophysiology of two neurodevelopmental diseases, schizophrenia, and autism. We further discuss how manipulations of GABA signaling may be used for novel therapeutic interventions.

  1. Classification of fusiform neocortical interneurons based on unsupervised clustering

    PubMed Central

    Cauli, Bruno; Porter, James T.; Tsuzuki, Keisuke; Lambolez, Bertrand; Rossier, Jean; Quenet, Brigitte; Audinat, Etienne

    2000-01-01

    A classification of fusiform neocortical interneurons (n = 60) was performed with an unsupervised cluster analysis based on the comparison of multiple electrophysiological and molecular parameters studied by patch-clamp and single-cell multiplex reverse transcription–PCR in rat neocortical acute slices. The multiplex reverse transcription–PCR protocol was designed to detect simultaneously the expression of GAD65, GAD67, calbindin, parvalbumin, calretinin, neuropeptide Y, vasoactive intestinal peptide (VIP), somatostatin (SS), cholecystokinin, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, kainate, N-methyl-d-aspartate, and metabotropic glutamate receptor subtypes. Three groups of fusiform interneurons with distinctive features were disclosed by the cluster analysis. The first type of fusiform neuron (n = 12), termed regular spiking nonpyramidal (RSNP)-SS cluster, was characterized by a firing pattern of RSNP cells and by a high occurrence of SS. The second type of fusiform neuron (n = 32), termed RSNP-VIP cluster, predominantly expressed VIP and also showed firing properties of RSNP neurons with accommodation profiles different from those of RSNP-SS cells. Finally, the last type of fusiform neuron (n = 16) contained a majority of irregular spiking-VIPergic neurons. In addition, the analysis of glutamate receptors revealed cell-type-specific expression profiles. This study shows that combinations of multiple independent criteria define distinct neocortical populations of interneurons potentially involved in specific functions. PMID:10823957

  2. Neocortical malformation as consequence of nonadaptive regulation of neuronogenetic sequence

    NASA Technical Reports Server (NTRS)

    Caviness, V. S. Jr; Takahashi, T.; Nowakowski, R. S.

    2000-01-01

    Variations in the structure of the neocortex induced by single gene mutations may be extreme or subtle. They differ from variations in neocortical structure encountered across and within species in that these "normal" structural variations are adaptive (both structurally and behaviorally), whereas those associated with disorders of development are not. Here we propose that they also differ in principle in that they represent disruptions of molecular mechanisms that are not normally regulatory to variations in the histogenetic sequence. We propose an algorithm for the operation of the neuronogenetic sequence in relation to the overall neocortical histogenetic sequence and highlight the restriction point of the G1 phase of the cell cycle as the master regulatory control point for normal coordinate structural variation across species and importantly within species. From considerations based on the anatomic evidence from neocortical malformation in humans, we illustrate in principle how this overall sequence appears to be disrupted by molecular biological linkages operating principally outside the control mechanisms responsible for the normal structural variation of the neocortex. MRDD Research Reviews 6:22-33, 2000. Copyright 2000 Wiley-Liss, Inc.

  3. Parvalbumin, somatostatin and cholecystokinin as chemical markers for specific GABAergic interneuron types in the rat frontal cortex.

    PubMed

    Kawaguchi, Yasuo; Kondo, Satoru

    2002-01-01

    It remains to be clarified how many classes of GABAergic nonpyramidal cells exist in the cortical circuit. We have divided GABA cells in the rat frontal cortex into 3 groups, based on their firing characteristics: fast-spiking (FS) cells, late-spiking (LS) cells, and non-FS cells. Expression of calcium-binding proteins and peptides could be shown in separate groups of GABA cells in layers II/III and V of the frontal cortex: (1) parvalbumin cells, (2) somatostatin cells, (3) calretinin and/or vasoactive intestinal polypeptide (VIP) cells [partially positive for cholecystokinin (CCK)] and (4) large CCK cells (almost negative for VIP/calretinin). Combining the physiological and chemical properties of morphologically diverse nonpyramidal cells allows division into several groups, including FS basket cells containing parvalbumin, non-FS somatostatin Martinotti cells with ascending axonal arbors, and non-FS large basket cells positive for CCK. These subtypes show characteristic spatial distributions of axon collaterals and the innervation tendency of postsynaptic elements. With synchronized activity induced by cortical excitatory or inhibitory circuits, firing patterns were also found to differ. Subtype-selective occurrence of electrical coupling, finding for potassium channel Kv3.1 proteins, and cholinergic and serotonergic modulation supports our tentative classification. To clarify the functional architecture in the frontal cortex, it is important to reveal the connectional characteristics of GABA cell subtypes and determine whether they are similar to those in other cortical regions.

  4. Impaired fast-spiking interneuron function in a genetic mouse model of depression

    PubMed Central

    Sauer, Jonas-Frederic; Strüber, Michael; Bartos, Marlene

    2015-01-01

    Rhythmic neuronal activity provides a frame for information coding by co-active cell assemblies. Abnormal brain rhythms are considered as potential pathophysiological mechanisms causing mental disease, but the underlying network defects are largely unknown. We find that mice expressing truncated Disrupted-in-Schizophrenia 1 (Disc1), which mirror a high-prevalence genotype for human psychiatric illness, show depression-related behavior. Theta and low-gamma synchrony in the prelimbic cortex (PrlC) is impaired in Disc1 mice and inversely correlated with the extent of behavioural despair. While weak theta activity is driven by the hippocampus, disturbance of low-gamma oscillations is caused by local defects of parvalbumin (PV)-expressing fast-spiking interneurons (FS-INs). The number of FS-INs is reduced, they receive fewer excitatory inputs, and form fewer release sites on targets. Computational analysis indicates that weak excitatory input and inhibitory output of FS-INs may lead to impaired gamma oscillations. Our data link network defects with a gene mutation underlying depression in humans. DOI: http://dx.doi.org/10.7554/eLife.04979.001 PMID:25735038

  5. Spectrotemporal processing differences between auditory cortical fast-spiking and regular-spiking neurons

    PubMed Central

    Atencio, Craig A.; Schreiner, Christoph E.

    2008-01-01

    Excitatory pyramidal neurons and inhibitory interneurons constitute the main elements of cortical circuitry and have distinctive morphologic and electrophysiological properties. Here, we differentiate them by analyzing the time course of their action potentials (APs) and characterizing their receptive field properties in auditory cortex. Pyramidal neurons have longer APs and discharge as Regular-Spiking Units (RSUs), while basket and chandelier cells, which are inhibitory interneurons, have shorter APs and are Fast-Spiking Units (FSUs). To compare these neuronal classes we stimulated cat primary auditory cortex neurons with a dynamic moving ripple stimulus and constructed single-unit spectrotemporal receptive fields (STRFs) and their associated nonlinearities. FSUs had shorter latencies, broader spectral tuning, greater stimulus specificity, and higher temporal precision than RSUs. The STRF structure of FSUs was more separable, suggesting more independence between spectral and temporal processing regimes. The nonlinearities associated with the two cell classes was indicative of higher feature selectivity for FSUs. These global functional differences between RSUs and FSUs suggest fundamental distinctions between putative excitatory and inhibitory neurons that shape auditory cortical processing. PMID:18400888

  6. GABAergic interneurons form transient layer-specific circuits in early postnatal neocortex.

    PubMed

    Anastasiades, Paul G; Marques-Smith, Andre; Lyngholm, Daniel; Lickiss, Tom; Raffiq, Sayda; Kätzel, Dennis; Miesenböck, Gero; Butt, Simon J B

    2016-02-04

    GABAergic interneurons play key roles in cortical circuits, yet little is known about their early connectivity. Here we use glutamate uncaging and a novel optogenetic strategy to track changes in the afferent and efferent synaptic connections of developing neocortical interneuron subtypes. We find that Nkx2-1-derived interneurons possess functional synaptic connections before emerging pyramidal cell networks. Subsequent interneuron circuit maturation is both subtype and layer dependent. Glutamatergic input onto fast spiking (FS), but not somatostatin-positive, non-FS interneurons increases over development. Interneurons of both subtype located in layers (L) 4 and 5b engage in transient circuits that disappear after the somatosensory critical period. These include a pathway mediated by L5b somatostatin-positive interneurons that specifically targets L4 during the first postnatal week. The innervation patterns of immature cortical interneuron circuits are thus neither static nor progressively strengthened but follow a layer-specific choreography of transient connections that differ from those of the adult brain.

  7. Molecular analysis of neocortical layer structure in the ferret

    PubMed Central

    Rowell, Joanna J.; Mallik, Atul K.; Dugas-Ford, Jennifer; Ragsdale, Clifton W.

    2010-01-01

    Molecular markers that distinguish specific layers of rodent neocortex are increasingly employed to study cortical development and the physiology of cortical circuits. The extent to which these markers represent general features of neocortical cell type identity across mammals is, however, unknown. To assess the conservation of layer markers more broadly, we isolated orthologs for fifteen layer-enriched genes in the ferret, a carnivore with a large, gyrencephalic brain, and analyzed their patterns of neocortical gene expression. Our major findings are: (1) Many but not all layer markers tested show similar patterns of layer-specific gene expression between mouse and ferret cortex, supporting the view that layer-specific cell type identity is conserved at a molecular level across mammalian superorders; (2) Our panel of deep layer markers (ER81/ETV1, SULF2, PCP4, FEZF2/ZNF312, CACNA1H, KCNN2/SK2, SYT6, FOXP2, CTGF) provides molecular evidence that the specific stratifications of layer 5 and 6 into 5a, 5b, 6a and 6b are also conserved between rodents and carnivores. (3) Variations in layer-specific gene expression are more pronounced across areas of ferret cortex than between homologous areas of mouse and ferret cortex; (4) This variation of area gene expression was clearest with the superficial layer markers studied (SERPINE2, MDGA1, CUX1, UNC5D, RORB/NR1F2, EAG2/KCNH5). Most dramatically, the layer 4 markers RORB and EAG2 disclosed a molecular sublamination to ferret visual cortex and demonstrated a molecular dissociation among the so-called agranular areas of the neocortex. Our findings establish molecular markers as a powerful complement to cytoarchitecture for neocortical layer and cell-type comparisons across mammals. PMID:20575059

  8. Microscale spatiotemporal dynamics during neocortical propagation of human focal seizures.

    PubMed

    Wagner, Fabien B; Eskandar, Emad N; Cosgrove, G Rees; Madsen, Joseph R; Blum, Andrew S; Potter, N Stevenson; Hochberg, Leigh R; Cash, Sydney S; Truccolo, Wilson

    2015-11-15

    Some of the most clinically consequential aspects of focal epilepsy, e.g. loss of consciousness, arise from the generalization or propagation of seizures through local and large-scale neocortical networks. Yet, the dynamics of such neocortical propagation remain poorly understood. Here, we studied the microdynamics of focal seizure propagation in neocortical patches (4×4 mm) recorded via high-density microelectrode arrays (MEAs) implanted in people with pharmacologically resistant epilepsy. Our main findings are threefold: (1) a newly developed stage segmentation method, applied to local field potentials (LFPs) and multiunit activity (MUA), revealed a succession of discrete seizure stages, each lasting several seconds. These different stages showed characteristic evolutions in overall activity and spatial patterns, which were relatively consistent across seizures within each of the 5 patients studied. Interestingly, segmented seizure stages based on LFPs or MUA showed a dissociation of their spatiotemporal dynamics, likely reflecting different contributions of non-local synaptic inputs and local network activity. (2) As previously reported, some of the seizures showed a peak in MUA that happened several seconds after local seizure onset and slowly propagated across the MEA. However, other seizures had a more complex structure characterized by, for example, several MUA peaks, more consistent with the succession of discrete stages than the slow propagation of a simple wavefront of increased MUA. In both cases, nevertheless, seizures characterized by spike-wave discharges (SWDs, ~2-3 Hz) eventually evolved into patterns of phase-locked MUA and LFPs. (3) Individual SWDs or gamma oscillation cycles (25-60 Hz), characteristic of two different types of recorded seizures, tended to propagate with varying degrees of directionality, directions of propagation and speeds, depending on the identified seizure stage. However, no clear relationship was observed between the MUA

  9. Gelastic seizures of neocortical origin confirmed by resective surgery.

    PubMed

    Kurle, P J; Sheth, R D

    2000-12-01

    Ictal laughter is a relatively unusual phenomenon that appears to arise from within hypothalamic hamartomas. Gelastic seizures of neocortical origin are rare and when reported typically originate from temporofrontal regions in proximity to the hypothalamus, raising the possibility of a subtle lesion in the hypothalamus. A girl with gelastic seizures originating in a dysembryoblastic neuroepithelial tumor at the cranial vertex had resolution of her seizures following surgical resection. Electrical propagation of seizures via the cingulate gyrus appears to be an alternative mechanism underlying gelastic seizures.

  10. Microscale Spatiotemporal Dynamics during Neocortical Propagation of Human Focal Seizures

    PubMed Central

    Wagner, Fabien B.; Eskandar, Emad N.; Cosgrove, G. Rees; Madsen, Joseph R.; Blum, Andrew S.; Potter, N. Stevenson; Hochberg, Leigh R.; Cash, Sydney S.; Truccolo, Wilson

    2015-01-01

    Some of the most clinically consequential aspects of focal epilepsy, e.g. loss of consciousness, arise from the generalization or propagation of seizures through local and large-scale neocortical networks. Yet, the dynamics of such neocortical propagation remain poorly understood. Here, we studied the microdynamics of focal seizure propagation in neocortical patches (4 × 4 mm) recorded via high-density microelectrode arrays (MEAs) implanted in people with pharmacologically resistant epilepsy. Our main findings are threefold: (1) A newly developed stage segmentation method, applied to local field potentials (LFPs) and multi-unit activity (MUA), revealed a succession of discrete seizure stages, each lasting several seconds. These different stages showed characteristic evolutions in overall activity and spatial patterns, which were relatively consistent across seizures within each of the 5 patients studied. Interestingly, segmented seizure stages based on LFPs or MUA showed a dissociation of their spatiotemporal dynamics, likely reflecting different contributions of non-local synaptic inputs and local network activity. (2) As previously reported, some of the seizures showed a peak in MUA that happened several seconds after local seizure onset and slowly propagated across the MEA. However, other seizures had a more complex structure characterized by, for example, several MUA peaks, more consistent with the succession of discrete stages than the slow propagation of a simple wavefront of increased MUA. In both cases, nevertheless, seizures characterized by spike-wave discharges (SWDs, ~ 2–3Hz) eventually evolved into patterns of phase-locked MUA and LFPs. (3) Individual SWDs or gamma oscillation cycles (25–60 Hz), characteristic of two different types of recorded seizures, tended to propagate with varying degrees of directionality, directions of propagation and speeds, depending on the identified seizure stage. However, no clear relationship was observed between the

  11. Kv3.1b and Kv3.3 channel subunit expression in murine spinal dorsal horn GABAergic interneurones.

    PubMed

    Nowak, A; Mathieson, H R; Chapman, R J; Janzsó, G; Yanagawa, Y; Obata, K; Szabo, G; King, A E

    2011-09-01

    GABAergic interneurones, including those within spinal dorsal horn, contain one of the two isoforms of the synthesizing enzyme glutamate decarboxylase (GAD), either GAD65 or GAD67. The physiological significance of these two GABAergic phenotypes is unknown but a more detailed anatomical and functional characterization may help resolve this issue. In this study, two transgenic Green Fluorescent Protein (GFP) knock-in murine lines, namely GAD65-GFP and GAD67-GFP (Δneo) mice, were used to profile expression of Shaw-related Kv3.1b and Kv3.3 K(+)-channel subunits in dorsal horn interneurones. Neuronal expression of these subunits confers specific biophysical characteristic referred to as 'fast-spiking'. Immuno-labelling for Kv3.1b or Kv3.3 revealed the presence of both of these subunits across the dorsal horn, most abundantly in laminae I-III. Co-localization studies in transgenic mice indicated that Kv3.1b but not Kv3.3 was associated with GAD65-GFP and GAD67-GFP immunopositive neurones. For comparison the distributions of Kv4.2 and Kv4.3 K(+)-channel subunits which are linked to an excitatory neuronal phenotype were characterized. No co-localization was found between GAD-GFP +ve neurones and Kv4.2 or Kv4.3. In functional studies to evaluate whether either GABAergic population is activated by noxious stimulation, hindpaw intradermal injection of capsaicin followed by c-fos quantification in dorsal horn revealed co-expression c-fos and GAD65-GFP (quantified as 20-30% of GFP +ve population). Co-expression was also detected for GAD67-GFP +ve neurones and capsaicin-induced c-fos but at a much reduced level of 4-5%. These data suggest that whilst both GAD65-GFP and GAD67-GFP +ve neurones express Kv3.1b and therefore may share certain biophysical traits, their responses to peripheral noxious stimulation are distinct.

  12. Artificial spatiotemporal touch inputs reveal complementary decoding in neocortical neurons

    PubMed Central

    Oddo, Calogero M.; Mazzoni, Alberto; Spanne, Anton; Enander, Jonas M. D.; Mogensen, Hannes; Bengtsson, Fredrik; Camboni, Domenico; Micera, Silvestro; Jörntell, Henrik

    2017-01-01

    Investigations of the mechanisms of touch perception and decoding has been hampered by difficulties in achieving invariant patterns of skin sensor activation. To obtain reproducible spatiotemporal patterns of activation of sensory afferents, we used an artificial fingertip equipped with an array of neuromorphic sensors. The artificial fingertip was used to transduce real-world haptic stimuli into spatiotemporal patterns of spikes. These spike patterns were delivered to the skin afferents of the second digit of rats via an array of stimulation electrodes. Combined with low-noise intra- and extracellular recordings from neocortical neurons in vivo, this approach provided a previously inaccessible high resolution analysis of the representation of tactile information in the neocortical neuronal circuitry. The results indicate high information content in individual neurons and reveal multiple novel neuronal tactile coding features such as heterogeneous and complementary spatiotemporal input selectivity also between neighboring neurons. Such neuronal heterogeneity and complementariness can potentially support a very high decoding capacity in a limited population of neurons. Our results also indicate a potential neuroprosthetic approach to communicate with the brain at a very high resolution and provide a potential novel solution for evaluating the degree or state of neurological disease in animal models. PMID:28374841

  13. Statistical mechanics of neocortical interactions: Canonical momenta indicatorsof electroencephalography

    NASA Astrophysics Data System (ADS)

    Ingber, Lester

    1997-04-01

    A series of papers has developed a statistical mechanics of neocortical interactions (SMNI), deriving aggregate behavior of experimentally observed columns of neurons from statistical electrical-chemical properties of synaptic interactions. While not useful to yield insights at the single neuron level, SMNI has demonstrated its capability in describing large-scale properties of short-term memory and electroencephalographic (EEG) systematics. The necessity of including nonlinear and stochastic structures in this development has been stressed. Sets of EEG and evoked potential data were fit, collected to investigate genetic predispositions to alcoholism and to extract brain ``signatures'' of short-term memory. Adaptive simulated annealing (ASA), a global optimization algorithm, was used to perform maximum likelihood fits of Lagrangians defined by path integrals of multivariate conditional probabilities. Canonical momenta indicators (CMI) are thereby derived for an individual's EEG data. The CMI give better signal recognition than the raw data, and can be used to advantage as correlates of behavioral states. These results give strong quantitative support for an accurate intuitive picture, portraying neocortical interactions as having common algebraic or physics mechanisms that scale across quite disparate spatial scales and functional or behavioral phenomena, i.e., describing interactions among neurons, columns of neurons, and regional masses of neurons.

  14. Hippocampal-neocortical functional reorganization underlies children's cognitive development.

    PubMed

    Qin, Shaozheng; Cho, Soohyun; Chen, Tianwen; Rosenberg-Lee, Miriam; Geary, David C; Menon, Vinod

    2014-09-01

    The importance of the hippocampal system for rapid learning and memory is well recognized, but its contributions to a cardinal feature of children's cognitive development-the transition from procedure-based to memory-based problem-solving strategies-are unknown. Here we show that the hippocampal system is pivotal to this strategic transition. Longitudinal functional magnetic resonance imaging (fMRI) in 7-9-year-old children revealed that the transition from use of counting to memory-based retrieval parallels increased hippocampal and decreased prefrontal-parietal engagement during arithmetic problem solving. Longitudinal improvements in retrieval-strategy use were predicted by increased hippocampal-neocortical functional connectivity. Beyond childhood, retrieval-strategy use continued to improve through adolescence into adulthood and was associated with decreased activation but more stable interproblem representations in the hippocampus. Our findings provide insights into the dynamic role of the hippocampus in the maturation of memory-based problem solving and establish a critical link between hippocampal-neocortical reorganization and children's cognitive development.

  15. The impact of cortical deafferentation on the neocortical slow oscillation.

    PubMed

    Lemieux, Maxime; Chen, Jen-Yung; Lonjers, Peter; Bazhenov, Maxim; Timofeev, Igor

    2014-04-16

    Slow oscillation is the main brain rhythm observed during deep sleep in mammals. Although several studies have demonstrated its neocortical origin, the extent of the thalamic contribution is still a matter of discussion. Using electrophysiological recordings in vivo on cats and computational modeling, we found that the local thalamic inactivation or the complete isolation of the neocortical slabs maintained within the brain dramatically reduced the expression of slow and fast oscillations in affected cortical areas. The slow oscillation began to recover 12 h after thalamic inactivation. The slow oscillation, but not faster activities, nearly recovered after 30 h and persisted for weeks in the isolated slabs. We also observed an increase of the membrane potential fluctuations recorded in vivo several hours after thalamic inactivation. Mimicking this enhancement in a network computational model with an increased postsynaptic activity of long-range intracortical afferents or scaling K(+) leak current, but not several other Na(+) and K(+) intrinsic currents was sufficient for recovering the slow oscillation. We conclude that, in the intact brain, the thalamus contributes to the generation of cortical active states of the slow oscillation and mediates its large-scale synchronization. Our study also suggests that the deafferentation-induced alterations of the sleep slow oscillation can be counteracted by compensatory intracortical mechanisms and that the sleep slow oscillation is a fundamental and intrinsic state of the neocortex.

  16. Developmental alterations in the functional properties of excitatory neocortical synapses

    PubMed Central

    Feldmeyer, Dirk; Radnikow, Gabriele

    2009-01-01

    In the neocortex, most excitatory, glutamatergic synapses are established during the first 4–5 weeks after birth. During this period profound changes in the properties of synaptic transmission occur. Excitatory postsynaptic potentials (EPSPs) at immature synaptic connections are profoundly and progressively reduced in response to moderate to high frequency (5–100 Hz) stimulation. With maturation, this frequency-dependent depression becomes progressively weaker and may eventually transform into a weak to moderate EPSP facilitation. In parallel to changes in the short-term plasticity, a reduction in the synaptic reliability occurs at most glutamatergic neocortical synapses: immature synapses show a high probability of neurotransmitter release as indicated by their low failure rate and small EPSP amplitude variation. This high reliability is reduced in mature synapses, which show considerably higher failure rates and more variable EPSP amplitudes. During early neocortical development synaptic vesicle pools are not yet fully differentiated and their replenishment may be slow, thus resulting in EPSP amplitude depression. The decrease in the probability of neurotransmitter release may be the result of an altered Ca2+ control in the presynaptic terminal with a reduced Ca2+ influx and/or a higher Ca2+ buffering capacity. This may lead to a lower synaptic reliability and a weaker short-term synaptic depression with maturation. PMID:19273572

  17. The Impact of Cortical Deafferentation on the Neocortical Slow Oscillation

    PubMed Central

    Lemieux, Maxime; Chen, Jen-Yung; Lonjers, Peter; Bazhenov, Maxim

    2014-01-01

    Slow oscillation is the main brain rhythm observed during deep sleep in mammals. Although several studies have demonstrated its neocortical origin, the extent of the thalamic contribution is still a matter of discussion. Using electrophysiological recordings in vivo on cats and computational modeling, we found that the local thalamic inactivation or the complete isolation of the neocortical slabs maintained within the brain dramatically reduced the expression of slow and fast oscillations in affected cortical areas. The slow oscillation began to recover 12 h after thalamic inactivation. The slow oscillation, but not faster activities, nearly recovered after 30 h and persisted for weeks in the isolated slabs. We also observed an increase of the membrane potential fluctuations recorded in vivo several hours after thalamic inactivation. Mimicking this enhancement in a network computational model with an increased postsynaptic activity of long-range intracortical afferents or scaling K+ leak current, but not several other Na+ and K+ intrinsic currents was sufficient for recovering the slow oscillation. We conclude that, in the intact brain, the thalamus contributes to the generation of cortical active states of the slow oscillation and mediates its large-scale synchronization. Our study also suggests that the deafferentation-induced alterations of the sleep slow oscillation can be counteracted by compensatory intracortical mechanisms and that the sleep slow oscillation is a fundamental and intrinsic state of the neocortex. PMID:24741059

  18. Reduced chemical and electrical connections of fast-spiking interneurons in experimental cortical dysplasia.

    PubMed

    Zhou, Fu-Wen; Roper, Steven N

    2014-09-15

    Aberrant neural connections are regarded as a principal factor contributing to epileptogenesis. This study examined chemical and electrical connections between fast-spiking (FS), parvalbumin (PV)-immunoreactive (FS-PV) interneurons and regular-spiking (RS) neurons (pyramidal neurons or spiny stellate neurons) in a rat model of prenatal irradiation-induced cortical dysplasia. Presynaptic action potentials were evoked by current injection and the elicited unitary inhibitory or excitatory postsynaptic potentials (uIPSPs or uEPSPs) were recorded in the postsynaptic cell. In dysplastic cortex, connection rates between presynaptic FS-PV interneurons and postsynaptic RS neurons and FS-PV interneurons, and uIPSP amplitudes were significantly smaller than controls, but both failure rates and coefficient of variation of uIPSP amplitudes were larger than controls. In contrast, connection rates from RS neurons to FS-PV interneurons and uEPSPs amplitude were similar in the two groups. Assessment of the paired pulse ratio showed a significant decrease in synaptic release probability at FS-PV interneuronal terminals, and the density of terminal boutons on axons of biocytin-filled FS-PV interneurons was also decreased, suggesting presynaptic dysfunction in chemical synapses formed by FS-PV interneurons. Electrical connections were observed between FS-PV interneurons, and the connection rates and coupling coefficients were smaller in dysplastic cortex than controls. In dysplastic cortex, we found a reduced synaptic efficiency for uIPSPs originating from FS-PV interneurons regardless of the type of target cell, and impaired electrical connections between FS-PV interneurons. This expands our understanding of the fundamental impairment of inhibition in this model and may have relevance for certain types of human cortical dysplasia.

  19. Dendritic calcium nonlinearities switch the direction of synaptic plasticity in fast-spiking interneurons.

    PubMed

    Camiré, Olivier; Topolnik, Lisa

    2014-03-12

    Postsynaptic calcium (Ca2+) nonlinearities allow neuronal coincidence detection and site-specific plasticity. Whether such events exist in dendrites of interneurons and play a role in regulation of synaptic efficacy remains unknown. Here, we used a combination of whole-cell patch-clamp recordings and two-photon Ca2+ imaging to reveal Ca2+ nonlinearities associated with synaptic integration in dendrites of mouse hippocampal CA1 fast-spiking interneurons. Local stimulation of distal dendritic branches within stratum oriens/alveus elicited fast Ca2+ transients, which showed a steep sigmoidal relationship to stimulus intensity. Supralinear Ca2+ events required Ca2+ entry through AMPA receptors with a subsequent Ca2+ release from internal stores. To investigate the functional significance of supralinear Ca2+ signals, we examined activity-dependent fluctuations in transmission efficacy triggered by Ca2+ signals of different amplitudes at excitatory synapses of interneurons. Subthreshold theta-burst stimulation (TBS) produced small amplitude postsynaptic Ca2+ transients and triggered long-term potentiation. In contrast, the suprathreshold TBS, which was associated with the generation of supralinear Ca2+ events, triggered long-term depression. Blocking group I/II metabotropic glutamate receptors (mGluRs) during suprathreshold TBS resulted in a slight reduction of supralinear Ca2+ events and induction of short-term depression. In contrast, blocking internal stores and supralinear Ca2+ signals during suprathreshold TBS switched the direction of plasticity from depression back to potentiation. These data reveal a novel type of supralinear Ca2+ events at synapses lacking the GluA2 AMPA subtype of glutamate receptors and demonstrate a general mechanism by which Ca2+ -permeable AMPA receptors, together with internal stores and mGluRs, control the direction of plasticity at interneuron excitatory synapses.

  20. The ionic mechanism of gamma resonance in rat striatal fast-spiking neurons.

    PubMed

    Sciamanna, Giuseppe; Wilson, Charles J

    2011-12-01

    Striatal fast-spiking (FS) cells in slices fire in the gamma frequency range and in vivo are often phase-locked to gamma oscillations in the field potential. We studied the firing patterns of these cells in slices from rats ages 16-23 days to determine the mechanism of their gamma resonance. The resonance of striatal FS cells was manifested as a minimum frequency for repetitive firing. At rheobase, cells fired a doublet of action potentials or doublets separated by pauses, with an instantaneous firing rate averaging 44 spikes/s. The minimum rate for sustained firing was also responsible for the stuttering firing pattern. Firing rate adapted during each episode of firing, and bursts were terminated when firing was reduced to the minimum sustainable rate. Resonance and stuttering continued after blockade of Kv3 current using tetraethylammonium (0.1-1 mM). Both gamma resonance and stuttering were strongly dependent on Kv1 current. Blockade of Kv1 channels with dendrotoxin-I (100 nM) completely abolished the stuttering firing pattern, greatly lowered the minimum firing rate, abolished gamma-band subthreshold oscillations, and slowed spike frequency adaptation. The loss of resonance could be accounted for by a reduction in potassium current near spike threshold and the emergence of a fixed spike threshold. Inactivation of the Kv1 channel combined with the minimum firing rate could account for the stuttering firing pattern. The resonant properties conferred by this channel were shown to be adequate to account for their phase-locking to gamma-frequency inputs as seen in vivo.

  1. GABAergic synapses: their plasticity and role in sensory cortex

    PubMed Central

    Griffen, Trevor C.; Maffei, Arianna

    2014-01-01

    The mammalian neocortex is composed of a variety of cell types organized in a highly interconnected circuit. GABAergic neurons account for only about 20% of cortical neurons. However, they show widespread connectivity and a high degree of diversity in morphology, location, electrophysiological properties and gene expression. In addition, distinct populations of inhibitory neurons have different sensory response properties, capacities for plasticity and sensitivities to changes in sensory experience. In this review we summarize experimental evidence regarding the properties of GABAergic neurons in primary sensory cortex. We will discuss how distinct GABAergic neurons and different forms of GABAergic inhibitory plasticity may contribute to shaping sensory cortical circuit activity and function. PMID:24723851

  2. Layer-specific generation and propagation of seizures in slices of developing neocortex: role of excitatory GABAergic synapses.

    PubMed

    Rheims, Sylvain; Represa, Alfonso; Ben-Ari, Yehezkel; Zilberter, Yuri

    2008-08-01

    The neonatal period is critical for seizure susceptibility, and neocortical networks are central in infantile epilepsies. We report that application of 4-aminopyridine (4-AP) to immature (P6-P9) neocortical slices generates layer-specific interictal seizures (IISs) that transform after recurrent seizures to ictal seizures (ISs). During IISs, cell-attached recordings show action potentials in interneurons and pyramidal cells in L5/6 and interneurons but not pyramidal neurons in L2/3. However, L2/3 pyramidal neurons also fire during ISs. Using single N-methyl-d-aspartate (NMDA) channel recordings for measuring the cell resting potential (Em), we show that transition from IISs to ISs is associated with a gradual Em depolarization of L2/3 and L5/6 pyramidal neurons that enhances their excitability. Bumetanide, a NKCC1 co-transporter antagonist, inhibits generation of IISs and prevents their transformation to ISs, indicating the role excitatory GABA in epilepsies. Therefore deep layer neurons are more susceptible to seizures than superficial ones. The initiating phase of seizures is characterized by IISs generated in L5/6 and supported by activation of both L5/6 interneurons and pyramidal cells. IISs propagate to L2/3 via activation of L2/3 interneurons but not pyramidal cells, which are mostly quiescent at this phase. In superficial layers, a persistent increase in excitability of pyramidal neurons caused by Em depolarization is associated with a transition from largely confined GABAergic IIS to ictal events that entrain the entire neocortex.

  3. Neocortical disconnectivity disrupts sensory integration in Alzheimer's disease.

    PubMed

    Festa, Elena K; Insler, Rachel Z; Salmon, David P; Paxton, Jessica; Hamilton, Joanne M; Heindel, William C

    2005-11-01

    The cortical pathology in Alzheimer's disease (AD) should lead to the loss of effective interaction between distinct neocortical areas. This study compared 2 conditions within a single sensory integration task that differed in the demands placed on effective cross-cortical interaction. AD patients were impaired in their ability to bind distinct visual features of a stimulus when this binding placed greater demands on cross-cortical interaction (i.e., motion and color) but were not impaired when this binding placed lesser demands on such interaction (i.e., motion and luminance). In contrast, neurologically intact individuals and patients with Huntington's disease were able to effectively bind features under both conditions. These results provide psychophysical support for the presence of functional disconnectivity in AD and demonstrate the utility of AD for investigating the neurocognitive substrates of sensory integration.

  4. Direct reactivation of a coherent neocortical memory of context

    PubMed Central

    Cowansage, Kiriana Kater; Shuman, Tristan; Dillingham, Blythe Christine; Chang, Allene; Golshani, Peyman; Mayford, Mark

    2014-01-01

    Summary Declarative memories are thought to be stored within anatomically distributed neuronal networks requiring the hippocampus; however, it is unclear how neocortical areas participate in memory at the time of encoding. Here, we use a c-fos-based genetic tagging system to selectively express the channelrhodopsin variant, ChEF, and optogenetically reactivate a specific neural ensemble in retrosplenial cortex (RSC) engaged by context fear conditioning. Artificial stimulation of RSC was sufficient to produce both context-specific behavior and downstream cellular activity commensurate with natural experience. Moreover, optogenetically, but not contextually-elicited responses were insensitive to hippocampal inactivation, suggesting that although the hippocampus is needed to coordinate activation by sensory cues, a higher-order cortical framework can independently subserve learned behavior, even shortly after learning. PMID:25308330

  5. Emx1 Is Required for Neocortical Area Patterning

    PubMed Central

    Stocker, Adam M.; O’Leary, Dennis D. M.

    2016-01-01

    Establishing appropriate area patterning in the neocortex is a critical developmental event, and transcription factors whose expression is graded across the developing neural axes have been implicated in this process. While previous reports suggested that the transcription factor Emx1 does not contribute to neocortical area patterning, those studies were performed at perinatal ages prior to the emergence of primary areas. We therefore examined two different Emx1 deletion mouse lines once primary areas possess mature features. Following the deletion of Emx1, the frontal and motor areas were expanded while the primary visual area was reduced, and overall the areas shifted posterio-medially. This patterning phenotype was consistent between the two Emx1 deletion strategies. The present study demonstrates that Emx1 is an area patterning transcription factor and is required for the specification of the primary visual area. PMID:26901526

  6. Optical neural stimulation modeling on degenerative neocortical neural networks

    NASA Astrophysics Data System (ADS)

    Zverev, M.; Fanjul-Vélez, F.; Salas-García, I.; Arce-Diego, J. L.

    2015-07-01

    Neurodegenerative diseases usually appear at advanced age. Medical advances make people live longer and as a consequence, the number of neurodegenerative diseases continuously grows. There is still no cure for these diseases, but several brain stimulation techniques have been proposed to improve patients' condition. One of them is Optical Neural Stimulation (ONS), which is based on the application of optical radiation over specific brain regions. The outer cerebral zones can be noninvasively stimulated, without the common drawbacks associated to surgical procedures. This work focuses on the analysis of ONS effects in stimulated neurons to determine their influence in neuronal activity. For this purpose a neural network model has been employed. The results show the neural network behavior when the stimulation is provided by means of different optical radiation sources and constitute a first approach to adjust the optical light source parameters to stimulate specific neocortical areas.

  7. The Yin and Yang of Memory Consolidation: Hippocampal and Neocortical

    PubMed Central

    Rossato, Janine I.; Jacobse, Justin; Grieves, Roddy M.; Spooner, Patrick A.; Battaglia, Francesco P.; Fernández, Guillen; Morris, Richard G. M.

    2017-01-01

    While hippocampal and cortical mechanisms of memory consolidation have long been studied, their interaction is poorly understood. We sought to investigate potential interactions with respect to trace dominance, strengthening, and interference associated with postencoding novelty or sleep. A learning procedure was scheduled in a watermaze that placed the impact of novelty and sleep in opposition. Distinct behavioural manipulations—context preexposure or interference during memory retrieval—differentially affected trace dominance and trace survival, respectively. Analysis of immediate early gene expression revealed parallel up-regulation in the hippocampus and cortex, sustained in the hippocampus in association with novelty but in the cortex in association with sleep. These findings shed light on dynamically interacting mechanisms mediating the stabilization of hippocampal and neocortical memory traces. Hippocampal memory traces followed by novelty were more dominant by default but liable to interference, whereas sleep engaged a lasting stabilization of cortical traces and consequent trace dominance after preexposure. PMID:28085883

  8. Transplanted embryonic neurons integrate into adult neocortical circuits.

    PubMed

    Falkner, Susanne; Grade, Sofia; Dimou, Leda; Conzelmann, Karl-Klaus; Bonhoeffer, Tobias; Götz, Magdalena; Hübener, Mark

    2016-11-10

    The ability of the adult mammalian brain to compensate for neuronal loss caused by injury or disease is very limited. Transplantation aims to replace lost neurons, but the extent to which new neurons can integrate into existing circuits is unknown. Here, using chronic in vivo two-photon imaging, we show that embryonic neurons transplanted into the visual cortex of adult mice mature into bona fide pyramidal cells with selective pruning of basal dendrites, achieving adult-like densities of dendritic spines and axonal boutons within 4-8 weeks. Monosynaptic tracing experiments reveal that grafted neurons receive area-specific, afferent inputs matching those of pyramidal neurons in the normal visual cortex, including topographically organized geniculo-cortical connections. Furthermore, stimulus-selective responses refine over the course of many weeks and finally become indistinguishable from those of host neurons. Thus, grafted neurons can integrate with great specificity into neocortical circuits that normally never incorporate new neurons in the adult brain.

  9. Efficient Ca2+ buffering in fast-spiking basket cells of rat hippocampus

    PubMed Central

    Aponte, Yexica; Bischofberger, Josef; Jonas, Peter

    2008-01-01

    Fast-spiking parvalbumin-expressing basket cells (BCs) represent a major type of inhibitory interneuron in the hippocampus. These cells inhibit principal cells in a temporally precise manner and are involved in the generation of network oscillations. Although BCs show a unique expression profile of Ca2+-permeable receptors, Ca2+-binding proteins and Ca2+-dependent signalling molecules, physiological Ca2+ signalling in these interneurons has not been investigated. To study action potential (AP)-induced dendritic Ca2+ influx and buffering, we combined whole-cell patch-clamp recordings with ratiometric Ca2+ imaging from the proximal apical dendrites of rigorously identified BCs in acute slices, using the high-affinity Ca2+ indicator fura-2 or the low-affinity dye fura-FF. Single APs evoked dendritic Ca2+ transients with small amplitude. Bursts of APs evoked Ca2+ transients with amplitudes that increased linearly with AP number. Analysis of Ca2+ transients under steady-state conditions with different fura-2 concentrations and during loading with 200 μm fura-2 indicated that the endogenous Ca2+-binding ratio was ∼200 (κS= 202 ± 26 for the loading experiments). The peak amplitude of the Ca2+ transients measured directly with 100 μm fura-FF was 39 nm AP−1. At ∼23°C, the decay time constant of the Ca2+ transients was 390 ms, corresponding to an extrusion rate of ∼600 s−1. At 34°C, the decay time constant was 203 ms and the corresponding extrusion rate was ∼1100 s−1. At both temperatures, continuous theta-burst activity with three to five APs per theta cycle, as occurs in vivo during exploration, led to a moderate increase in the global Ca2+ concentration that was proportional to AP number, whereas more intense stimulation was required to reach micromolar Ca2+ concentrations and to shift Ca2+ signalling into a non-linear regime. In conclusion, dentate gyrus BCs show a high endogenous Ca2+-binding ratio, a small AP-induced dendritic Ca2+ influx, and a

  10. Draxin from neocortical neurons controls the guidance of thalamocortical projections into the neocortex

    PubMed Central

    Shinmyo, Yohei; Asrafuzzaman Riyadh, M.; Ahmed, Giasuddin; Bin Naser, Iftekhar; Hossain, Mahmud; Takebayashi, Hirohide; Kawasaki, Hiroshi; Ohta, Kunimasa; Tanaka, Hideaki

    2015-01-01

    The thalamocortical tract carries sensory information to the neocortex. It has long been recognized that the neocortical pioneer axons of subplate neurons are essential for thalamocortical development. Herein we report that an axon guidance cue, draxin, is expressed in early-born neocortical neurons, including subplate neurons, and is necessary for thalamocortical development. In draxin−/− mice, thalamocortical axons do not enter the neocortex. This phenotype is sufficiently rescued by the transgenic expression of draxin in neocortical neurons. Genetic interaction data suggest that draxin acts through Deleted in colorectal cancer (DCC) and Neogenin (Neo1), to regulate thalamocortical projections in vivo. Draxin promotes the outgrowth of thalamic axons in vitro and this effect is abolished in thalamic neurons from Dcc and Neo1 double mutants. These results suggest that draxin from neocortical neurons controls thalamocortical projections into the neocortex, and that this effect is mediated through the DCC and Neo1 receptors. PMID:26659141

  11. Draxin from neocortical neurons controls the guidance of thalamocortical projections into the neocortex.

    PubMed

    Shinmyo, Yohei; Asrafuzzaman Riyadh, M; Ahmed, Giasuddin; Bin Naser, Iftekhar; Hossain, Mahmud; Takebayashi, Hirohide; Kawasaki, Hiroshi; Ohta, Kunimasa; Tanaka, Hideaki

    2015-12-14

    The thalamocortical tract carries sensory information to the neocortex. It has long been recognized that the neocortical pioneer axons of subplate neurons are essential for thalamocortical development. Herein we report that an axon guidance cue, draxin, is expressed in early-born neocortical neurons, including subplate neurons, and is necessary for thalamocortical development. In draxin(-/-) mice, thalamocortical axons do not enter the neocortex. This phenotype is sufficiently rescued by the transgenic expression of draxin in neocortical neurons. Genetic interaction data suggest that draxin acts through Deleted in colorectal cancer (DCC) and Neogenin (Neo1), to regulate thalamocortical projections in vivo. Draxin promotes the outgrowth of thalamic axons in vitro and this effect is abolished in thalamic neurons from Dcc and Neo1 double mutants. These results suggest that draxin from neocortical neurons controls thalamocortical projections into the neocortex, and that this effect is mediated through the DCC and Neo1 receptors.

  12. Influence of Pyrethroid Insecticides on Sodium and Calcium Influx in Neocortical Neurons

    EPA Science Inventory

    Pyrethroid insecticides bind to voltage-gated sodium channels and modify their gating kinetics, thereby disrupting neuronal function. Using murine neocortical neurons in primary culture, we have compared the ability of 11 structurally diverse pyrethroid insecticides to evoke Na+ ...

  13. The GABAergic Hypothesis for Cognitive Disabilities in Down Syndrome

    PubMed Central

    Contestabile, Andrea; Magara, Salvatore; Cancedda, Laura

    2017-01-01

    Down syndrome (DS) is a genetic disorder caused by the presence of a third copy of chromosome 21. DS affects multiple organs, but it invariably results in altered brain development and diverse degrees of intellectual disability. A large body of evidence has shown that synaptic deficits and memory impairment are largely determined by altered GABAergic signaling in trisomic mouse models of DS. These alterations arise during brain development while extending into adulthood, and include genesis of GABAergic neurons, variation of the inhibitory drive and modifications in the control of neural-network excitability. Accordingly, different pharmacological interventions targeting GABAergic signaling have proven promising preclinical approaches to rescue cognitive impairment in DS mouse models. In this review, we will discuss recent data regarding the complex scenario of GABAergic dysfunctions in the trisomic brain of DS mice and patients, and we will evaluate the state of current clinical research targeting GABAergic signaling in individuals with DS. PMID:28326014

  14. Migratory pathways of GABAergic interneurons when they enter the neocortex.

    PubMed

    Tanaka, Daisuke H; Nakajima, Kazunori

    2012-06-01

    Inhibitory gamma-aminobutyric-acid-containing interneurons play important roles in the functions of the neocortex. During rodent development, most neocortical interneurons are generated in the subpallium and migrate tangentially toward the neocortex. They migrate through multiple pathways to enter the neocortex. Failure of interneuron migration through these pathways during development leads to an abnormal distribution and abnormal functions of interneurons in the postnatal brain. Because of recent discoveries regarding the novel origins and migratory pathways of neocortical interneurons, in this article we review the literature on the migratory pathways of interneurons when they enter the neocortex.

  15. What is GABAergic inhibition? How is it modified in epilepsy?

    PubMed

    Bernard, C; Cossart, R; Hirsch, J C; Esclapez, M; Ben-Ari, Y

    2000-01-01

    A deficit of gamma-aminobutyric acid-ergic (GABAergic) inhibition is hypothesized to underlie most forms of epilepsy. Although apparently a straightforward and logical hypothesis to test, the search for a deficit of GABAergic inhibition in epileptic tissue has revealed itself to be as difficult as the quest for the Holy Grail. The investigator faces many obstacles, including the multiplicity of GABAergic inhibitory pathways and the multiplicity of variables that characterize the potency of inhibition within each inhibitory pathway. Perhaps more importantly, there seems to be no consensual definition of GABAergic inhibition. The first goal of this review is to try to clarify the notion of GABAergic inhibition. The second goal is to summarize our current knowledge of the various alterations that occur in the GABAergic pathways in temporal lobe epilepsy. Two important features will emerge: (a) according to the variable used to measure GABAergic inhibition, it may appear increased, decreased, or unchanged; and (b) these modifications are brain area- and inhibitory pathway-specific. The possible functional consequences of these alterations are discussed.

  16. Monoaminergic modulation of GABAergic transmission onto cerebellar globular cells.

    PubMed

    Hirono, Moritoshi; Nagao, Soichi; Yanagawa, Yuchio; Konishi, Shiro

    2017-03-11

    Cerebellar Purkinje cells (PCs) project their axon collaterals to underneath of the PC layer and make GABAergic synaptic contacts with globular cells, a subgroup of Lugaro cells. GABAergic transmission derived from the PC axon collaterals is so powerful that it could inhibit globular cells and regulate their firing patterns. However, the physiological properties and implications of the GABAergic synapses on globular cells remain unknown. Using whole-cell patch-clamp recordings from globular cells in the mouse cerebellum, we examined the monoaminergic modulation of GABAergic inputs to these cells. Application of either serotonin (5-HT) or noradrenaline (NA) excited globular cells, thereby leading to their firing. The 5-HT- and NA-induced firing was temporally confined and attenuated by GABAergic transmission, although 5-HT and NA exerted an inhibitory effect on the release of GABA from presynaptic terminals of PC axon collaterals. Agonists for 5-HT1B receptors and α2-adrenoceptors mimicked the 5-HT- and NA-induced suppression of GABAergic activity. Through their differential modulatory actions on the cerebellar inhibitory neural circuits, 5-HT facilitated PC firing, whereas NA suppressed it. These results indicate that 5-HT and NA regulate the membrane excitability of globular cells and PCs through their differential modulation of not only the membrane potential but also GABAergic synaptic circuits. Monoaminergic modulation of the neural connections between globular cells and PCs could play a role in cerebellar motor coordination.

  17. Endocannabinoid-mediated long-term depression of afferent excitatory synapses in hippocampal pyramidal cells and GABAergic interneurons.

    PubMed

    Péterfi, Zoltán; Urbán, Gabriella M; Papp, Orsolya I; Németh, Beáta; Monyer, Hannah; Szabó, Gábor; Erdélyi, Ferenc; Mackie, Ken; Freund, Tamás F; Hájos, Norbert; Katona, István

    2012-10-10

    Although endocannabinoids have emerged as essential retrograde messengers in several forms of synaptic plasticity, it remains controversial whether they mediate long-term depression (LTD) of glutamatergic synapses onto excitatory and inhibitory neurons in the hippocampus. Here, we show that parvalbumin- and somatostatin/metabotropic glutamate receptor 1(a) (mGlu(1a))-positive GABAergic interneurons express diacylglycerol lipase-α (DGL-α), a synthesizing enzyme of the endocannabinoid 2-arachidonoylglycerol (2-AG), albeit at lower levels than principal cells. Moreover, this lipase accumulates postsynaptically around afferent excitatory synapses in all three cell types. To address the role of retrograde 2-AG signaling in LTD, we investigated two forms: (1) produced by postsynaptic spiking paired with subsequent presynaptic stimulation or (2) induced by group I mGlu activation by (S)-3,5-dihydroxyphenylglycine (DHPG). Neither form of LTD was evoked in the presence of the mGlu(5) antagonist MPEP [2-methyl-6-(phenylethynyl)-pyridine], the DGL inhibitor THL [N-formyl-l-leucine (1S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl ester], or the intracellularly applied Ca(2+) chelator BAPTA in CA1 pyramidal cells, fast-spiking interneurons (representing parvalbumin-containing cells) and interneurons projecting to stratum lacunosum-moleculare (representing somatostatin/mGlu(1a)-expressing interneurons). Both forms of LTD were completely absent in CB(1) cannabinoid receptor knock-out mice, whereas pharmacological blockade of CB(1) led to inconsistent results. Notably, in accordance with their lower DGL-α level, a higher stimulation frequency or higher DHPG concentration was required for LTD induction in interneurons compared with pyramidal cells. These findings demonstrate that hippocampal principal cells and interneurons produce endocannabinoids to mediate LTD in a qualitatively similar, but quantitatively different manner. The shifted induction threshold implies that

  18. Endogenous zinc depresses GABAergic transmission via T-type Ca2+ channels and broadens the time window for integration of glutamatergic inputs in dentate granule cells

    PubMed Central

    Grauert, Antonia; Engel, Dominique; Ruiz, Arnaud J

    2014-01-01

    Abstract Zinc actions on synaptic transmission span the modulation of neurotransmitter receptors, transporters, activation of intracellular cascades and alterations in gene expression. Whether and how zinc affects inhibitory synaptic signalling in the dentate gyrus remains largely unexplored. We found that mono- and di-synaptic GABAergic inputs onto dentate granule cells were reversibly depressed by exogenous zinc application and enhanced by zinc chelation. Blocking T-type Ca2+ channels prevented the effect of zinc chelation. When recording from dentate fast-spiking interneurones, zinc chelation facilitated T-type Ca2+ currents, increased action potential half-width and decreased spike threshold. It also increased the offset of the input–output relation in a manner consistent with enhanced excitability. In granule cells, chelation of zinc reduced the time window for the integration of glutamatergic inputs originating from perforant path synapses, resulting in reduced spike transfer. Thus, zinc-mediated modulation of dentate interneurone excitability and GABA release regulates information flow to local targets and hippocampal networks. PMID:24081159

  19. Endogenous zinc depresses GABAergic transmission via T-type Ca(2+) channels and broadens the time window for integration of glutamatergic inputs in dentate granule cells.

    PubMed

    Grauert, Antonia; Engel, Dominique; Ruiz, Arnaud J

    2014-01-01

    Zinc actions on synaptic transmission span the modulation of neurotransmitter receptors, transporters, activation of intracellular cascades and alterations in gene expression. Whether and how zinc affects inhibitory synaptic signalling in the dentate gyrus remains largely unexplored. We found that mono- and di-synaptic GABAergic inputs onto dentate granule cells were reversibly depressed by exogenous zinc application and enhanced by zinc chelation. Blocking T-type Ca(2+) channels prevented the effect of zinc chelation. When recording from dentate fast-spiking interneurones, zinc chelation facilitated T-type Ca(2+) currents, increased action potential half-width and decreased spike threshold. It also increased the offset of the input-output relation in a manner consistent with enhanced excitability. In granule cells, chelation of zinc reduced the time window for the integration of glutamatergic inputs originating from perforant path synapses, resulting in reduced spike transfer. Thus, zinc-mediated modulation of dentate interneurone excitability and GABA release regulates information flow to local targets and hippocampal networks.

  20. Fast IPSPs elicited via multiple synaptic release sites by different types of GABAergic neurone in the cat visual cortex.

    PubMed Central

    Tamás, G; Buhl, E H; Somogyi, P

    1997-01-01

    cells established multiple synaptic junctions on their postsynaptic target cells. A basket cell innervated a pyramidal cell via fifteen release sites; the numbers of synapses formed by three dendrite-targeting cells on pyramidal cells were seventeen and eight respectively, and three on a spiny stellate cell; the interaction between a double bouquet cell and a postsynaptic pyramidal cell was mediated by ten synaptic junctions. 5. All three types of interneurone (n = 6; 2 for each type of cell) elicited short-latency IPSPs with fast rise time (10-90%; 2.59 +/- 1.02 ms) and short duration (at half-amplitude, 15.82 +/- 5.24 ms), similar to those mediated by GABAA receptors. 6. Average amplitudes of unitary IPSPs (n = 6) were 845 +/- 796 microV (range, 134-2265 microV). Variability of IPSP amplitude was moderate, the average ratio of IPSP and baseline noise variance was 1.54 +/- 0.96. High frequency activation of single presynaptic dendrite-targeting cells led to an initial summation followed by use-dependent depression of the averaged postsynaptic response. Double bouquet cell-evoked IPSPs, recorded in the soma, had a smaller amplitude than those evoked by the other two cell types. In all connections, transmission failures were rare or absent, particularly when mediated by a high number of release sites. 7. The results demonstrate that different types of neocortical GABAergic neurones innervate distinct domains on the surface of their postsynaptic target cells. Nevertheless, all three types of cell studied here elicit fast IPSPs and provide GABAergic input through multiple synaptic release sites with few, if any, failures of transmission. Images Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 PMID:9161987

  1. A novel GABAergic afferent input to the pontine reticular formation: the mesopontine GABAergic column.

    PubMed

    Liang, Chang-Lin; Marks, Gerald A

    2009-11-10

    Pharmacological manipulations of gamma-aminobutyric acid (GABA) neurotransmission in the nucleus pontis oralis (PnO) of the rat brainstem produce alterations in sleep/wake behavior. Local applications of GABA(A) receptor antagonists and agonists increase REM sleep and wake, respectively. These findings support a role for GABAergic mechanisms of the PnO in the control of arousal state. We have been investigating sources of GABA innervation of the PnO that may interact with local GABA(A) receptors in the control of state. Utilizing a retrograde tracer, cholera toxin-B subunit (CTb), injected into the PnO and dual-label immunohistochemistry with an antibody against glutamic acid decarboxalase-67 (GAD67), we report on a previously unidentified GABAergic neuronal population projecting to the contralateral PnO appearing as a column of cells, with long-axis in the sagittal plane, extending through the midbrain and pons. We refer to these neurons as the mesopontine GABAergic column (MPGC). The contiguous, columnar, anatomical distribution suggests operation as a functional neural system, which may influence expression of REM sleep, wake and other behaviors subserved by the PnO.

  2. 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.

  3. GABAergic signaling in the rat pineal gland.

    PubMed

    Yu, Haijie; Benitez, Sergio G; Jung, Seung-Ryoung; Farias Altamirano, Luz E; Kruse, Martin; Seo, Jong Bae; Koh, Duk-Su; Muñoz, Estela M; Hille, Bertil

    2016-08-01

    Pinealocytes secrete melatonin at night in response to norepinephrine released from sympathetic nerve terminals in the pineal gland. The gland also contains many other neurotransmitters whose cellular disposition, activity, and relevance to pineal function are not understood. Here, we clarify sources and demonstrate cellular actions of the neurotransmitter γ-aminobutyric acid (GABA) using Western blotting and immunohistochemistry of the gland and electrical recording from pinealocytes. GABAergic cells and nerve fibers, defined as containing GABA and the synthetic GAD67, were identified. The cells represent a subset of interstitial cells while the nerve fibers were distinct from the sympathetic innervation. The GABAA receptor subunit α1 was visualized in close proximity of both GABAergic and sympathetic nerve fibers as well as fine extensions among pinealocytes and blood vessels. The GABAB 1 receptor subunit was localized in the interstitial compartment but not in pinealocytes. Electrophysiology of isolated pinealocytes revealed that GABA and muscimol elicit strong inward chloride currents sensitive to bicuculline and picrotoxin, clear evidence for functional GABAA receptors on the surface membrane. Applications of elevated potassium solution or the neurotransmitter acetylcholine depolarized the pinealocyte membrane potential enough to open voltage-gated Ca(2+) channels leading to intracellular calcium elevations. GABA repolarized the membrane and shut off such calcium rises. In 48-72-h cultured intact glands, GABA application neither triggered melatonin secretion by itself nor affected norepinephrine-induced secretion. Thus, strong elements of GABA signaling are present in pineal glands that make large electrical responses in pinealocytes, but physiological roles need to be found.

  4. Chemical-genetic attenuation of focal neocortical seizures.

    PubMed

    Kätzel, Dennis; Nicholson, Elizabeth; Schorge, Stephanie; Walker, Matthew C; Kullmann, Dimitri M

    2014-05-27

    Focal epilepsy is commonly pharmacoresistant, and resective surgery is often contraindicated by proximity to eloquent cortex. Many patients have no effective treatment options. Gene therapy allows cell-type specific inhibition of neuronal excitability, but on-demand seizure suppression has only been achieved with optogenetics, which requires invasive light delivery. Here we test a combined chemical-genetic approach to achieve localized suppression of neuronal excitability in a seizure focus, using viral expression of the modified muscarinic receptor hM4Di. hM4Di has no effect in the absence of its selective, normally inactive and orally bioavailable agonist clozapine-N-oxide (CNO). Systemic administration of CNO suppresses focal seizures evoked by two different chemoconvulsants, pilocarpine and picrotoxin. CNO also has a robust anti-seizure effect in a chronic model of focal neocortical epilepsy. Chemical-genetic seizure attenuation holds promise as a novel approach to treat intractable focal epilepsy while minimizing disruption of normal circuit function in untransduced brain regions or in the absence of the specific ligand.

  5. Theory of Electric Resonance in the Neocortical Apical Dendrite

    PubMed Central

    Kasevich, Ray S.; LaBerge, David

    2011-01-01

    Pyramidal neurons of the neocortex display a wide range of synchronous EEG rhythms, which arise from electric activity along the apical dendrites of neocortical pyramidal neurons. Here we present a theoretical description of oscillation frequency profiles along apical dendrites which exhibit resonance frequencies in the range of 10 to 100 Hz. The apical dendrite is modeled as a leaky coaxial cable coated with a dielectric, in which a series of compartments act as coupled electric circuits that gradually narrow the resonance profile. The tuning of the peak frequency is assumed to be controlled by the average amplitude of voltage-gated outward currents, which in turn are regulated by the subthreshold noise in the thousands of synaptic spines that are continuously bombarded by local circuits. The results of simulations confirmed the ability of the model both to tune the peak frequency in the 10–100 Hz range and to gradually narrow the resonance profile. Considerable additional narrowing of the resonance profile is provided by repeated looping through the apical dendrite via the corticothalamocortical circuit, which reduced the width of each resonance curve (at half-maximum) to approximately 1 Hz. Synaptic noise in the neural circuit is discussed in relation to the ways it can influence the narrowing process. PMID:21853129

  6. Long-range population dynamics of anatomically defined neocortical networks

    PubMed Central

    Chen, Jerry L; Voigt, Fabian F; Javadzadeh, Mitra; Krueppel, Roland; Helmchen, Fritjof

    2016-01-01

    The coordination of activity across neocortical areas is essential for mammalian brain function. Understanding this process requires simultaneous functional measurements across the cortex. In order to dissociate direct cortico-cortical interactions from other sources of neuronal correlations, it is furthermore desirable to target cross-areal recordings to neuronal subpopulations that anatomically project between areas. Here, we combined anatomical tracers with a novel multi-area two-photon microscope to perform simultaneous calcium imaging across mouse primary (S1) and secondary (S2) somatosensory whisker cortex during texture discrimination behavior, specifically identifying feedforward and feedback neurons. We find that coordination of S1-S2 activity increases during motor behaviors such as goal-directed whisking and licking. This effect was not specific to identified feedforward and feedback neurons. However, these mutually projecting neurons especially participated in inter-areal coordination when motor behavior was paired with whisker-texture touches, suggesting that direct S1-S2 interactions are sensory-dependent. Our results demonstrate specific functional coordination of anatomically-identified projection neurons across sensory cortices. DOI: http://dx.doi.org/10.7554/eLife.14679.001 PMID:27218452

  7. Synaptic information transfer in computer models of neocortical columns

    PubMed Central

    Jacobs, Kimberle M.; Fenton, André A.; Lytton, William W.

    2010-01-01

    Understanding the direction and quantity of information flowing in neuronal networks is a fundamental problem in neuroscience. Brains and neuronal networks must at the same time store information about the world and react to information in the world. We sought to measure how the activity of the network alters information flow from inputs to output patterns. Using neocortical column neuronal network simulations, we demonstrated that networks with greater internal connectivity reduced input/output correlations from excitatory synapses and decreased negative correlations from inhibitory synapses, measured by Kendall's τ correlation. Both of these changes were associated with reduction in information flow, measured by normalized transfer entropy (nTE). Information handling by the network reflected the degree of internal connectivity. With no internal connectivity, the feedforward network transformed inputs through nonlinear summation and thresholding. With greater connectivity strength, the recurrent network translated activity and information due to contribution of activity from intrinsic network dynamics. This dynamic contribution amounts to added information drawn from that stored in the network. At still higher internal synaptic strength, the network corrupted the external information, producing a state where little external information came through. The association of increased information retrieved from the network with increased gamma power supports the notion of gamma oscillations playing a role in information processing. PMID:20556639

  8. Neocortical vasculature abnormalities in the Fragile X mental retardation syndrome.

    PubMed

    Galvan, Ashley M; Galvez, Roberto

    2012-08-30

    The Fragile X syndrome (FXS) is the leading form of inherited mental retardation. To date, the most prominent neuronal phenotype associated with the syndrome is an abundance of long thin spines exhibiting an immature morphology. However, in addition to synaptic abnormalities, recent case studies have demonstrated that Fragile X (FX) patients also exhibit abnormal cerebral blood flow (CBF). To examine the role of the Fragile X mental retardation protein (FMRP) in altering CBF, we examined blood vessel density (BVD) in the visual cortex of Adult and Middle-aged FX mice. Analysis of Middle-aged FX mice demonstrated elevated BVD compared to wildtype controls, suggesting that FX mice exhibit a lack of age-induced BVD plasticity. However, Adult FX and wildtype mice did not exhibit consistent differences in BVD. These data demonstrate that FMRP is required for age-induced neocortical vasculature plasticity. Furthermore, these data suggest a new role for FMRP in blood vessel regulation that would have profound implications towards appropriately timed delivery of neuronal nutrients, thus contributing to or exacerbating FX cognitive and neuronal abnormalities.

  9. Hippocampal-neocortical interaction: a hierarchy of associativity.

    PubMed

    Lavenex, P; Amaral, D G

    2000-01-01

    The structures forming the medial temporal lobe appear to be necessary for the establishment of long-term declarative memory. In particular, they may be involved in the "consolidation" of information in higher-order associational cortices, perhaps through feedback projections. This review highlights the fact that the medial temporal lobe is organized as a hierarchy of associational networks. Indeed, associational connections within the perirhinal, parahippocampal, and entorhinal cortices enables a significant amount of integration of unimodal and polymodal inputs, so that only highly integrated information reaches the remainder of the hippocampal formation. The feedback efferent projections from the perirhinal and parahippocampal cortices to the neocortex largely reciprocate the afferent projections from the neocortex to these areas. There are, however, noticeable differences in the degree of reciprocity of connections between the perirhinal and parahippocampal cortices and certain areas of the neocortex, in particular in the frontal and temporal lobes. These observations are particularly important for models of hippocampal-neocortical interaction and long-term storage of information in the neocortex. Furthermore, recent functional studies suggest that the perirhinal and parahippocampal cortices are more than interfaces for communication between the neocortex and the hippocampal formation. These structures participate actively in memory processes, but the precise role they play in the service of memory or other cognitive functions is currently unclear.

  10. Theory of electric resonance in the neocortical apical dendrite.

    PubMed

    Kasevich, Ray S; LaBerge, David

    2011-01-01

    Pyramidal neurons of the neocortex display a wide range of synchronous EEG rhythms, which arise from electric activity along the apical dendrites of neocortical pyramidal neurons. Here we present a theoretical description of oscillation frequency profiles along apical dendrites which exhibit resonance frequencies in the range of 10 to 100 Hz. The apical dendrite is modeled as a leaky coaxial cable coated with a dielectric, in which a series of compartments act as coupled electric circuits that gradually narrow the resonance profile. The tuning of the peak frequency is assumed to be controlled by the average amplitude of voltage-gated outward currents, which in turn are regulated by the subthreshold noise in the thousands of synaptic spines that are continuously bombarded by local circuits. The results of simulations confirmed the ability of the model both to tune the peak frequency in the 10-100 Hz range and to gradually narrow the resonance profile. Considerable additional narrowing of the resonance profile is provided by repeated looping through the apical dendrite via the corticothalamocortical circuit, which reduced the width of each resonance curve (at half-maximum) to approximately 1 Hz. Synaptic noise in the neural circuit is discussed in relation to the ways it can influence the narrowing process.

  11. GABAergic circuits control spike-timing-dependent plasticity.

    PubMed

    Paille, Vincent; Fino, Elodie; Du, Kai; Morera-Herreras, Teresa; Perez, Sylvie; Kotaleski, Jeanette Hellgren; Venance, Laurent

    2013-05-29

    The spike-timing-dependent plasticity (STDP), a synaptic learning rule for encoding learning and memory, relies on relative timing of neuronal activity on either side of the synapse. GABAergic signaling has been shown to control neuronal excitability and consequently the spike timing, but whether GABAergic circuits rule the STDP remained unknown. Here we show that GABAergic signaling governs the polarity of STDP, because blockade of GABAA receptors was able to completely reverse the temporal order of plasticity at corticostriatal synapses in rats and mice. GABA controls the polarity of STDP in both striatopallidal and striatonigral output neurons. Biophysical simulations and experimental investigations suggest that GABA controls STDP polarity through depolarizing effects at distal dendrites of striatal output neurons by modifying the balance of two calcium sources, NMDARs and voltage-sensitive calcium channels. These findings establish a central role for GABAergic circuits in shaping STDP and suggest that GABA could operate as a Hebbian/anti-Hebbian switch.

  12. GABAergic circuit dysfunction in the Drosophila Fragile X syndrome model

    PubMed Central

    Gatto, Cheryl L.; Pereira, Daniel; Broadie, Kendal

    2014-01-01

    Fragile X syndrome (FXS), caused by loss of FMR1 gene function, is the most common heritable cause of intellectual disability and autism spectrum disorders. The FMR1 protein (FMRP) translational regulator mediates activity-dependent control of synapses. In addition to the metabotropic glutamate receptor (mGluR) hyperexcitation FXS theory, the GABA theory postulates that hypoinhibition is causative for disease state symptoms. Here, we use the Drosophila FXS model to assay central brain GABAergic circuitry, especially within the Mushroom Body (MB) learning center. All 3 GABAA receptor (GABAAR) subunits are reportedly downregulated in dfmr1 null brains. We demonstrate parallel downregulation of glutamic acid decarboxylase (GAD), the rate-limiting GABA synthesis enzyme, although GABAergic cell numbers appear unaffected. Mosaic analysis with a repressible cell marker (MARCM) single-cell clonal studies show that dfmr1 null GABAergic neurons innervating the MB calyx display altered architectural development, with early underdevelopment followed by later overelaboration. In addition, a new class of extra-calyx terminating GABAergic neurons is shown to include MB intrinsic α/β Kenyon Cells (KCs), revealing a novel level of MB inhibitory regulation. Functionally, dfmr1 null GABAergic neurons exhibit elevated calcium signaling and altered kinetics in response to acute depolarization. To test the role of these GABAergic changes, we attempted to pharmacologically restore GABAergic signaling and assay effects on the compromised MB-dependent olfactory learning in dfmr1 mutants, but found no improvement. Our results show that GABAergic circuit structure and function are impaired in the FXS disease state, but that correction of hypoinhibition alone is not sufficient to rescue a behavioral learning impairment. PMID:24423648

  13. The Basolateral Amygdala GABAergic System in Health and Disease

    PubMed Central

    Prager, Eric M; Bergstrom, Hadley C; Wynn, Gary H; Braga, Maria F. M.

    2015-01-01

    The brain comprises an excitatory/inhibitory neuronal network that maintains a finely tuned balance of activity critical for normal functioning. Excitatory activity in the basolateral amygdala (BLA), a brain region that plays a central role in emotion and motivational processing, is tightly regulated by a relatively small population of gamma-aminobutyric acid (GABA) inhibitory neurons. Disruption in GABAergic inhibition in the BLA can occur when there is a loss of local GABAergic interneurons, alterations in GABAA receptor activation, or dysregulation of mechanisms that modulate BLA GABAergic inhibition. Disruptions in GABAergic control of the BLA emerge during development, in aging populations, or after a trauma, ultimately resulting in hyperexcitability. BLA hyperexcitability manifests behaviorally as an increase in anxiety, emotional dysregulation, or the development of seizure activity. This article reviews the anatomy, development, and physiology of the GABAergic system in the BLA, and circuits that modulate GABAergic inhibition, including the dopaminergic, serotonergic, noradrenergic, and cholinergic systems. We highlight how alterations in various neurotransmitter receptors, including the acid sensing ion channel 1a (ASIC1a), cannabinoid receptor 1 (CB1), and glutamate receptor subtypes, expressed on BLA interneurons, modulate GABAergic transmission and how defects of these systems affects inhibitory tonus within the BLA. Finally, we discuss alterations in the BLA GABAergic system in neurodevelopmental (autism/Fragile X syndrome) and neurodegenerative (Alzheimer’s disease) diseases, and after the development of epilepsy, anxiety, and traumatic brain injury. A more complete understanding of the intrinsic excitatory/inhibitory circuit balance of the amygdala and how imbalances in inhibitory control contribute to excessive BLA excitability will guide the development of novel therapeutic approaches in neuropsychiatric diseases. PMID:26586374

  14. GABAergic circuit dysfunction in the Drosophila Fragile X syndrome model.

    PubMed

    Gatto, Cheryl L; Pereira, Daniel; Broadie, Kendal

    2014-05-01

    Fragile X syndrome (FXS), caused by loss of FMR1 gene function, is the most common heritable cause of intellectual disability and autism spectrum disorders. The FMR1 protein (FMRP) translational regulator mediates activity-dependent control of synapses. In addition to the metabotropic glutamate receptor (mGluR) hyperexcitation FXS theory, the GABA theory postulates that hypoinhibition is causative for disease state symptoms. Here, we use the Drosophila FXS model to assay central brain GABAergic circuitry, especially within the Mushroom Body (MB) learning center. All 3 GABAA receptor (GABAAR) subunits are reportedly downregulated in dfmr1 null brains. We demonstrate parallel downregulation of glutamic acid decarboxylase (GAD), the rate-limiting GABA synthesis enzyme, although GABAergic cell numbers appear unaffected. Mosaic analysis with a repressible cell marker (MARCM) single-cell clonal studies show that dfmr1 null GABAergic neurons innervating the MB calyx display altered architectural development, with early underdevelopment followed by later overelaboration. In addition, a new class of extra-calyx terminating GABAergic neurons is shown to include MB intrinsic α/β Kenyon Cells (KCs), revealing a novel level of MB inhibitory regulation. Functionally, dfmr1 null GABAergic neurons exhibit elevated calcium signaling and altered kinetics in response to acute depolarization. To test the role of these GABAergic changes, we attempted to pharmacologically restore GABAergic signaling and assay effects on the compromised MB-dependent olfactory learning in dfmr1 mutants, but found no improvement. Our results show that GABAergic circuit structure and function are impaired in the FXS disease state, but that correction of hypoinhibition alone is not sufficient to rescue a behavioral learning impairment.

  15. Localization of the Brainstem GABAergic Neurons Controlling Paradoxical (REM) Sleep

    PubMed Central

    Bérod, Anne; Goutagny, Romain; Léger, Lucienne; Ravassard, Pascal; Clément, Olivier; Hanriot, Lucie; Fort, Patrice; Luppi, Pierre-Hervé

    2009-01-01

    Paradoxical sleep (PS) is a state characterized by cortical activation, rapid eye movements and muscle atonia. Fifty years after its discovery, the neuronal network responsible for the genesis of PS has been only partially identified. We recently proposed that GABAergic neurons would have a pivotal role in that network. To localize these GABAergic neurons, we combined immunohistochemical detection of Fos with non-radioactive in situ hybridization of GAD67 mRNA (GABA synthesis enzyme) in control rats, rats deprived of PS for 72 h and rats allowed to recover after such deprivation. Here we show that GABAergic neurons gating PS (PS-off neurons) are principally located in the ventrolateral periaqueductal gray (vlPAG) and the dorsal part of the deep mesencephalic reticular nucleus immediately ventral to it (dDpMe). Furthermore, iontophoretic application of muscimol for 20 min in this area in head-restrained rats induced a strong and significant increase in PS quantities compared to saline. In addition, we found a large number of GABAergic PS-on neurons in the vlPAG/dDPMe region and the medullary reticular nuclei known to generate muscle atonia during PS. Finally, we showed that PS-on neurons triggering PS localized in the SLD are not GABAergic. Altogether, our results indicate that multiple populations of PS-on GABAergic neurons are distributed in the brainstem while only one population of PS-off GABAergic neurons localized in the vlPAG/dDpMe region exist. From these results, we propose a revised model for PS control in which GABAergic PS-on and PS-off neurons localized in the vlPAG/dDPMe region play leading roles. PMID:19169414

  16. YAP stabilizes SMAD1 and promotes BMP2-induced neocortical astrocytic differentiation.

    PubMed

    Huang, Zhihui; Hu, Jinxia; Pan, Jinxiu; Wang, Ying; Hu, Guoqing; Zhou, Jiliang; Mei, Lin; Xiong, Wen-Cheng

    2016-07-01

    ‪YAP (yes-associated protein), a key transcriptional co-factor that is negatively regulated by the Hippo pathway, is crucial for the development and size control of multiple organs, including the liver. However, its role in the brain remains unclear. Here, we provide evidence for YAP regulation of mouse neocortical astrocytic differentiation and proliferation. YAP was undetectable in neurons, but selectively expressed in neural stem cells (NSCs) and astrocytes. YAP in NSCs was required for neocortical astrocytic differentiation, with no apparent role in self-renewal or neural differentiation. However, YAP in astrocytes was necessary for astrocytic proliferation. Yap (Yap1) knockout, Yap(nestin) conditional knockout and Yap(GFAP) conditional knockout mice displayed fewer neocortical astrocytes and impaired astrocytic proliferation and, consequently, death of neocortical neurons. Mechanistically, YAP was activated by BMP2, and the active/nuclear YAP was crucial for BMP2 induction and stabilization of SMAD1 and astrocytic differentiation. Expression of SMAD1 in YAP-deficient NSCs partially rescued the astrocytic differentiation deficit in response to BMP2. Taken together, these results identify a novel function of YAP in neocortical astrocytic differentiation and proliferation, and reveal a BMP2-YAP-SMAD1 pathway underlying astrocytic differentiation in the developing mouse neocortex.

  17. Neuropsychiatric Symptoms and Regional Neocortical Atrophy in Mild Cognitive Impairment and Alzheimer’s Disease

    PubMed Central

    Rafii, Michael S.; Taylor, Curtis S.; Kim, Hyun T.; Desikan, Rahul S.; Fleisher, Adam S.; Katibian, David; Brewer, James B.; Dale, Anders M.; Aisen, Paul S.

    2017-01-01

    Background To assess the relationship between regional neocortical atrophy and psychotic symptoms in adults with mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Methods Rates of change in regional neocortical atrophy as measured by longitudinal magnetic resonance imaging scans and the occurrence of psychotic symptoms and/or the long-term use of antipsychotic medications in 389 outpatients with MCI or AD in Alzheimer’s Disease Neuroimaging Initiative. Results Atrophy rate of 3 specific neocortical regions, lateral frontal, lateral parietal, and anterior cingulate gyrus, was significantly associated with the onset of psychosis including delusions, agitation, wandering, and hallucinations and/or the need for chronic antipsychotic medications. Atrophy rate of the lateral frontal lobe correlated most significantly with onset of psychotic symptoms or need for chronic antipsychotic medications. Conclusions Psychosis was associated with volume loss in specific regions of the lateral frontal and parietal lobes as well as anterior cingulate gyrus. PMID:24164929

  18. Action potential initiation and propagation in rat neocortical pyramidal neurons.

    PubMed

    Stuart, G; Schiller, J; Sakmann, B

    1997-12-15

    1. Initiation and propagation of action potentials evoked by extracellular synaptic stimulation was studied using simultaneous dual and triple patch pipette recordings from different locations on neocortical layer 5 pyramidal neurons in brain slices from 4-week-old rats (P26-30) at physiological temperatures. 2. Simultaneous cell-attached and whole-cell voltage recordings from the apical trunk (up to 700 microns distal to the soma) and the soma indicated that proximal synaptic stimulation (layer 4) initiated action potentials first at the soma, whereas distal stimulation (upper layer 2/3) could initiate dendritic regenerative potentials prior to somatic action potentials following stimulation at higher intensity. 3. Somatic action potentials, once initiated, propagated back into the apical dendrites in a decremented manner which was frequency dependent. The half-width of back propagating action potentials increased and their maximum rate of rise decreased with distance from the soma, with the peak of these action potentials propagating with a conduction velocity of approximately 0.5 m s-1. 4. Back-propagation of action potentials into the dendritic tree was associated with dendritic calcium electrogenesis, which was particularly prominent during bursts of somatic action potentials. 5. When dendritic regenerative potentials were evoked prior to somatic action potentials, the more distal the dendritic recording was made from the soma the longer the time between the onset of the dendritic regenerative potential relative to somatic action potential. This suggested that dendritic regenerative potentials were initiated in the distal apical dendrites, possibly in the apical tuft. 6. At any one stimulus intensity, the initiation of dendritic regenerative potentials prior to somatic action potentials could fluctuate, and was modulated by depolarizing somatic or hyperpolarizing dendritic current injection. 7. Dendritic regenerative potentials could be initiated prior to

  19. Forebrain GABAergic projections to locus coeruleus in mouse.

    PubMed

    Dimitrov, Eugene L; Yanagawa, Yuchio; Usdin, Ted B

    2013-07-01

    The noradrenergic locus coeruleus (LC) regulates arousal, memory, sympathetic nervous system activity, and pain. Forebrain projections to LC have been characterized in rat, cat, and primates, but not systematically in mouse. We surveyed mouse forebrain LC-projecting neurons by examining retrogradely labeled cells following LC iontophoresis of Fluoro-Gold and anterograde LC labeling after forebrain injection of biotinylated dextran amine or viral tracer. Similar to other species, the central amygdalar nucleus (CAmy), anterior hypothalamus, paraventricular nucleus, and posterior lateral hypothalamic area (PLH) provide major LC inputs. By using mice expressing green fluorescent protein in γ-aminobutyric acid (GABA)ergic neurons, we found that more than one-third of LC-projecting CAmy and PLH neurons are GABAergic. LC colocalization of biotinylated dextran amine, following CAmy or PLH injection, with either green fluorescent protein or glutamic acid decarboxylase (GAD)65/67 immunoreactivity confirmed these GABAergic projections. CAmy injection of adeno-associated virus encoding channelrhodopsin-2-Venus showed similar fiber labeling and association with GAD65/67-immunoreactive (ir) and tyrosine hydroxylase (TH)-ir neurons. CAmy and PLH projections were densest in a pericoerulear zone, but many fibers entered the LC proper. Close apposition between CAmy GABAergic projections and TH-ir processes suggests that CAmy GABAergic neurons may directly inhibit noradrenergic principal neurons. Direct LC neuron targeting was confirmed by anterograde transneuronal labeling of LC TH-ir neurons following CAmy or PLH injection of a herpes virus that expresses red fluorescent protein following activation by Cre recombinase in mice that express Cre recombinase in GABAergic neurons. This description of GABAergic projections from the CAmy and PLH to the LC clarifies important forebrain sources of inhibitory control of central nervous system noradrenergic activity.

  20. Control of REM sleep by ventral medulla GABAergic neurons.

    PubMed

    Weber, Franz; Chung, Shinjae; Beier, Kevin T; Xu, Min; Luo, Liqun; Dan, Yang

    2015-10-15

    Rapid eye movement (REM) sleep is a distinct brain state characterized by activated electroencephalogram and complete skeletal muscle paralysis, and is associated with vivid dreams. Transection studies by Jouvet first demonstrated that the brainstem is both necessary and sufficient for REM sleep generation, and the neural circuits in the pons have since been studied extensively. The medulla also contains neurons that are active during REM sleep, but whether they play a causal role in REM sleep generation remains unclear. Here we show that a GABAergic (γ-aminobutyric-acid-releasing) pathway originating from the ventral medulla powerfully promotes REM sleep in mice. Optogenetic activation of ventral medulla GABAergic neurons rapidly and reliably initiated REM sleep episodes and prolonged their durations, whereas inactivating these neurons had the opposite effects. Optrode recordings from channelrhodopsin-2-tagged ventral medulla GABAergic neurons showed that they were most active during REM sleep (REMmax), and during wakefulness they were preferentially active during eating and grooming. Furthermore, dual retrograde tracing showed that the rostral projections to the pons and midbrain and caudal projections to the spinal cord originate from separate ventral medulla neuron populations. Activating the rostral GABAergic projections was sufficient for both the induction and maintenance of REM sleep, which are probably mediated in part by inhibition of REM-suppressing GABAergic neurons in the ventrolateral periaqueductal grey. These results identify a key component of the pontomedullary network controlling REM sleep. The capability to induce REM sleep on command may offer a powerful tool for investigating its functions.

  1. Caenorhabditis elegans flamingo cadherin fmi-1 regulates GABAergic neuronal development.

    PubMed

    Najarro, Elvis Huarcaya; Wong, Lianna; Zhen, Mei; Carpio, Edgar Pinedo; Goncharov, Alexandr; Garriga, Gian; Lundquist, Erik A; Jin, Yishi; Ackley, Brian D

    2012-03-21

    In a genetic screen for regulators of synaptic morphology, we identified the single Caenorhabditis elegans flamingo-like cadherin fmi-1. The fmi-1 mutants exhibit defective axon pathfinding, reduced synapse number, aberrant synapse size and morphology, as well as an abnormal accumulation of synaptic vesicles at nonsynaptic regions. Although FMI-1 is primarily expressed in the nervous system, it is not expressed in the ventral D-type (VD) GABAergic motorneurons, which are defective in fmi-1 mutants. The axon and synaptic defects of VD neurons could be rescued when fmi-1 was expressed exclusively in non-VD neighboring neurons, suggesting a cell nonautonomous action of FMI-1. FMI-1 protein that lacked its intracellular domain still retained its ability to rescue the vesicle accumulation defects of GABAergic motorneurons, indicating that the extracellular domain was sufficient for this function of FMI-1 in GABAergic neuromuscular junction development. Mutations in cdh-4, a Fat-like cadherin, cause similar defects in GABAergic motorneurons. The cdh-4 is expressed by the VD neurons and seems to function in the same genetic pathway as fmi-1 to regulate GABAergic neuron development. Thus, fmi-1 and cdh-4 cadherins might act together to regulate synapse development and axon pathfinding.

  2. Cortical fast-spiking parvalbumin interneurons enwrapped in the perineuronal net express the metallopeptidases Adamts8, Adamts15 and Neprilysin.

    PubMed

    Rossier, J; Bernard, A; Cabungcal, J-H; Perrenoud, Q; Savoye, A; Gallopin, T; Hawrylycz, M; Cuénod, M; Do, K; Urban, A; Lein, Ed S

    2015-02-01

    The in situ hybridization Allen Mouse Brain Atlas was mined for proteases expressed in the somatosensory cerebral cortex. Among the 480 genes coding for protease/peptidases, only four were found enriched in cortical interneurons: Reln coding for reelin; Adamts8 and Adamts15 belonging to the class of metzincin proteases involved in reshaping the perineuronal net (PNN) and Mme encoding for Neprilysin, the enzyme degrading amyloid β-peptides. The pattern of expression of metalloproteases (MPs) was analyzed by single-cell reverse transcriptase multiplex PCR after patch clamp and was compared with the expression of 10 canonical interneurons markers and 12 additional genes from the Allen Atlas. Clustering of these genes by K-means algorithm displays five distinct clusters. Among these five clusters, two fast-spiking interneuron clusters expressing the calcium-binding protein Pvalb were identified, one co-expressing Pvalb with Sst (PV-Sst) and another co-expressing Pvalb with three metallopeptidases Adamts8, Adamts15 and Mme (PV-MP). By using Wisteria floribunda agglutinin, a specific marker for PNN, PV-MP interneurons were found surrounded by PNN, whereas the ones expressing Sst, PV-Sst, were not.

  3. Statistical models suggest presence of two distinct subpopulations of miniature EPSCs in fast-spiking interneurons of rat prefrontal cortex.

    PubMed

    Malkin, S L; Kim, K K; Tikhonov, D B; Magazanik, L G; Zaitsev, A V

    2015-08-20

    Properties of excitatory synaptic responses in fast-spiking interneurons (FSIs) and pyramidal neurons (PNs) are different; however, the mechanisms and determinants of this diversity have not been fully investigated. In the present study, voltage-clamp recording of miniature excitatory post-synaptic currents (mEPSCs) was performed of layer 2-3 FSIs and PNs in the medial prefrontal cortex of rats aged 19-22days. The average mEPSCs in the FSIs exhibited amplitudes that were two times larger than those of the PNs and with much faster rise and decay. The mEPSC amplitude distributions in both cell types were asymmetric and in FSIs, the distributions were more skewed and had two-times larger coefficients of variation than in the PNs. In PNs but not in FSIs, the amplitude distributions were fitted well by different skewed unimodal functions that have been used previously for this purpose. In the FSIs, the distributions were well approximated only by a sum of two such functions, suggesting the presence of at least two subpopulations of events with different modal amplitudes. According to our estimates, two-thirds of the mEPSCs in FSIs belong to the high-amplitude subpopulation, and the modal amplitude in this subpopulation is approximately two times larger than that in the low-amplitude subpopulation. Using different statistical models, varying binning size, and data subsets, we confirmed the robustness and consistency of these findings.

  4. Neuregulin-Dependent Regulation of Fast-Spiking Interneuron Excitability Controls the Timing of the Critical Period.

    PubMed

    Gu, Yu; Tran, Trinh; Murase, Sachiko; Borrell, Andrew; Kirkwood, Alfredo; Quinlan, Elizabeth M

    2016-10-05

    Maturation of excitatory drive onto fast-spiking interneurons (FS INs) in the visual cortex has been implicated in the control of the timing of the critical period for ocular dominance plasticity. However, the mechanisms that regulate the strength of these synapses over cortical development are not understood. Here we use a mouse model to show that neuregulin (NRG) and the receptor tyrosine kinase erbB4 regulate the timing of the critical period. NRG1 enhanced the strength of excitatory synapses onto FS INs, which inhibited ocular dominance plasticity during the critical period but rescued plasticity in transgenics with hypoexcitable FS INs. Blocking the effects of endogenous neuregulin via inhibition of erbBs rescued ocular dominance plasticity in postcritical period adults, allowing recovery from amblyopia induced by chronic monocular deprivation. Thus, the strength of excitation onto FS INs is a key determinant of critical period plasticity and is maintained at high levels by NRG-erbB4 signaling to constrain plasticity in adulthood.

  5. Fast gamma oscillations are generated intrinsically in CA1 without the involvement of fast-spiking basket cells.

    PubMed

    Craig, Michael T; McBain, Chris J

    2015-02-25

    Information processing in neuronal networks relies on the precise synchronization of ensembles of neurons, coordinated by the diverse family of inhibitory interneurons. Cortical interneurons can be usefully parsed by embryonic origin, with the vast majority arising from either the caudal or medial ganglionic eminences (CGE and MGE). Here, we examine the activity of hippocampal interneurons during gamma oscillations in mouse CA1, using an in vitro model where brief epochs of rhythmic activity were evoked by local application of kainate. We found that this CA1 KA-evoked gamma oscillation was faster than that in CA3 and, crucially, did not appear to require the involvement of fast-spiking basket cells. In contrast to CA3, we also found that optogenetic inhibition of pyramidal cells in CA1 did not significantly affect the power of the oscillation, suggesting that excitation may not be essential for gamma genesis in this region. We found that MGE-derived interneurons were generally more active than CGE interneurons during CA1 gamma, although a group of CGE-derived interneurons, putative trilaminar cells, were strongly phase-locked with gamma oscillations and, together with MGE-derived axo-axonic and bistratified cells, provide attractive candidates for being the driver of this locally generated, predominantly interneuron-driven model of gamma oscillations.

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

    ERIC Educational Resources Information Center

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

    2015-01-01

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

  7. Statistical mechanics of neocortical interactions: Constraints on 40-Hz models of short-term memory

    NASA Astrophysics Data System (ADS)

    Ingber, Lester

    1995-10-01

    Calculations presented in L. Ingber and P.L. Nunez, Phys. Rev. E 51, 5074 (1995) detailed the evolution of short-term memory in the neocortex, supporting the empirical 7+/-2 rule of constraints on the capacity of neocortical processing. These results are given further support when other recent models of 40-Hz subcycles of low-frequency oscillations are considered.

  8. Temporal Coding at the Immature Depolarizing GABAergic Synapse

    PubMed Central

    Valeeva, Guzel; Abdullin, Azat; Tyzio, Roman; Skorinkin, Andrei; Nikolski, Evgeny; Ben-Ari, Yehezkiel; Khazipov, Rustem

    2010-01-01

    In the developing hippocampus, GABA exerts depolarizing and excitatory actions and contributes to the generation of neuronal network driven giant depolarizing potentials (GDPs). Here, we studied spike time coding at immature GABAergic synapses and its impact on synchronization of the neuronal network during GDPs in the neonatal (postnatal days P2–6) rat hippocampal slices. Using extracellular recordings, we found that the delays of action potentials (APs) evoked by synaptic activation of GABA(A) receptors are long (mean, 65 ms) and variable (within a time window of 10–200 ms). During patch-clamp recordings, depolarizing GABAergic responses were mainly subthreshold and their amplification by persistent sodium conductance was required to trigger APs. AP delays at GABAergic synapses shortened and their variability reduced with an increase in intracellular chloride concentration during whole-cell recordings. Negative shift of the GABA reversal potential (EGABA) with low concentrations of bumetanide, or potentiation of GABA(A) receptors with diazepam reduced GDPs amplitude, desynchronized neuronal firing during GDPs and slowed down GDPs propagation. Partial blockade of GABA(A) receptors with bicuculline increased neuronal synchronization and accelerated GDPs propagation. We propose that spike timing at depolarizing GABA synapses is determined by intracellular chloride concentration. At physiological levels of intracellular chloride GABAergic depolarization does not reach the action potential threshold and amplification of GABAergic responses by non-inactivating sodium conductance is required for postsynaptic AP initiation. Slow and variable excitation at GABAergic synapse determines the level of neuronal synchrony and the rate of GDPs propagation in the developing hippocampus. PMID:20725525

  9. Temporal coding at the immature depolarizing GABAergic synapse.

    PubMed

    Valeeva, Guzel; Abdullin, Azat; Tyzio, Roman; Skorinkin, Andrei; Nikolski, Evgeny; Ben-Ari, Yehezkiel; Khazipov, Rustem

    2010-01-01

    In the developing hippocampus, GABA exerts depolarizing and excitatory actions and contributes to the generation of neuronal network driven giant depolarizing potentials (GDPs). Here, we studied spike time coding at immature GABAergic synapses and its impact on synchronization of the neuronal network during GDPs in the neonatal (postnatal days P2-6) rat hippocampal slices. Using extracellular recordings, we found that the delays of action potentials (APs) evoked by synaptic activation of GABA(A) receptors are long (mean, 65 ms) and variable (within a time window of 10-200 ms). During patch-clamp recordings, depolarizing GABAergic responses were mainly subthreshold and their amplification by persistent sodium conductance was required to trigger APs. AP delays at GABAergic synapses shortened and their variability reduced with an increase in intracellular chloride concentration during whole-cell recordings. Negative shift of the GABA reversal potential (E(GABA)) with low concentrations of bumetanide, or potentiation of GABA(A) receptors with diazepam reduced GDPs amplitude, desynchronized neuronal firing during GDPs and slowed down GDPs propagation. Partial blockade of GABA(A) receptors with bicuculline increased neuronal synchronization and accelerated GDPs propagation. We propose that spike timing at depolarizing GABA synapses is determined by intracellular chloride concentration. At physiological levels of intracellular chloride GABAergic depolarization does not reach the action potential threshold and amplification of GABAergic responses by non-inactivating sodium conductance is required for postsynaptic AP initiation. Slow and variable excitation at GABAergic synapse determines the level of neuronal synchrony and the rate of GDPs propagation in the developing hippocampus.

  10. Leptin potentiates GABAergic synaptic transmission in the developing rodent hippocampus

    PubMed Central

    Guimond, Damien; Diabira, Diabe; Porcher, Christophe; Bader, Francesca; Ferrand, Nadine; Zhu, Mingyan; Appleyard, Suzanne M.; Wayman, Gary A.; Gaiarsa, Jean-Luc

    2014-01-01

    It is becoming increasingly clear that leptin is not only a hormone regulating energy homeostasis but also a neurotrophic factor impacting a number of brain regions, including the hippocampus. Although leptin promotes the development of GABAergic transmission in the hypothalamus, little is known about its action on the GABAergic system in the hippocampus. Here we show that leptin modulates GABAergic transmission onto developing CA3 pyramidal cells of newborn rats. Specifically, leptin induces a long-lasting potentiation (LLP-GABAA) of miniature GABAA receptor-mediated postsynaptic current (GABAA-PSC) frequency. Leptin also increases the amplitude of evoked GABAA-PSCs in a subset of neurons along with a decrease in the coefficient of variation and no change in the paired-pulse ratio, pointing to an increased recruitment of functional synapses. Adding pharmacological blockers to the recording pipette showed that the leptin-induced LLP-GABAA requires postsynaptic calcium released from internal stores, as well as postsynaptic MAPK/ERK kinases 1 and/or 2 (MEK1/2), phosphoinositide 3 kinase (PI3K) and calcium-calmodulin kinase kinase (CaMKK). Finally, study of CA3 pyramidal cells in leptin-deficient ob/ob mice revealed a reduction in the basal frequency of miniature GABAA-PSCs compared to wild type littermates. In addition, presynaptic GAD65 immunostaining was reduced in the CA3 stratum pyramidale of mutant animals, both results converging to suggest a decreased number of functional GABAergic synapses in ob/ob mice. Overall, these results show that leptin potentiates and promotes the development of GABAergic synaptic transmission in the developing hippocampus likely via an increase in the number of functional synapses, and provide insights into the intracellular pathways mediating this effect. This study further extends the scope of leptin's neurotrophic action to a key regulator of hippocampal development and function, namely GABAergic transmission. PMID:25177272

  11. Impact of ethanol on the developing GABAergic system.

    PubMed

    Isayama, Ricardo Noboro; Leite, Paulo Emilio Correa; Lima, Jean Pierre Mendes; Uziel, Daniela; Yamasaki, Edna Nanami

    2009-12-01

    Alcohol intake during pregnancy has a tremendous impact on the developing brain. Embryonic and early postnatal alcohol exposures have been investigated experimentally to elucidate the fetal alcohol spectrum disorders' (FASD) milieu, and new data have emerged to support a devastating effect on the GABAergic system in the adult and developing nervous system. GABA is a predominantly inhibitory neurotransmitter that during development excites neurons and orchestrates several developmental processes such as proliferation, migration, differentiation, and synaptogenesis. This review summarizes and brings new data on neurodevelopmental aspects of the GABAergic system with FASD in experimental telencephalic models.

  12. Statistical mechanics of neocortical interactions: A scaling paradigm applied to electroencephalography

    NASA Astrophysics Data System (ADS)

    Ingber, Lester

    1991-09-01

    A series of papers has developed a statistical mechanics of neocortical interactions (SMNI), deriving aggregate behavior of experimentally observed columns of neurons from statistical electrical-chemical properties of synaptic interactions. While not useful to yield insights at the single-neuron level, SMNI has demonstrated its capability in describing large-scale properties of short-term memory and electroencephalographic (EEG) systematics. The necessity of including nonlinear and stochastic structures in this development has been stressed. In this paper, a more stringent test is placed on SMNI: The algebraic and numerical algorithms previously developed in this and similar systems are brought to bear to fit large sets of EEG and evoked-potential data being collected to investigate genetic predispositions to alcoholism and to extract brain ``signatures'' of short-term memory. Using the numerical algorithm of very fast simulated reannealing, it is demonstrated that SMNI can indeed fit these data within experimentally observed ranges of its underlying neuronal-synaptic parameters, and the quantitative modeling results are used to examine physical neocortical mechanisms to discriminate high-risk and low-risk populations genetically predisposed to alcoholism. Since this study is a control to span relatively long time epochs, similar to earlier attempts to establish such correlations, this discrimination is inconclusive because of other neuronal activity which can mask such effects. However, the SMNI model is shown to be consistent with EEG data during selective attention tasks and with neocortical mechanisms describing short-term memory previously published using this approach. This paper explicitly identifies similar nonlinear stochastic mechanisms of interaction at the microscopic-neuronal, mesoscopic-columnar, and macroscopic-regional scales of neocortical interactions. These results give strong quantitative support for an accurate intuitive picture, portraying

  13. Change of Patient Selection Strategy and Improved Surgical Outcome in MRI-negative Neocortical Epilepsy

    PubMed Central

    Moon, Hye-Jin; Kim, Dong Wook; Chung, Chun-Kee; Shin, Jung-won; Moon, Jangsup; Kang, Bong Su; Lee, Soon-Tae; Jung, Keun-Hwa; Chu, Kon; Jung, Ki-Young; Cho, Yong Won; Lee, Sang Kun

    2016-01-01

    Background and Purpose It is crucial to make selection strategy to identify surgical candidates among medically refractory MRI-negative neocortical epilepsy patients. In our previous study, we suggested two or more concordance between noninvasive studies (EEG, ictal scalp EEG, interictal FDG-PET, and SPECT) as a new patient selection strategy for MRI-negative neocortical epilepsy surgery. The objective of this study was to evaluate the surgical outcomes of MRI-negative neocortical epilepsy patients before and after the implementation of a new selection strategy. Methods From 1995 to 2011, we included 153 consecutive MRI-negative neocortical epilepsy patients who received focal resection and had a follow-up period of at least 2 years. These patients were divided into two groups according to their date of surgery (before and after July 2002). The old group consisted of 89 patients and the new one consisted of 53 patients. Clinical characteristics, presurgical evaluations, and pathology were reviewed. Results The new patient selection strategy led to a significant increase in the concordance between two or more modalities. The improvement in surgical outcome after 2002 was significant (seizure-free outcome, 47.2% vs. 75.5%; p = 0.001). Concordance between two or more presurgical evaluations and localizing PET were related to a seizure-free outcome in a multivariate analysis. Conclusions After a change in surgical strategy to select patients with two or more concordance between noninvasive studies, the seizure-free outcome improved up to 75.5%. MRI-negative neocortical epilepsy patients with two or more concordance between noninvasive studies seem to be good candidates for epilepsy surgery. PMID:28101477

  14. Implications of GABAergic Neurotransmission in Alzheimer’s Disease

    PubMed Central

    Li, Yanfang; Sun, Hao; Chen, Zhicai; Xu, Huaxi; Bu, Guojun; Zheng, Hui

    2016-01-01

    Alzheimer’s disease (AD) is characterized pathologically by the deposition of β-amyloid peptides (Aβ) and the accumulation of neurofibrillary tangles (NFTs) composed of hyper-phosphorylated tau. Regardless of the pathological hallmarks, synaptic dysfunction is widely accepted as a causal event in AD. Of the two major types of synapses in the central nervous system (CNS): glutamatergic and GABAergic, which provide excitatory and inhibitory outputs respectively, abundant data implicate an impaired glutamatergic system during disease progression. However, emerging evidence supports the notion that disrupted default neuronal network underlies impaired memory, and that alterations of GABAergic circuits, either plays a primary role or as a compensatory response to excitotoxicity, may also contribute to AD by disrupting the overall network function. The goal of this review is to provide an overview of the involvement of Aβ, tau and apolipoprotein E4 (apoE4), the major genetic risk factor in late-onset AD (LOAD), in GABAergic neurotransmission and the potential of modulating the GABAergic function as AD therapy. PMID:26941642

  15. Synapse-associated protein 97 regulates the membrane properties of fast-spiking parvalbumin interneurons in the visual cortex.

    PubMed

    Akgul, Gulcan; Wollmuth, Lonnie P

    2013-07-31

    Fast-spiking parvalbumin (PV)-positive interneurons in layers 2/3 of the visual cortex regulate gain control and tuning of visual processing. Synapse-associated protein 97 (SAP97) belongs to a family of proteins that have been implicated in regulating glutamatergic synaptic transmission at pyramidal-to-pyramidal connections in the nervous system. For PV interneurons in mouse visual cortex, the expression of SAP97 is developmentally regulated, being expressed in almost all juvenile but only a fraction, ~40%, of adult PV interneurons. Using whole-cell patch-clamping, single-cell RT-PCR to assay endogenous expression of SAP97 and exogenous expression of SAP97, we investigated the functional significance of SAP97 in PV interneurons in layers 2/3 of the visual cortex. PV interneurons expressing SAP97, either endogenously or via exogenous expression, showed distinct membrane properties from those not expressing SAP97. This included an overall decrease in membrane excitability, as indexed by a decrease in membrane resistance and an increase in the stimulus threshold for the first action potential firing. Additionally, SAP97-expressing PV interneurons fired action potentials more frequently and, at moderate stimulus intensities, showed irregular or stuttering firing patterns. Furthermore, SAP97-expressing PV interneurons showed increased glutamatergic input and more extensive dendritic branching when compared with non-expressing PV interneurons. These differences in membrane and synaptic properties would significantly alter how PV interneurons expressing SAP97 compared with those not expressing SAP97 would function in local networks. Thus, our results indicate that the scaffolding protein SAP97 is a critical molecular factor regulating the input-output relationships of cortical PV interneurons.

  16. Balance of inhibitory and excitatory synaptic activity is altered in fast-spiking interneurons in experimental cortical dysplasia.

    PubMed

    Zhou, Fu-Wen; Chen, Huan-Xin; Roper, Steven N

    2009-10-01

    Cortical dysplasia (CD) is a common cause of intractable epilepsy in children and adults. We have studied rats irradiated in utero as a model of CD to better understand mechanisms that underlie dysplasia-associated epilepsy. Prior studies have shown a reduction in the number of cortical interneurons and in the frequency of inhibitory postsynaptic currents (IPSCs) in pyramidal cells in this model. They have also shown a reduced frequency of spontaneous and miniature excitatory postsynaptic currents (EPSCs) in the surviving cortical interneurons. However, the inhibitory synaptic contacts were not examined in that study. The current experiments were performed to assess inhibitory synaptic activity in fast-spiking (FS) interneurons in irradiated rats and controls and the balance of excitatory and inhibitory synaptic activity in these cells. Whole cell recordings were obtained from layer IV FS cells in controls and comparable FS cells in irradiated rats. The frequency of spontaneous and miniature IPSCs was reduced in dysplastic cortex, but the amplitude of these currents was unchanged. Stimulus-evoked IPSCs showed short-term depression in control and short-term facilitation in dysplastic cortex. Simultaneous recording of spontaneous EPSCs and IPSCs showed a shift in the ratio of excitation-to-inhibition in favor of inhibition in FS cells from dysplastic cortex. The same shift toward inhibition was seen when miniature EPSCs and IPSCs were examined. These results show that FS cells in dysplastic cortex have a relative lack of excitatory drive. This may result in an important class of inhibitory cells that are less able to perform their normal function especially in periods of increased excitatory activity.

  17. Status epilepticus enhances tonic GABA currents and depolarizes GABA reversal potential in dentate fast-spiking basket cells

    PubMed Central

    Yu, Jiandong; Proddutur, Archana; Elgammal, Fatima S.; Ito, Takahiro

    2013-01-01

    Temporal lobe epilepsy is associated with loss of interneurons and inhibitory dysfunction in the dentate gyrus. While status epilepticus (SE) leads to changes in granule cell inhibition, whether dentate basket cells critical for regulating granule cell feedforward and feedback inhibition express tonic GABA currents (IGABA) and undergo changes in inhibition after SE is not known. We find that interneurons immunoreactive for parvalbumin in the hilar-subgranular region express GABAA receptor (GABAAR) δ-subunits, which are known to underlie tonic IGABA. Dentate fast-spiking basket cells (FS-BCs) demonstrate baseline tonic IGABA blocked by GABAAR antagonists. In morphologically and physiologically identified FS-BCs, tonic IGABA is enhanced 1 wk after pilocarpine-induced SE, despite simultaneous reduction in spontaneous inhibitory postsynaptic current (sIPSC) frequency. Amplitude of tonic IGABA in control and post-SE FS-BCs is enhanced by 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), demonstrating the contribution of GABAAR δ-subunits. Whereas FS-BC resting membrane potential is unchanged after SE, perforated-patch recordings from FS-BCs show that the reversal potential for GABA currents (EGABA) is depolarized after SE. In model FS-BCs, increasing tonic GABA conductance decreased excitability when EGABA was shunting and increased excitability when EGABA was depolarizing. Although simulated focal afferent activation evoked seizurelike activity in model dentate networks with FS-BC tonic GABA conductance and shunting EGABA, excitability of identical networks with depolarizing FS-BC EGABA showed lower activity levels. Thus, together, post-SE changes in tonic IGABA and EGABA maintain homeostasis of FS-BC activity and limit increases in dentate excitability. These findings have implications for normal FS-BC function and can inform studies examining comorbidities and therapeutics following SE. PMID:23324316

  18. Immunological GABAergic interactions and therapeutic applications in autoimmune diseases.

    PubMed

    Prud'homme, Gérald J; Glinka, Yelena; Wang, Qinghua

    2015-11-01

    Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain. However, it is also produced in other sites; notably by pancreatic β cells and immune cells. The function of GABA in the immune system is at an early stage of study, but it exerts inhibitory effects that are relevant to autoimmune diseases. The study of GABAergic interactions in the immune system has centered on three main aspects: 1) the expression of GABA and the relevant GABAergic molecular machinery; 2) the in vitro response of immune cells; and 3) therapeutic applications in autoimmune diseases. T cells and macrophages can produce GABA, and express all the components necessary for a GABAergic response. There are two types of GABA receptors, but lymphocytes appear to express only type A (GABAAR); a ligand-gated chloride channel. Other immune cells may also express the type B receptor (GABABR); a G-protein coupled receptor. Activation of GABA receptors on T cells and macrophages inhibits responses such as production of inflammatory cytokines. In T cells, GABA blocks the activation-induced calcium signal, and it also inhibits NF-κB activation. In preclinical models, therapeutic application of GABA, or GABAergic (agonistic) drugs, protects against type 1 diabetes (T1D), experimental autoimmune encephalomyelitis (EAE), collagen-induced arthritis (CIA) and contact dermatitis. In addition, GABA exerts anti-apoptotic and proliferative effects on islet β cells, which may be applicable to islet transplantation. Autoimmunity against glutamic acid decarboxylase 65 (GAD65; synthesizes GABA) occurs in T1D. Antigen therapy of T1D with GAD65 or proinsulin in mice has protective effects, which are markedly enhanced by combined GABA therapy. Clinically, autoantibodies against GAD65 and/or GABA receptors play a pathogenic role in several neurological conditions, including stiff person syndrome (SPS), some forms of encephalitis, and autoimmune epilepsy. GABAergic drugs are widely used in

  19. Fluoxetine impairs GABAergic signaling in hippocampal slices from neonatal rats

    PubMed Central

    Caiati, Maddalena D.; Cherubini, Enrico

    2013-01-01

    Fluoxetine (Prozac), an antidepressant known to selectively inhibit serotonin reuptake, is widely used to treat mood disorders in women suffering from depression during pregnancy and postpartum period. Several lines of evidence suggest that this drug, which crosses the human placenta and is secreted into milk during lactation, exerts its action not only by interfering with serotoninergic but also with GABAergic transmission. GABA is known to play a crucial role in the construction of neuronal circuits early in postnatal development. The immature hippocampus is characterized by an early type of network activity, the so-called Giant Depolarizing Potentials (GDPs), generated by the synergistic action of glutamate and GABA, both depolarizing and excitatory. Here we tested the hypothesis that fluoxetine may interfere with GABAergic signaling during the first postnatal week, thus producing harmful effects on brain development. At micromolar concentrations fluoxetine severely depressed GDPs frequency (IC50 22 μM) in a reversible manner and independently of its action on serotonin reuptake. This effect was dependent on a reduced GABAergic (but not glutamatergic) drive to principal cells most probably from parvalbumin-positive fast spiking neurons. Cholecystokinin-positive GABAergic interneurons were not involved since the effects of the drug persisted when cannabinoid receptors were occluded with WIN55,212-2, a CB1/CB2 receptor agonist. Fluoxetine effects on GABAergic transmission were associated with a reduced firing rate of both principal cells and interneurons further suggesting that changes in network excitability account for GDPs disruption. This may have critical consequences on the functional organization and stabilization of neuronal circuits early in postnatal development. PMID:23641199

  20. Control of REM Sleep by Ventral Medulla GABAergic Neurons

    PubMed Central

    Weber, Franz; Chung, Shinjae; Beier, Kevin T.; Luo, Liqun; Dan, Yang

    2015-01-01

    Rapid eye movement (REM) sleep is a distinct brain state characterized by activated electroencephalogram (EEG) and complete skeletal muscle paralysis, and it is associated with vivid dreams1-3. Transection studies by Jouvet first demonstrated that the brainstem is both necessary and sufficient for REM sleep generation2, and the neural circuits in the pons have since been studied extensively4-8. The medulla also contains neurons that are active during REM sleep9-13, but whether they play a causal role in REM sleep generation remains unclear. Here we show that a GABAergic pathway originating from the ventral medulla (vM) powerfully promotes REM sleep. Optogenetic activation of vM GABAergic neurons rapidly and reliably initiated REM sleep episodes and prolonged their durations, whereas inactivating these neurons had the opposite effects. Optrode recordings from channelrhodopsin 2 (ChR2)-tagged vM GABAergic neurons showed that they were most active during REM sleep (REM-max), and during wakefulness they were preferentially active during eating and grooming. Furthermore, dual retrograde tracing showed that the rostral projections to the pons and midbrain and caudal projections to the spinal cord originate from separate vM neuron populations. Activating the rostral GABAergic projections was sufficient for both the induction and maintenance of REM sleep, which are likely mediated in part by inhibition of REM-suppressing GABAergic neurons in the ventrolateral periaqueductal gray (vlPAG). These results identify a key component of the pontomedullary network controlling REM sleep. The capability to induce REM sleep on command may offer a powerful tool for investigating its functions. PMID:26444238

  1. The Neocortical Network Representing Associative Memory Reorganizes with Time in a Process Engaging the Anterior Temporal Lobe

    PubMed Central

    Takashima, Atsuko; Oostenveld, Robert; McNaughton, Bruce L.; Fernández, Guillén; Jensen, Ole

    2012-01-01

    During encoding, the distributed neocortical representations of memory components are presumed to be associatively linked by the hippocampus. With time, a reorganization of brain areas supporting memory takes place, which can ultimately result in memories becoming independent of the hippocampus. While it is theorized that with time, the neocortical representations become linked by higher order neocortical association areas, this remains to be experimentally supported. In this study, 24 human participants encoded sets of face–location associations, which they retrieved 1 or 25 h later (“recent” and “remote” conditions, respectively), while their brain activity was recorded using whole-head magnetoencephalography. We investigated changes in the functional interactions between the neocortical representational areas emerging over time. To assess functional interactions, trial-by-trial high gamma (60–140 Hz) power correlations were calculated between the neocortical representational areas relevant to the encoded information, namely the fusiform face area (FFA) and posterior parietal cortex (PPC). With time, both the FFA and the PPC increased their functional interactions with the anterior temporal lobe (ATL). Given that the ATL is involved in semantic representation of paired associates, our results suggest that, already within 25 h after acquiring new memory associations, neocortical functional links are established via higher order semantic association areas. PMID:22139815

  2. Temporally defined neocortical translation and polysome assembly are determined by the RNA-binding protein Hu antigen R.

    PubMed

    Kraushar, Matthew L; Thompson, Kevin; Wijeratne, H R Sagara; Viljetic, Barbara; Sakers, Kristina; Marson, Justin W; Kontoyiannis, Dimitris L; Buyske, Steven; Hart, Ronald P; Rasin, Mladen-Roko

    2014-09-09

    Precise spatiotemporal control of mRNA translation machinery is essential to the development of highly complex systems like the neocortex. However, spatiotemporal regulation of translation machinery in the developing neocortex remains poorly understood. Here, we show that an RNA-binding protein, Hu antigen R (HuR), regulates both neocorticogenesis and specificity of neocortical translation machinery in a developmental stage-dependent manner in mice. Neocortical absence of HuR alters the phosphorylation states of initiation and elongation factors in the core translation machinery. In addition, HuR regulates the temporally specific positioning of functionally related mRNAs into the active translation sites, the polysomes. HuR also determines the specificity of neocortical polysomes by defining their combinatorial composition of ribosomal proteins and initiation and elongation factors. For some HuR-dependent proteins, the association with polysomes likewise depends on the eukaryotic initiation factor 2 alpha kinase 4, which associates with HuR in prenatal developing neocortices. Finally, we found that deletion of HuR before embryonic day 10 disrupts both neocortical lamination and formation of the main neocortical commissure, the corpus callosum. Our study identifies a crucial role for HuR in neocortical development as a translational gatekeeper for functionally related mRNA subgroups and polysomal protein specificity.

  3. Experience and activity-dependent maturation of perisomatic GABAergic innervation in primary visual cortex during a postnatal critical period.

    PubMed

    Chattopadhyaya, Bidisha; Di Cristo, Graziella; Higashiyama, Hiroyuki; Knott, Graham W; Kuhlman, Sandra J; Welker, Egbert; Huang, Z Josh

    2004-10-27

    The neocortical GABAergic network consists of diverse interneuron cell types that display distinct physiological properties and target their innervations to subcellular compartments of principal neurons. Inhibition directed toward the soma and proximal dendrites is crucial in regulating the output of pyramidal neurons, but the development of perisomatic innervation is poorly understood because of the lack of specific synaptic markers. In the primary visual cortex, for example, it is unknown whether, and to what extent, the formation and maturation of perisomatic synapses are intrinsic to cortical circuits or are regulated by sensory experience. Using bacterial artificial chromosome transgenic mice that label a defined class of perisomatic synapses with green fluorescent protein, here we show that perisomatic innervation developed during a protracted postnatal period after eye opening. Maturation of perisomatic innervation was significantly retarded by visual deprivation during the third, but not the fifth, postnatal week, implicating an important role for sensory input. To examine the role of cortical intrinsic mechanisms, we developed a method to visualize perisomatic synapses from single basket interneurons in cortical organotypic cultures. Characteristic perisomatic synapses formed through a stereotyped process, involving the extension of distinct terminal branches and proliferation of perisomatic boutons. Neuronal spiking in organotypic cultures was necessary for the proliferation of boutons and the extension, but not the maintenance, of terminal branches. Together, our results suggest that although the formation of perisomatic synapses is intrinsic to the cortex, visual experience can influence the maturation and pattern of perisomatic innervation during a postnatal critical period by modulating the level of neural activity within cortical circuits.

  4. Recurring Functional Interactions Predict Network Architecture of Interictal and Ictal States in Neocortical Epilepsy.

    PubMed

    Khambhati, Ankit N; Bassett, Danielle S; Oommen, Brian S; Chen, Stephanie H; Lucas, Timothy H; Davis, Kathryn A; Litt, Brian

    2017-01-01

    Human epilepsy patients suffer from spontaneous seizures, which originate in brain regions that also subserve normal function. Prior studies demonstrate focal, neocortical epilepsy is associated with dysfunction, several hours before seizures. How does the epileptic network perpetuate dysfunction during baseline periods? To address this question, we developed an unsupervised machine learning technique to disentangle patterns of functional interactions between brain regions, or subgraphs, from dynamic functional networks constructed from approximately 100 h of intracranial recordings in each of 22 neocortical epilepsy patients. Using this approach, we found: (1) subgraphs from ictal (seizure) and interictal (baseline) epochs are topologically similar, (2) interictal subgraph topology and dynamics can predict brain regions that generate seizures, and (3) subgraphs undergo slower and more coordinated fluctuations during ictal epochs compared to interictal epochs. Our observations suggest that seizures mark a critical shift away from interictal states that is driven by changes in the dynamical expression of strongly interacting components of the epileptic network.

  5. Heat-induced immunoreactivity of tau protein in neocortical neurons of fire fatalities.

    PubMed

    Kibayashi, Kazuhiko; Shojo, Hideki

    2003-10-01

    Tau protein is the main component of neurofibrillary tangles of Alzheimer's disease (AD). Immunohistochemistry of tau protein is useful in the diagnosis of AD but produces diffuse staining of neocortical neurons in fire fatalities. To learn the cause of this phenomenon, we examined the temporal neocortex of 13 fire fatalities and 9 fatalities unrelated to fire. The diffuse tau immunoreactive neurons were observed in 10 fire fatalities with heat coagulation of the cerebrum. Diffuse staining was not found in the three fire fatalities without heat coagulation of the cerebrum or in fatalities unrelated to fire. The immunoreactivity progressively increased as a function of the degree of cerebral heat coagulation. These results demonstrate that diffuse tau immunoreactivity of neocortical neurons is a post-mortem phenomenon caused by prolonged exposure of the head to intense heat. Forensic pathologists should consider this phenomenon when they diagnose AD in fire fatalities.

  6. Recurring Functional Interactions Predict Network Architecture of Interictal and Ictal States in Neocortical Epilepsy

    PubMed Central

    Bassett, Danielle S.; Oommen, Brian S.; Chen, Stephanie H.; Lucas, Timothy H.

    2017-01-01

    Abstract Human epilepsy patients suffer from spontaneous seizures, which originate in brain regions that also subserve normal function. Prior studies demonstrate focal, neocortical epilepsy is associated with dysfunction, several hours before seizures. How does the epileptic network perpetuate dysfunction during baseline periods? To address this question, we developed an unsupervised machine learning technique to disentangle patterns of functional interactions between brain regions, or subgraphs, from dynamic functional networks constructed from approximately 100 h of intracranial recordings in each of 22 neocortical epilepsy patients. Using this approach, we found: (1) subgraphs from ictal (seizure) and interictal (baseline) epochs are topologically similar, (2) interictal subgraph topology and dynamics can predict brain regions that generate seizures, and (3) subgraphs undergo slower and more coordinated fluctuations during ictal epochs compared to interictal epochs. Our observations suggest that seizures mark a critical shift away from interictal states that is driven by changes in the dynamical expression of strongly interacting components of the epileptic network. PMID:28303256

  7. Off-line replay maintains declarative memories in a model of hippocampal-neocortical interactions.

    PubMed

    Káli, Szabolcs; Dayan, Peter

    2004-03-01

    During sleep, neural activity in the hippocampus and neocortex seems to recapitulate aspects of its earlier, awake form. This replay may be a substrate for the consolidation of long-term declarative memories, whereby they become independent of the hippocampus and are stored in neocortex. In contrast to storage, other crucial facets of competent long-term memory, such as maintenance of access to stored traces and preservation of their correct interpretation, have received little attention. We investigate long-term episodic and semantic memory in a theoretical model of neocortical-hippocampal interaction. We find that, in the absence of regular hippocampal reactivation, even supposedly consolidated episodic memories are fragile in the face of cortical semantic plasticity. Replay allows access to episodes stored in the hippocampus to be maintained, by keeping them in appropriate register with changing neocortical representations. Hippocampal storage and replay also has a constructive role in the recall of structured, semantic information.

  8. Awake reactivation of emotional memory traces through hippocampal-neocortical interactions.

    PubMed

    de Voogd, Lycia D; Fernández, Guillén; Hermans, Erno J

    2016-07-01

    Emotionally arousing experiences are typically well remembered not only due to immediate effects at encoding, but also through further strengthening of subsequent consolidation processes. A large body of research shows how neuromodulatory systems promote synaptic consolidation. However, how emotionally arousing experiences alter systems-level interactions, presumably a consequence of modifications at a synaptic level, remains unclear. Animal models predict that memory traces are maintained by spontaneous reactivations across hippocampal-neocortical circuits during "offline" periods such as post-learning rest, and suggest this might be stronger for emotional memories. The present study was designed to test this hypothesis in humans using functional Magnetic Resonance Imaging. Participants underwent a two-category localizer paradigm followed by a categorical differential delay fear conditioning paradigm interleaved with blocks of awake rest. Counterbalanced across participants, exemplars of one category (CS+), but not the other (CS-), were paired with mild electrical shocks. Fear recall (differential conditioned pupil dilation) was tested 24h later. Analyses of the localizer paradigm replicate earlier work showing category-specific response patterns in neocortical higher-order visual regions. Critically, we show that during post-learning rest, spontaneous reactivation of these neocortical patterns was stronger for the CS+ than the CS- category. Furthermore, hippocampal connectivity with the regions exhibiting these reactivations predicted strength of fear recall 24h later. We conclude that emotional arousal during learning promotes spontaneous post-learning reactivation of neocortical representations of recent experiences, which leads to better memory when coinciding with hippocampal connectivity. Our findings reveal a systems-level mechanism that may explain the persistence of long-term memory for emotional experiences.

  9. [GABAergic mechanisms in generalized epilepsies: the neuroanatomical dimension].

    PubMed

    Depaulis, A; Deransart, C; Vergnes, M; Marescaux, C

    1997-01-01

    Generalized epileptic seizures are underlied by specific circuits where GABAergic synapses are involved at different levels. The role of these synapses depends on (i) the type of epilepsy and (ii) their localization within the central nervous system. This dual complexity can be illustrated by two examples from animal experimentation. Clinical, as well as experimental data have shown that the neural mechanisms underlying generalized non-convulsive seizures (e.g., absence-epilepsy) are distinct from those involved in convulsive generalized seizures. Pharmacological reactivity to anti-epileptic compounds is different between these two forms of seizures. Hippocampus and amygdala are key-structures in convulsive seizures whereas they are not involved in absence-epilepsy. A thalamo-cortical circuit generates the spike-and-wave discharges in absence epilepsy. Global activation of GABAergic transmission by systemic administration generally suppresses convulsive seizures whereas it aggravates absence in both humans and animals. Further investigations using a genetic model of absence seizures in the rat have suggested that this aggravation may be related to the role of post-synaptic GABA-B receptors in slow hyperpolarization, in the relay nuclei of the thalamus. By "de-inactivating" low-threshold calcium currents, activation of these receptors facilitates rhythmic activity in the thalamo-cortical circuit. In addition, regulation of transmitter release by presynaptic GABA-B receptors in the thalamus and the cortex may also contribute to the control of absence seizures. A blockade of the GABA-B receptors, either locally in the thalamus or systemically suppresses absence seizures. The critical role of the substantia nigra in the control of different forms of seizures has been demonstrated recently in the rat. This structure is one of the richest regions of the brain for GABAergic terminals, neurons and receptors. Local applications of GABA mimetics resulting in the

  10. Divergence and inheritance of neocortical heterotopia in inbred and genetically-engineered mice.

    PubMed

    Toia, Alyssa R; Cuoco, Joshua A; Esposito, Anthony W; Ahsan, Jawad; Joshi, Alok; Herron, Bruce J; Torres, German; Bolivar, Valerie J; Ramos, Raddy L

    2017-01-18

    Cortical function emerges from the intrinsic properties of neocortical neurons and their synaptic connections within and across lamina. Neurodevelopmental disorders affecting migration and lamination of the neocortex result in cognitive delay/disability and epilepsy. Molecular layer heterotopia (MLH), a dysplasia characterized by over-migration of neurons into layer I, are associated with cognitive deficits and neuronal hyperexcitability in humans and mice. The breadth of different inbred mouse strains that exhibit MLH and inheritance patterns of heterotopia remain unknown. A neuroanatomical survey of numerous different inbred mouse strains, 2 first filial generation (F1) hybrids, and one consomic strain (C57BL/6J-Chr 1(A/J)/NaJ) revealed MLH only in C57BL/6 mice and the consomic strain. Heterotopia were observed in numerous genetically-engineered mouse lines on a congenic C57BL/6 background. These data indicate that heterotopia formation is a weakly penetrant trait requiring homozygosity of one or more C57BL/6 alleles outside of chromosome 1. These data are relevant toward understanding neocortical development and disorders affecting neocortical lamination.

  11. Repetition reveals ups and downs of hippocampal, thalamic, and neocortical engagement during mnemonic decisions.

    PubMed

    Reagh, Zachariah M; Murray, Elizabeth A; Yassa, Michael A

    2017-02-01

    The extent to which current information is consistent with past experiences and our capacity to recognize or discriminate accordingly are key factors in flexible memory-guided behavior. Despite a wealth of evidence linking hippocampal and neocortical computations to these phenomena, many important factors remain poorly understood. One such factor is repeated encoding of learned information. In this experiment, participants completed a task in which study stimuli were incidentally encoded either once or three separate times during high-resolution fMRI scanning. We asked how repetition influenced recognition and discrimination memory judgments, and how this affects engagement of hippocampal and neocortical regions. Repetition revealed shifts in engagement in an anterior (ventral) CA1-thalamic-medial prefrontal network related to true and false recognition. Conversely, repetition revealed shifts in a posterior (dorsal) dentate/CA3-parahippocampal-restrosplenial network related to accurate discrimination. These differences in engagement were accompanied by task-related correlations in respective anterior and posterior networks. In particular, the anterior thalamic region observed during recognition judgments is functionally and anatomically consistent with nucleus reuniens in humans, and was found to mediate correlations between the anterior CA1 and medial prefrontal cortex. These findings offer new insights into how repeated experience affects memory and its neural substrates in hippocampal-neocortical networks. © 2016 Wiley Periodicals, Inc.

  12. Spontaneous Neuronal Activity in Developing Neocortical Networks: From Single Cells to Large-Scale Interactions

    PubMed Central

    Luhmann, Heiko J.; Sinning, Anne; Yang, Jenq-Wei; Reyes-Puerta, Vicente; Stüttgen, Maik C.; Kirischuk, Sergei; Kilb, Werner

    2016-01-01

    Neuronal activity has been shown to be essential for the proper formation of neuronal circuits, affecting developmental processes like neurogenesis, migration, programmed cell death, cellular differentiation, formation of local and long-range axonal connections, synaptic plasticity or myelination. Accordingly, neocortical areas reveal distinct spontaneous and sensory-driven neuronal activity patterns already at early phases of development. At embryonic stages, when immature neurons start to develop voltage-dependent channels, spontaneous activity is highly synchronized within small neuronal networks and governed by electrical synaptic transmission. Subsequently, spontaneous activity patterns become more complex, involve larger networks and propagate over several neocortical areas. The developmental shift from local to large-scale network activity is accompanied by a gradual shift from electrical to chemical synaptic transmission with an initial excitatory action of chloride-gated channels activated by GABA, glycine and taurine. Transient neuronal populations in the subplate (SP) support temporary circuits that play an important role in tuning early neocortical activity and the formation of mature neuronal networks. Thus, early spontaneous activity patterns control the formation of developing networks in sensory cortices, and disturbances of these activity patterns may lead to long-lasting neuronal deficits. PMID:27252626

  13. GABAergic hub neurons orchestrate synchrony in developing hippocampal networks.

    PubMed

    Bonifazi, P; Goldin, M; Picardo, M A; Jorquera, I; Cattani, A; Bianconi, G; Represa, A; Ben-Ari, Y; Cossart, R

    2009-12-04

    Brain function operates through the coordinated activation of neuronal assemblies. Graph theory predicts that scale-free topologies, which include "hubs" (superconnected nodes), are an effective design to orchestrate synchronization. Whether hubs are present in neuronal assemblies and coordinate network activity remains unknown. Using network dynamics imaging, online reconstruction of functional connectivity, and targeted whole-cell recordings in rats and mice, we found that developing hippocampal networks follow a scale-free topology, and we demonstrated the existence of functional hubs. Perturbation of a single hub influenced the entire network dynamics. Morphophysiological analysis revealed that hub cells are a subpopulation of gamma-aminobutyric acid-releasing (GABAergic) interneurons possessing widespread axonal arborizations. These findings establish a central role for GABAergic interneurons in shaping developing networks and help provide a conceptual framework for studying neuronal synchrony.

  14. GABAergic function in detoxified heroin addicts: relationship to anxiety disorders.

    PubMed

    Gerra, G; Ferri, M; Zaimovic, A; Giucastro, G; Palladino, M; Sartori, R; Delsignore, R; Maestri, D; Marzocchi, G; Brambilla, F

    1998-02-09

    The function of the GABAergic system was examined in 20 subjects with heroin dependence and abuse, 2 months after detoxification, and in 10 healthy volunteers, by measuring the growth hormone (GH) response to a challenge with the GABA B receptor agonist baclofen. Ten heroin addicts had comorbid anxiety disorder (Group A), while the other ten had heroin addiction uncomplicated by Axis I and II psychopathologies (Group B). GH responses to baclofen stimulation of Group A patients were significantly blunted, while those of Group B subjects did not differ from responses of healthy volunteers. Our data show that the function of the GABAergic system is impaired only in heroin addicts with comorbid anxiety disorders (anxious cluster), suggesting that the GABA system is not persistently influenced by prolonged exposure to opioid receptor stimulation.

  15. KChIP1: a potential modulator to GABAergic system.

    PubMed

    Xiong, Hui; Xia, Kun; Li, Benshang; Zhao, Guoping; Zhang, Zhuohua

    2009-04-01

    Compelling evidences from transgenic mice, immunoprecipitation data, gene expression analysis, and functional heterologous expression studies supported the role of Kv channel interacting proteins (KChIPs) as modulators of Kv4 (Shal) channels underlying the cardiac transient outward current and neuronal A-type current. Till now, there are four members (KChIP1-4) identified in this family. KChIP1 is expressed predominantly in brain, with relative abundance in Purkinje cells of cerebellum, the reticular thalamic nuclei, the medial habenular nuclei, the hippocampus, and striatum. Our results from in situ hybridization and immunostaining assay revealed that KChIP1 was expressed in a subpopulation of parvalbumin-positive neurons suggesting its functional relationship with the GABAergic inhibitory neurons. Moreover, results obtained from KChIP1-deficient mice showed that KChIP1 mutation did not impair survival or alter the overall brain architecture, arguing against its essential function in brain development. However, the mice bearing KChIP1 deletion showed increased susceptibility to anti-GABAergic convulsive drug pentylenetetrazole-induced seizure, indicating that KChIP1 might play pivotal roles in the GABAergic inhibitory system.

  16. GABAergic drugs inhibit amphetamine-induced distractibility in the rat.

    PubMed

    Agmo, A; Medrano, A; Garrido, N; Alonso, P

    1997-09-01

    Drugs facilitating GABAergic neurotransmission have been reported to block some behavioral actions of dopaminergic stimulation but not others. The present experiments were performed with the purpose to extend the range of behaviors in which the interaction between GABA and dopamine have been studied. The ability of the GABAB agonist baclofen and the GABA transaminase inhibitor sodium valproate to block the enhanced distractibility produced by amphetamine was evaluated in a procedure especially designed for analyzing drugs' effects on distractibility. Briefly, rats were trained to traverse a straight runway with a sucrose solution as reinforcement. Once the response had been acquired, an additional runway ending in an empty box was connected. The time spent investigating this additional runway is the measure of distractibility. Male rats treated with amphetamine, 1 mg/kg, displayed an increase of the time spent in the additional runway. Baclofen, 2.5 and 5 mg/kg, and sodium valproate, 100 and 200 mg/kg, had no effect on distraction behavior when administered alone. However, when these drugs were administered together with amphetamine, 1 mg/kg, they completely inhibited the effects of the stimulant on distractibility. These data show that distractibility is similar to discrimination learning with regard to the capacity of GABAergic drugs to block the effects of dopaminergic stimulation. It is different from locomotor activity, however, where GABAergic drugs are ineffective in this respect.

  17. Cryopreservation of GABAergic Neuronal Precursors for Cell-Based Therapy

    PubMed Central

    2017-01-01

    Cryopreservation protocols are essential for stem cells storage in order to apply them in the clinic. Here we describe a new standardized cryopreservation protocol for GABAergic neural precursors derived from the medial glanglionic eminence (MGE), a promising source of GABAergic neuronal progenitors for cell therapy against interneuron-related pathologies. We used 10% Me2SO as cryoprotectant and assessed the effects of cell culture amplification and cellular organization, as in toto explants, neurospheres, or individualized cells, on post-thaw cell viability and retrieval. We confirmed that in toto cryopreservation of MGE explants is an optimal preservation system to keep intact the interneuron precursor properties for cell transplantation, together with a high cell viability (>80%) and yield (>70%). Post-thaw proliferation and self-renewal of the cryopreserved precursors were tested in vitro. In addition, their migration capacity, acquisition of mature neuronal morphology, and potency to differentiate into multiple interneuron subtypes were also confirmed in vivo after transplantation. The results show that the cryopreserved precursor features remained intact and were similar to those immediately transplanted after their dissection from the MGE. We hope this protocol will facilitate the generation of biobanks to obtain a permanent and reliable source of GABAergic precursors for clinical application in cell-based therapies against interneuronopathies. PMID:28122047

  18. Turning a Negative into a Positive: Ascending GABAergic Control of Cortical Activation and Arousal

    PubMed Central

    Brown, Ritchie E.; McKenna, James T.

    2015-01-01

    Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain. Recent technological advances have illuminated the role of GABAergic neurons in control of cortical arousal and sleep. Sleep-promoting GABAergic neurons in the preoptic hypothalamus are well-known. Less well-appreciated are GABAergic projection neurons in the brainstem, midbrain, hypothalamus, and basal forebrain, which paradoxically promote arousal and fast electroencephalographic (EEG) rhythms. Thus, GABA is not purely a sleep-promoting neurotransmitter. GABAergic projection neurons in the brainstem nucleus incertus and ventral tegmental nucleus of Gudden promote theta (4–8 Hz) rhythms. Ventral tegmental area GABAergic neurons, neighboring midbrain dopamine neurons, project to the frontal cortex and nucleus accumbens. They discharge faster during cortical arousal and regulate reward. Thalamic reticular nucleus GABAergic neurons initiate sleep spindles in non-REM sleep. In addition, however, during wakefulness, they tonically regulate the activity of thalamocortical neurons. Other GABAergic inputs to the thalamus arising in the globus pallidus pars interna, substantia nigra pars reticulata, zona incerta, and basal forebrain regulate motor activity, arousal, attention, and sensory transmission. Several subpopulations of cortically projecting GABAergic neurons in the basal forebrain project to the thalamus and neocortex and preferentially promote cortical gamma-band (30–80 Hz) activity and wakefulness. Unlike sleep-active GABAergic neurons, these ascending GABAergic neurons are fast-firing neurons which disinhibit and synchronize the activity of their forebrain targets, promoting the fast EEG rhythms typical of conscious states. They are prominent targets of GABAergic hypnotic agents. Understanding the properties of ascending GABAergic neurons may lead to novel treatments for diseases involving disorders of cortical activation and wakefulness. PMID:26124745

  19. Acidosis-Induced Dysfunction of Cortical GABAergic Neurons through Astrocyte-Related Excitotoxicity

    PubMed Central

    Guan, Sudong; Zhu, Yan; Wang, Jin-Hui

    2015-01-01

    Background Acidosis impairs cognitions and behaviors presumably by acidification-induced changes in neuronal metabolism. Cortical GABAergic neurons are vulnerable to pathological factors and their injury leads to brain dysfunction. How acidosis induces GABAergic neuron injury remains elusive. As the glia cells and neurons interact each other, we intend to examine the role of the astrocytes in acidosis-induced GABAergic neuron injury. Results Experiments were done at GABAergic cells and astrocytes in mouse cortical slices. To identify astrocytic involvement in acidosis-induced impairment, we induced the acidification in single GABAergic neuron by infusing proton intracellularly or in both neurons and astrocytes by using proton extracellularly. Compared the effects of intracellular acidification and extracellular acidification on GABAergic neurons, we found that their active intrinsic properties and synaptic outputs appeared more severely impaired in extracellular acidosis than intracellular acidosis. Meanwhile, extracellular acidosis deteriorated glutamate transporter currents on the astrocytes and upregulated excitatory synaptic transmission on the GABAergic neurons. Moreover, the antagonists of glutamate NMDA-/AMPA-receptors partially reverse extracellular acidosis-induced injury in the GABAergic neurons. Conclusion Our studies suggest that acidosis leads to the dysfunction of cortical GABAergic neurons by astrocyte-mediated excitotoxicity, in addition to their metabolic changes as indicated previously. PMID:26474076

  20. Live-Cell, Label-Free Identification of GABAergic and Non-GABAergic Neurons in Primary Cortical Cultures Using Micropatterned Surface

    PubMed Central

    Kono, Sho; Kushida, Takatoshi; Hirano-Iwata, Ayumi; Niwano, Michio; Tanii, Takashi

    2016-01-01

    Excitatory and inhibitory neurons have distinct roles in cortical dynamics. Here we present a novel method for identifying inhibitory GABAergic neurons from non-GABAergic neurons, which are mostly excitatory glutamatergic neurons, in primary cortical cultures. This was achieved using an asymmetrically designed micropattern that directs an axonal process to the longest pathway. In the current work, we first modified the micropattern geometry to improve cell viability and then studied the axon length from 2 to 7 days in vitro (DIV). The cell types of neurons were evaluated retrospectively based on immunoreactivity against GAD67, a marker for inhibitory GABAergic neurons. We found that axons of non-GABAergic neurons grow significantly longer than those of GABAergic neurons in the early stages of development. The optimal threshold for identifying GABAergic and non-GABAergic neurons was evaluated to be 110 μm at 6 DIV. The method does not require any fluorescence labelling and can be carried out on live cells. The accuracy of identification was 98.2%. We confirmed that the high accuracy was due to the use of a micropattern, which standardized the development of cultured neurons. The method promises to be beneficial both for engineering neuronal networks in vitro and for basic cellular neuroscience research. PMID:27513933

  1. Afferent inputs to cortical fast-spiking interneurons organize pyramidal cell network oscillations at high-gamma frequencies (60–200 Hz)

    PubMed Central

    Crone, Nathan E.; Franaszczuk, Piotr J.

    2014-01-01

    High-gamma activity, ranging in frequency between ∼60 Hz and 200 Hz, has been observed in local field potential, electrocorticography, EEG and magnetoencephalography signals during cortical activation, in a variety of functional brain systems. The origin of these signals is yet unknown. Using computational modeling, we show that a cortical network model receiving thalamic input generates high-gamma responses comparable to those observed in local field potential recorded in monkey somatosensory cortex during vibrotactile stimulation. These high-gamma oscillations appear to be mediated mostly by an excited population of inhibitory fast-spiking interneurons firing at high-gamma frequencies and pacing excitatory regular-spiking pyramidal cells, which fire at lower rates but in phase with the population rhythm. The physiological correlates of high-gamma activity, in this model of local cortical circuits, appear to be similar to those proposed for hippocampal ripples generated by subsets of interneurons that regulate the discharge of principal cells. PMID:25210164

  2. Adult-generated hippocampal and neocortical neurons in macaques have a transient existence

    PubMed Central

    Gould, E.; Vail, N.; Wagers, M.; Gross, C. G.

    2001-01-01

    Previously we reported that new neurons are added to the hippocampus and neocortex of adult macaque monkeys. Here we compare the production and survival of adult-generated neurons and glia in the dentate gyrus, prefrontal cortex, and inferior temporal cortex. Twelve adult macaques were injected with the thymidine analogue BrdUrd, and the phenotypes of labeled cells were examined after 2 h, 24 h, 2 wk, 5 wk, 9 wk, and 12 wk by using the following immunocytochemical markers: for immature and mature neurons, class III β-tubulin (TuJ1); for mature neurons, neuronal nuclei; for astrocytes, glial fibrillary acidic protein; and for oligodendrocytes, 2′,3′-cyclic nucleotide 3′ phosphodiesterase. We found that the dentate gyrus had many more BrdUrd-labeled cells than either neocortical area. Furthermore, a greater percentage of BrdUrd-labeled cells expressed a neuronal marker in the dentate gyrus than in either neocortical area. The number of new cells in all three areas declined by 9 wk after BrdUrd labeling, suggesting that some of the new cells have a transient existence. BrdUrd-labeled cells also were found in the subventricular zone and in the white matter between the lateral ventricle and neocortex; some of the latter cells were double-labeled for BrdUrd and TuJ1. Adult neocortical neurogenesis is not restricted to primates. Five adult rats were injected with BrdUrd, and after a 3-wk survival time, there were cells double-labeled for BrdUrd and either TuJ1 or neuronal nuclei in the anterior neocortex as well as the dentate gyrus. PMID:11526209

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

    PubMed

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

    2016-07-01

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

  4. Potassium Model for Slow (2-3 Hz) In Vivo Neocortical Paroxysmal Oscillations

    PubMed Central

    Bazhenov, M.; Timofeev, I.; Steriade, M.; Sejnowski, T. J.

    2010-01-01

    In slow neocortical paroxysmal oscillations, the de- and hyperpolarizing envelopes in neocortical neurons are large compared with slow sleep oscillations. Increased local synchrony of membrane potential oscillations during seizure is reflected in larger electroencephalographic oscillations and the appearance of spike- or polyspike-wave complex recruitment at 2- to 3-Hz frequencies. The oscillatory mechanisms underlying this paroxysmal activity were investigated in computational models of cortical networks. The extracellular K+ concentration ([K+]o) was continuously computed based on neuronal K+ currents and K+ pumps as well as glial buffering. An increase of [K+]o triggered a transition from normal awake-like oscillations to 2- to 3-Hz seizure-like activity. In this mode, the cells fired periodic bursts and nearby neurons oscillated highly synchronously; in some cells depolarization led to spike inactivation lasting 50–100 ms. A [K+]o increase, sufficient to produce oscillations could result from excessive firing (e.g., induced by external stimulation) or inability of K+ regulatory system (e.g., when glial buffering was blocked). A combination of currents including high-threshold Ca2+, persistent Na+ and hyperpolarization-activated depolarizing (Ih) currents was sufficient to maintain 2- to 3-Hz activity. In a network model that included lateral K+ diffusion between cells, increase of [K+]o in a small region was generally sufficient to maintain paroxysmal oscillations in the whole network. Slow changes of [K+]o modulated the frequency of bursting and, in some case, led to fast oscillations in the 10- to 15-Hz frequency range, similar to the fast runs observed during seizures in vivo. These results suggest that modifications of the intrinsic currents mediated by increase of [K+]o can explain the range of neocortical paroxysmal oscillations in vivo. PMID:15056684

  5. Persistent hypersynchronization of neocortical neurons in the mocha mutant of mouse.

    PubMed

    Noebels, J L; Sidman, R L

    1989-09-01

    A recessive mutation in the mouse at the mocha locus (mh, chromosome 10) modulates the synchronous synaptic activation of neocortical neurons, resulting in a constant 6-7 Hz (theta) wave pattern in the electrocorticogram. The gene-linked brain rhythm is unaffected by motor behavior and cannot be desynchronized by sensory stimuli. This exemplary neurological mutation affecting cortical excitability is the first to reveal clearly that the predominance of a specific pattern of spontaneous brain wave activity can be inherited as a recessive trait.

  6. Persistent hypersynchronization of neocortical neurons in the mocha mutant of mouse.

    PubMed

    Noebels, J L; Sidman, R L

    2007-01-01

    A recessive mutation in the mouse at the mocha locus (mh, chromosome 10) modulates the synchronous synaptic activation of neocortical neurons, resulting in a constant 6-7 Hz (theta) wave pattern in the electrocorticogram. The gene-linked brain rhythm is unaffected by motor behavior and cannot be desynchronized by sensory stimuli. This exemplary neurological mutation affecting cortical excitability is the first to reveal clearly that the predominance of a specific pattern of spontaneous brain wave activity can be inherited as a recessive trait.

  7. Regulation of cortical microcircuits by unitary GABAergic volume transmission

    PubMed Central

    Oláh, Szabolcs; Füle, Miklós; Komlósi, Gergely; Varga, Csaba; Báldi, Rita; Barzó, Pál; Tamás, Gábor

    2009-01-01

    Gamma-aminobutyric acid (GABA) is predominantly released by local interneurons in the cerebral cortex to particular subcellular domains of the target cells1,2. This suggests that compartmentalized, synapse specific action of GABA is required in cortical networks for phasic inhibition2–4. However, GABA released at the synaptic cleft diffuses to receptors outside the postsynaptic density and thus tonically activates extrasynaptic GABAA and GABAB receptors, which include subtypes of both receptor families especially sensitive to low concentrations of GABA3–7. The synaptic and extrasynaptic action of GABA is in line with idea that neurons of the brain use synaptic (or wiring) transmission and nonsynaptic (or volume) transmission for communication8,9. However, reuptake mechanisms restrict the spatial extent of extrasynaptic GABAergic effects10,11 and it was proposed that concerted action of several presynaptic interneurons or sustained firing of individual cells or increased release site density is required to reach ambient GABA levels sufficient to activate extrasynaptic receptors4,9,11–13. Here we show that individual neurogliaform cells release GABA sufficient for volume transmission within the axonal cloud and thus neurogliaform cells do not require synapses to produce inhibitory responses in the overwhelming majority of nearby neurons. Neurogliaform cells suppress connections between other neurons acting on presynaptic terminals which do not receive synapses at all in the cerebral cortex and, moreover, reach extrasynaptic, δ subunit containing GABAA (GABAAδ) receptors responsible for tonic inhibition. We reveal that GABAAδ receptors are localized to neurogliaform cells preferentially among cortical interneurons. Neurosteroids, which are modulators of GABAAδ receptors, alter unitary GABAergic effects between neurogliaform cells. In contrast to the specifically placed synapses formed by other interneurons, the output of neurosteroid sensitive neurogliaform

  8. GABAergic inhibition shapes SAM responses in rat auditory thalamus.

    PubMed

    Cai, R; Caspary, D M

    2015-07-23

    Auditory thalamus (medial geniculate body [MGB]) receives ascending inhibitory GABAergic inputs from inferior colliculus (IC) and descending GABAergic projections from the thalamic reticular nucleus (TRN) with both inputs postulated to play a role in shaping temporal responses. Previous studies suggested that enhanced processing of temporally rich stimuli occurs at the level of MGB, with our recent study demonstrating enhanced GABA sensitivity in MGB compared to IC. The present study used sinusoidal amplitude-modulated (SAM) stimuli to generate modulation transfer functions (MTFs), to examine the role of GABAergic inhibition in shaping the response properties of MGB single units in anesthetized rats. Rate MTFs (rMTFs) were parsed into "bandpass (BP)", "mixed (Mixed)", "highpass (HP)" or "atypical" response types, with most units showing the Mixed response type. GABAA receptor blockade with iontophoretic application of the GABAA receptor (GABAAR) antagonist gabazine (GBZ) selectively altered the response properties of most MGB neurons examined. Mixed and HP units showed significant GABAAR-mediated SAM-evoked rate response changes at higher modulation frequencies (fms), which were also altered by N-methyl-d-aspartic acid (NMDA) receptor blockade (2R)-amino-5-phosphonopentanoate (AP5). BP units, and the lower arm of Mixed units responded to GABAAR blockade with increased responses to SAM stimuli at or near the rate best modulation frequency (rBMF). The ability of GABA circuits to shape responses at higher modulation frequencies is an emergent property of MGB units, not observed at lower levels of the auditory pathway and may reflect activation of MGB NMDA receptors (Rabang and Bartlett, 2011; Rabang et al., 2012). Together, GABAARs exert selective rate control over selected fms, generally without changing the units' response type. These results showed that coding of modulated stimuli at the level of auditory thalamus is at least, in part, strongly controlled by GABA

  9. Peripheral and spinal GABAergic regulation of incisional pain in rats.

    PubMed

    Reichl, Sylvia; Augustin, Mirjam; Zahn, Peter K; Pogatzki-Zahn, Esther M

    2012-01-01

    Impairment of spinal GABAergic inhibition is demonstrated to contribute to pathologic chronic pain states. We investigated spinal and peripheral GABAergic regulation of incisional pain in rats. We found that intrathecal but not peripheral administration of muscimol (GABA-A receptor agonist) and baclofen (GABA-B receptor agonist) reduced mechanical and thermal hyperalgesia after plantar incision in rats. Nonevoked pain behavior after incision was unaffected by these agonists. Similarly, nociception in unincised rats was not reduced by the same dose of agonists. Thus, GABA-A and GABA-B receptors are involved in mediating incision-induced hyperalgesia (but not nonevoked pain). Intrathecal and systemic application of L-838,417, a subtype-selective benzodiazepine site agonist (α2, α3, α5), reduced mechanical and heat hyperalgesia after incision, indicating a role of these subunits in mediating incision-induced hyperalgesia. Interestingly, the effects of all agonists were more intense and prolonged on the day after surgery than on the day of incision. Similarly, spinally administered GABA-A and GABA-B antagonists increased pain behavior, again with a greater effect 1 day after incision. One possible explanation for this finding might be that an incision modulates GABA-mediated inhibition 1 day after incision. However, expression of GABA-A receptor subunits α2 and α3 and GABA-B receptor subunits within the dorsal horn of the spinal cord were unchanged after incision, indicating that receptor expression cannot explain a possible modulation of GABAergic inhibition after incision. Thus, other mechanisms need to be considered. In conclusion, GABA-A and GABA-B receptors are promising targets for postoperative, incisional pain in humans.

  10. GABAergic Signaling as Therapeutic Target for Autism Spectrum Disorders

    PubMed Central

    Cellot, Giada; Cherubini, Enrico

    2014-01-01

    γ-Aminobutyric acid (GABA), the main inhibitory neurotransmitter in the adult brain, early in postnatal life exerts a depolarizing and excitatory action. This depends on accumulation of chloride inside the cell via the cation–chloride importer NKCC1, being the expression of the chloride exporter KCC2 very low at birth. The developmentally regulated expression of KCC2 results in extrusion of chloride with age and a shift of GABA from the depolarizing to the hyperpolarizing direction. The depolarizing action of GABA leads to intracellular calcium rise through voltage-dependent calcium channels and/or N-methyl-d-aspartate receptors. GABA-mediated calcium signals regulate a variety of developmental processes from cell proliferation migration, differentiation, synapse maturation, and neuronal wiring. Therefore, it is not surprising that some forms of neuro-developmental disorders such as autism spectrum disorders (ASDs) are associated with alterations of GABAergic signaling and impairment of the excitatory/inhibitory balance in selective neuronal circuits. In this review, we will discuss how changes of GABAA-mediated neurotransmission affect several forms of ASDs including the Fragile X, the Angelman, and Rett syndromes. Then, we will describe various animal models of ASDs with GABAergic dysfunctions, highlighting their behavioral deficits and the possibility to rescue them by targeting selective components of the GABAergic synapse. In particular, we will discuss how in some cases, reverting the polarity of GABA responses from the depolarizing to the hyperpolarizing direction with the diuretic bumetanide, a selective blocker of NKCC1, may have beneficial effects on ASDs, thus opening new therapeutic perspectives for the treatment of these devastating disorders. PMID:25072038

  11. Neurotensin activates GABAergic interneurons in the prefrontal cortex.

    PubMed

    Petrie, Kimberly A; Schmidt, Dennis; Bubser, Michael; Fadel, Jim; Carraway, Robert E; Deutch, Ariel Y

    2005-02-16

    Converging data suggest a dysfunction of prefrontal cortical GABAergic interneurons in schizophrenia. Morphological and physiological studies indicate that cortical GABA cells are modulated by a variety of afferents. The peptide transmitter neurotensin may be one such modulator of interneurons. In the rat prefrontal cortex (PFC), neurotensin is exclusively localized to dopamine axons and has been suggested to be decreased in schizophrenia. However, the effects of neurotensin on cortical interneurons are poorly understood. We used in vivo microdialysis in freely moving rats to assess whether neurotensin regulates PFC GABAergic interneurons. Intra-PFC administration of neurotensin concentration-dependently increased extracellular GABA levels; this effect was impulse dependent, being blocked by treatment with tetrodotoxin. The ability of neurotensin to increase GABA levels in the PFC was also blocked by pretreatment with 2-[1-(7-chloro-4-quinolinyl)-5-(2,6-dimethoxyphenyl)pyrazole-3-yl)carbonylamino]tricyclo(3.3.1.1 [EC] .3.7)decan-2-carboxylic acid (SR48692), a high-affinity neurotensin receptor 1 (NTR1) antagonist. This finding is consistent with our observation that NTR1 was localized to GABAergic interneurons in the PFC, particularly parvalbumin-containing interneurons. Because neurotensin is exclusively localized to dopamine axons in the PFC, we also determined whether neurotensin plays a role in the ability of dopamine agonists to increase extracellular GABA levels. We found that D2 agonist-elicited increases in PFC GABA levels were blocked by pretreatment with SR48692, consistent with data indicating that D2 autoreceptor agonists increase neurotensin release from dopamine-neurotensin axons in the PFC. These findings suggest that neurotensin plays an important role in regulating prefrontal cortical interneurons and that it may be useful to consider neurotensin agonists as an adjunct in the treatment of schizophrenia.

  12. Neuropsychological, Neurovirological and Neuroimmune Aspects of Abnormal GABAergic Transmission in HIV Infection.

    PubMed

    Buzhdygan, Tetyana; Lisinicchia, Joshua; Patel, Vipulkumar; Johnson, Kenneth; Neugebauer, Volker; Paessler, Slobodan; Jennings, Kristofer; Gelman, Benjamin

    2016-06-01

    The prevalence of HIV-associated neurocognitive disorders (HAND) remains high in patients with effective suppression of virus replication by combination antiretroviral therapy (cART). Several neurotransmitter systems were reported to be abnormal in HIV-infected patients, including the inhibitory GABAergic system, which mediates fine-tuning of neuronal processing and plays an essential role in cognitive functioning. To elucidate the role of abnormal GABAergic transmission in HAND, the expression of GABAergic markers was measured in 449 human brain specimens from HIV-infected patients with and without HAND. Using real-time polymerase chain reaction, immunoblotting and immunohistochemistry we found that the GABAergic markers were significantly decreased in most sectors of cerebral neocortex, the neostriatum, and the cerebellum of HIV-infected subjects. Low GABAergic expression in frontal neocortex was correlated significantly with high expression of endothelial cell markers, dopamine receptor type 2 (DRD2L), and preproenkephalin (PENK) mRNAs, and with worse performance on tasks of verbal fluency. Significant associations were not found between low GABAergic mRNAs and HIV-1 RNA concentration in the brain, the history of cART, or HIV encephalitis. Pathological evidence of neurodegeneration of the affected GABAergic neurons was not present. We conclude that abnormally low expression of GABAergic markers is prevalent in HIV-1 infected patients. Interrelationships with other neurotransmitter systems including dopaminergic transmission and with endothelial cell markers lend added support to suggestions that synaptic plasticity and cerebrovascular anomalies are involved with HAND in virally suppressed patients.

  13. Investigation of synapse formation and function in a glutamatergic-GABAergic two-neuron microcircuit.

    PubMed

    Chang, Chia-Ling; Trimbuch, Thorsten; Chao, Hsiao-Tuan; Jordan, Julia-Christine; Herman, Melissa A; Rosenmund, Christian

    2014-01-15

    Neural circuits are composed of mainly glutamatergic and GABAergic neurons, which communicate through synaptic connections. Many factors instruct the formation and function of these synapses; however, it is difficult to dissect the contribution of intrinsic cell programs from that of extrinsic environmental effects in an intact network. Here, we perform paired recordings from two-neuron microculture preparations of mouse hippocampal glutamatergic and GABAergic neurons to investigate how synaptic input and output of these two principal cells develop. In our reduced preparation, we found that glutamatergic neurons showed no change in synaptic output or input regardless of partner neuron cell type or neuronal activity level. In contrast, we found that glutamatergic input caused the GABAergic neuron to modify its output by way of an increase in synapse formation and a decrease in synaptic release efficiency. These findings are consistent with aspects of GABAergic synapse maturation observed in many brain regions. In addition, changes in GABAergic output are cell wide and not target-cell specific. We also found that glutamatergic neuronal activity determined the AMPA receptor properties of synapses on the partner GABAergic neuron. All modifications of GABAergic input and output required activity of the glutamatergic neuron. Because our system has reduced extrinsic factors, the changes we saw in the GABAergic neuron due to glutamatergic input may reflect initiation of maturation programs that underlie the formation and function of in vivo neural circuits.

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

    PubMed

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

    2016-11-09

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

  15. Development of cortical GABAergic circuits and its implications for neurodevelopmental disorders.

    PubMed

    Di Cristo, G

    2007-07-01

    GABAergic interneurons powerfully control the function of cortical networks. In addition, they strongly regulate cortical development by modulating several cellular processes such as neuronal proliferation, migration, differentiation and connectivity. Not surprisingly, aberrant development of GABAergic circuits has been implicated in many neurodevelopmental disorders including schizophrenia, autism and Tourette's syndrome. Unfortunately, efforts directed towards the comprehension of the mechanisms regulating GABAergic circuits formation and function have been impaired by the strikingly heterogeneity, both at the morphological and functional level, of GABAergic interneurons. Recent technical advances, including the improvement of interneurons-specific labelling techniques, have started to reveal the basic principles underlying this process. This review summarizes recent findings on the mechanisms underlying the construction of GABAergic circuits in the cortex, with a particular focus on potential implications for brain diseases with neurodevelopmental origin.

  16. An Overview of the Mechanisms of Abnormal GABAergic Interneuronal Cortical Migration Associated with Prenatal Ethanol Exposure.

    PubMed

    Shenoda, Botros B

    2017-02-03

    GABAergic Interneuronal migration constitutes an essential process during corticogenesis. Derived from progenitor cells located in the proliferative zones of the ventral telencephalon, newly generated GABAergic Interneuron migrate to their cortical destinations. Cortical dysfunction associated with defects in neuronal migration results in severe developmental consequences. There is growing evidence linking prenatal ethanol exposure to abnormal GABAergic interneuronal migration and subsequent cortical dysfunction. Investigating the pathophysiological mechanisms behind disrupted GABAergic interneuronal migration encountered with prenatal alcohol exposure is crucial for understanding and managing fetal alcohol spectrum disorders. This review explores the molecular pathways regulating GABAergic interneuronal cortical migration that might be altered by prenatal ethanol exposure thus opening new avenues for further research in this topic.

  17. The amyloid precursor protein controls adult hippocampal neurogenesis through GABAergic interneurons.

    PubMed

    Wang, Baiping; Wang, Zilai; Sun, Lu; Yang, Li; Li, Hongmei; Cole, Allysa L; Rodriguez-Rivera, Jennifer; Lu, Hui-Chen; Zheng, Hui

    2014-10-01

    Impaired neurogenesis in the adult hippocampus has been implicated in AD pathogenesis. Here we reveal that the APP plays an important role in the neural progenitor proliferation and newborn neuron maturation in the mouse dentate gyrus. APP controls adult neurogenesis through a non cell-autonomous mechanism by GABAergic neurons, as selective deletion of GABAergic, but not glutamatergic, APP disrupts adult hippocampal neurogenesis. APP, highly expressed in the majority of GABAergic neurons in the dentate gyrus, enhances the inhibitory tone to granule cells. By regulating both tonic and phasic GABAergic inputs to dentate granule cells, APP maintains excitatory-inhibitory balance and preserves cognitive functions. Our studies uncover an indispensable role of APP in the GABAergic system for controlling adult hippocampal neurogenesis, and our findings indicate that APP dysfunction may contribute to impaired neurogenesis and cognitive decline associated with AD.

  18. Neocortical connections with perihippocampal and periamygdalar regions in the hedgehog tenrec.

    PubMed

    Künzle, H

    2003-12-01

    The perihippocampal fields represent the most important regions connecting the neocortex and the hippocampus in rat, cat and monkey but little is known about their presence and connectivity in species with poorly differentiated brain. Using axonal tracer substances we have recently studied the distribution of cortical cells projecting to the hippocampus in the hedgehog tenrec. In the present study we determined the regions of the paleocortex and the rhinal cortex connected with the neocortex, and provide a tentative view of the site and the extent of the tenrec's entorhinal, perirhinal and postrhinal/parahippocampal fields. It is shown that only the dorsal portions of the posterior rhinal cortex may be considered equivalent to the perirhinal and postrhinal fields of higher mammals, while a considerable expanse of the ventral rhinal cortex may be part of the entorhinal area (its so-called dorsal portion) connected with both the dentate gyrus and the neocortex. A few cells projecting to the neocortex were also noted in the dorsal-most portion of the three-layered paleocortex (ventral entorhinal portion). These cells were linearly arranged and reminiscent of the neocortical projecting cells in the entorhinal layer 4/5 in more differentiated mammals. The main portion of the paleocortex caudal to the corpus callosum remained unlabeled following neocortical and hippocampal tracer injections. Unexpectedly, the area in the most ventral paleocortex adjacent to the amygdala also projected to the neocortex, particularly the tenrec's somatosensorimotor cortex.

  19. Local cerebral glucose utilization in the neocortical areas of the rat brain.

    PubMed

    Wree, A; Zilles, K; Schleicher, A

    1990-01-01

    The neocortex of the rat brain can be subdivided into regions of different local cerebral glucose utilization (LCGU). However, only a few neocortical areas can be delineated by differences in mean LCGUs between neighbouring areas. These area borders correspond exactly with cytoarchitectonically defined borders found in adjacent Nissl-stained preparations. On the other hand, nearly all of the architectonically defined area borders are also recognizable in the LCGU pictures, if differences in laminar distribution patterns of LCGU are taken into account. Furthermore, interareal differences in mean LCGU mainly reflect changes in layer IV, whereas layers II-III and V-VI show nearly identical LCGU values in all neocortical areas of the rat brain. The primary sensory areas exhibit the highest LCGU in layer IV, while the primary motor cortex shows a high LCGU in layer V. As the cytoarchitectonically defined pattern of the cortex is generally corroborated by the regional and laminar LCGU distribution, anatomical, metabolic and functional aspects of cortical architecture are associated.

  20. Neural mechanisms of transient neocortical beta rhythms: Converging evidence from humans, computational modeling, monkeys, and mice

    PubMed Central

    Sherman, Maxwell A.; Lee, Shane; Law, Robert; Haegens, Saskia; Thorn, Catherine A.; Hämäläinen, Matti S.; Moore, Christopher I.; Jones, Stephanie R.

    2016-01-01

    Human neocortical 15–29-Hz beta oscillations are strong predictors of perceptual and motor performance. However, the mechanistic origin of beta in vivo is unknown, hindering understanding of its functional role. Combining human magnetoencephalography (MEG), computational modeling, and laminar recordings in animals, we present a new theory that accounts for the origin of spontaneous neocortical beta. In our MEG data, spontaneous beta activity from somatosensory and frontal cortex emerged as noncontinuous beta events typically lasting <150 ms with a stereotypical waveform. Computational modeling uniquely designed to infer the electrical currents underlying these signals showed that beta events could emerge from the integration of nearly synchronous bursts of excitatory synaptic drive targeting proximal and distal dendrites of pyramidal neurons, where the defining feature of a beta event was a strong distal drive that lasted one beta period (∼50 ms). This beta mechanism rigorously accounted for the beta event profiles; several other mechanisms did not. The spatial location of synaptic drive in the model to supragranular and infragranular layers was critical to the emergence of beta events and led to the prediction that beta events should be associated with a specific laminar current profile. Laminar recordings in somatosensory neocortex from anesthetized mice and awake monkeys supported these predictions, suggesting this beta mechanism is conserved across species and recording modalities. These findings make several predictions about optimal states for perceptual and motor performance and guide causal interventions to modulate beta for optimal function. PMID:27469163

  1. A gradient in the duration of the G1 phase in the murine neocortical proliferative epithelium

    NASA Technical Reports Server (NTRS)

    Miyama, S.; Takahashi, T.; Nowakowski, R. S.; Caviness, V. S. Jr

    1997-01-01

    Neuronogenesis in the neocortical pseudostratified ventricular epithelium (PVE) is initiated rostrolaterally and progresses caudo-medially as development progresses. Here we have measured the cytokinetic parameters and the fractional neuronal output parameter, Q, of laterally located early-maturing regions over the principal embryonic days (E12-E15) of neocortical neuronogenesis in the mouse. These measures are compared with ones previously made of a medial, late-maturing portion of the PVE. Laterally, as medially, the duration of the neuronogenetic interval is 6 days and comprises 11 integer cell cycles. Also, in both lateral and medial areas the length of G1 phase (TG1) increases nearly 4-fold and is the only cell cycle parameter to change. Q progresses essentially identically laterally and medially with respect to the succession of integer cell cycles. Most importantly, from E12 to E13 there is a steeply declining lateral to medial gradient in TG1. The gradient is due both to the lateral to medial graded stage of neuronogenesis and to the stepwise increase in TG1 with each integer cycle during the neuronogenetic interval. To our knowledge this gradient in TG1 of the cerebral PVE is the first cell biological gradient to be demonstrated experimentally in such an extensive proliferative epithelial sheet. We suggest that this gradient in TG1 is the cellular mechanism for positionally encoding a protomap of the neocortex within the PVE.

  2. A large fraction of neocortical myelin ensheathes axons of local inhibitory neurons

    PubMed Central

    Micheva, Kristina D; Wolman, Dylan; Mensh, Brett D; Pax, Elizabeth; Buchanan, JoAnn; Smith, Stephen J; Bock, Davi D

    2016-01-01

    Myelin is best known for its role in increasing the conduction velocity and metabolic efficiency of long-range excitatory axons. Accordingly, the myelin observed in neocortical gray matter is thought to mostly ensheath excitatory axons connecting to subcortical regions and distant cortical areas. Using independent analyses of light and electron microscopy data from mouse neocortex, we show that a surprisingly large fraction of cortical myelin (half the myelin in layer 2/3 and a quarter in layer 4) ensheathes axons of inhibitory neurons, specifically of parvalbumin-positive basket cells. This myelin differs significantly from that of excitatory axons in distribution and protein composition. Myelin on inhibitory axons is unlikely to meaningfully hasten the arrival of spikes at their pre-synaptic terminals, due to the patchy distribution and short path-lengths observed. Our results thus highlight the need for exploring alternative roles for myelin in neocortical circuits. DOI: http://dx.doi.org/10.7554/eLife.15784.001 PMID:27383052

  3. Stimulus intensity determines experience-dependent modifications in neocortical neuron firing rates

    PubMed Central

    Glazewski, Stanislaw; Barth, Alison L

    2015-01-01

    Although subthreshold inputs of neocortical sensory neurons are broadly tuned, the spiking output is more restricted. These subthreshold inputs provide a substrate for stimulus intensity-dependent changes their spiking output, as well as for experience-dependent plasticity to alter firing properties. Here we investigated how different stimulus intensities modified the firing output of individual neurons in layer 2/3 of the mouse barrel cortex. Decreasing stimulus intensity over a 30-fold range lowered the firing rates evoked by principal whisker stimulation and reduced the overall size of the responding ensemble in whisker-undeprived animals. We then examined how these responses were changed after single-whisker experience (SWE). After 7 days of SWE, the mean magnitude of response to spared whisker stimulation at the highest stimulus intensity was not altered. However, lower-intensity whisker stimulation revealed a more than 10-fold increase in mean firing output compared with control animals. Also, under control conditions, only ∽15% of neurons showed any firing at low stimulus intensity, compared with more than 70% of neurons after SWE. However, response changes measured in the immediately surrounding representations were detected only for the highest stimulus intensity. Overall, these data showed that the measurement of experience-dependent changes in the spike output of neocortical neurons was highly dependent upon stimulus intensity. PMID:25546174

  4. Neocortical efferent neurons with very slowly conducting axons: strategies for reliable antidromic identification.

    PubMed

    Swadlow, H A

    1998-02-20

    Although simple in concept, reliable antidromic identification of efferent populations poses numerous technical challenges and is subject to a host of sampling biases, most of which select against the detection of the neurons with slowly conducting axons. This problem is particularly acute in studies of the neocortex. Many neocortical efferent systems have large sub-populations with very slowly conducting, nonmyelinated axons and these elements have been relatively neglected in antidromic studies of neocortical neurons. The present review attempts to redress this problem by analyzing the steps that must necessarily precede antidromic identification and the sampling biases associated with each of these steps. These steps include (1) initial recognition that the microelectrode is near a neuron; (2) activation of the efferent axon via the stimulating electrode; (3) conduction of the antidromic impulse from stimulation site to soma; (4) detection of the antidromic spike in the extracellular record and (5) discriminating antidromic from synaptic activation. Experimental strategies are suggested for minimizing the sampling biases associated with each of these steps; most of which can be reduced or eliminated by appropriate experimental procedures. Careful attention to such procedures will make it possible to better understand the nature and function of the information flow along the very slowly conducting axonal systems of the neocortex.

  5. Ultrastructural characterization of GABAergic and excitatory synapses in the inferior colliculus.

    PubMed

    Nakamoto, Kyle T; Mellott, Jeffrey G; Killius, Jeanette; Storey-Workley, Megan E; Sowick, Colleen S; Schofield, Brett R

    2014-01-01

    In the inferior colliculus (IC) cells integrate inhibitory input from the brainstem and excitatory input from both the brainstem and auditory cortex. In order to understand how these inputs are integrated by IC cells identification of their synaptic arrangements is required. We used electron microscopy to characterize GABAergic synapses in the dorsal cortex, central nucleus, and lateral cortex of the IC (ICd, ICc, and IClc) of guinea pigs. Throughout the IC, GABAergic synapses are characterized by pleomorphic vesicles and symmetric junctions. Comparisons of GABAergic synapses with excitatory synapses revealed differences (in some IC subdivisions) between the distributions of these synapse types onto IC cells. For excitatory cells in the IClc and ICd GABAergic synapses are biased toward the somas and large dendrites, whereas the excitatory boutons are biased toward spines and small dendrites. This arrangement could allow for strong inhibitory gating of excitatory inputs. Such differences in synaptic distributions were not observed in the ICc, where the two classes of bouton have similar distributions along the dendrites of excitatory cells. Interactions between excitatory and GABAergic inputs on the dendrites of excitatory ICc cells may be more restricted (i.e., reflecting local dendritic processing) than in the other IC subdivisions. Comparisons across IC subdivisions revealed evidence for two classes of GABAergic boutons, a small GABAergic (SG) class that is present throughout the IC and a large GABAergic (LG) class that is almost completely restricted to the ICc. In the ICc, LG, and SG boutons differ in their targets. SG boutons contact excitatory dendritic shafts most often, but also contact excitatory spines and somas (excitatory and GABAergic). LG synapses make comparatively fewer contacts on excitatory shafts, and make comparatively more contacts on excitatory spines and on somas (excitatory and GABAergic). LG boutons likely have a lemniscal origin.

  6. GABAergic Projections to the Oculomotor Nucleus in the Goldfish (carassius Auratus)

    PubMed Central

    Luque, M. Angeles; Torres-Torrelo, Julio; Carrascal, Livia; Torres, Blas; Herrero, Luis

    2010-01-01

    The mammalian oculomotor nucleus receives a strong γ-aminobutyric acid (GABA)ergic synaptic input, whereas such projections have rarely been reported in fish. In order to determine whether this synaptic organization is preserved across vertebrates, we investigated the GABAergic projections to the oculomotor nucleus in the goldfish by combining retrograde transport of biotin dextran amine, injected into the antidromically identified oculomotor nucleus, and GABA immunohistochemistry. The main source of GABAergic afferents to the oculomotor nucleus was the ipsilateral anterior octaval nucleus, with only a few, if any, GABAergic neurons being located in the contralateral tangential and descending nuclei of the octaval column. In mammals there is a nearly GABAergic inhibitory inputs; thus, the vestibulooculomotor GABAergic circuitry follows a plan that appears to be shared throughout the vertebrate phylogeny. The second major source of GABAergic projections was the rhombencephalic reticular formation, primarily from the medial area but, to a lesser extent, from the inferior area. A few GABAergic oculomotor projecting neurons were also observed in the ipsilateral nucleus of the medial longitudinal fasciculus. The GABAergic projections from neurons located in both the reticular formation surrounding the abducens nucleus and the nucleus of the medial reticular formation have primarily been related to the control of saccadic eye movements. Finally, all retrogradely labeled internuclear neurons of the abducens nucleus, and neurons in the cerebellum (close to the caudal lobe), were negative for GABA. These data suggest that the vestibuloocular and saccadic inhibitory GABAergic systems appear early in vertebrate phylogeny to modulate the firing properties of the oculomotor nucleus motoneurons. PMID:21331170

  7. Properties of Mouse Spinal Lamina I GABAergic Interneurons.

    PubMed Central

    Dougherty, Kimberly J.; Sawchuk, Michael A.; Hochman, Shawn

    2009-01-01

    Lamina I is a sensory relay region containing projection cells and local interneurons involved in thermal and nociceptive signaling. These neurons differ in morphology, sensory response modality, and firing characteristics. We examined intrinsic properties of mouse lamina I GABAergic neurons expressing enhanced green fluorescent protein (EGFP). GABAergic neuron identity was confirmed by a high correspondence between GABA immunolabeling and EGFP fluorescence. Morphologies of these EGFP+/GABA+ cells were multipolar (65%), fusiform (31%), and pyramidal (4%). In whole cell recordings, cells fired a single spike (44%), tonically (35%), or an initial burst (21%) in response to current steps, representing a subset of reported lamina I firing properties. Membrane properties of tonic and initial burst cells were indistinguishable and these neurons may represent one functional population because, in individual neurons, their firing patterns could interconvert. Single spike cells were less excitable with lower membrane resistivity and higher rheobase. Most fusiform cells (64%) fired tonically while most multipolar cells (56%) fired single spikes. In summary, lamina I inhibitory interneurons are functionally divisible into at least two major groups both of which presumably function to limit excitatory transmission. PMID:16014799

  8. Rat hippocampal GABAergic molecular markers are differentially affected by ageing.

    PubMed

    Vela, José; Gutierrez, Antonia; Vitorica, Javier; Ruano, Diego

    2003-04-01

    We previously reported that the pharmacological properties of the hippocampal GABAA receptor and the expression of several subunits are modified during normal ageing. However, correlation between these post-synaptic modifications and pre-synaptic deficits were not determined. To address this issue, we have analysed the mRNA levels of several GABAergic molecular markers in young and old rat hippocampus, including glutamic acid decarboxylase enzymes, parvalbumin, calretinin, somatostatin, neuropeptide Y and vasoactive intestinal peptide (VIP). There was a differential age-related decrease in these interneuronal mRNAs that was inversely correlated with up-regulation of the alpha1 GABA receptor subunit. Somatostatin and neuropeptide Y mRNAs were most frequently affected (75% of the animals), then calretinin and VIP mRNAs (50% of the animals), and parvalbumin mRNA (25% of the animals) in the aged hippocampus. This selective vulnerability was well correlated at the protein/cellular level as analysed by immunocytochemistry. Somatostatin interneurones, which mostly innervate principal cell distal dendrites, were more vulnerable than calretinin interneurones, which target other interneurones. Parvalbumin interneurones, which mostly innervate perisomatic domains of principal cells, were preserved. This age-dependent differential reduction of specific hippocampal inteneuronal subpopulations might produce functional alterations in the GABAergic tone which might be compensated, at the post-synaptic level, by up-regulation of the expression of the alpha1 GABAA receptor subunit.

  9. Dystroglycan mediates homeostatic synaptic plasticity at GABAergic synapses.

    PubMed

    Pribiag, Horia; Peng, Huashan; Shah, Waris Ali; Stellwagen, David; Carbonetto, Salvatore

    2014-05-06

    Dystroglycan (DG), a cell adhesion molecule well known to be essential for skeletal muscle integrity and formation of neuromuscular synapses, is also present at inhibitory synapses in the central nervous system. Mutations that affect DG function not only result in muscular dystrophies, but also in severe cognitive deficits and epilepsy. Here we demonstrate a role of DG during activity-dependent homeostatic regulation of hippocampal inhibitory synapses. Prolonged elevation of neuronal activity up-regulates DG expression and glycosylation, and its localization to inhibitory synapses. Inhibition of protein synthesis prevents the activity-dependent increase in synaptic DG and GABAA receptors (GABAARs), as well as the homeostatic scaling up of GABAergic synaptic transmission. RNAi-mediated knockdown of DG blocks homeostatic scaling up of inhibitory synaptic strength, as does knockdown of like-acetylglucosaminyltransferase (LARGE)--a glycosyltransferase critical for DG function. In contrast, DG is not required for the bicuculline-induced scaling down of excitatory synaptic strength or the tetrodotoxin-induced scaling down of inhibitory synaptic strength. The DG ligand agrin increases GABAergic synaptic strength in a DG-dependent manner that mimics homeostatic scaling up induced by increased activity, indicating that activation of this pathway alone is sufficient to regulate GABAAR trafficking. These data demonstrate that DG is regulated in a physiologically relevant manner in neurons and that DG and its glycosylation are essential for homeostatic plasticity at inhibitory synapses.

  10. Characterization of a GABAergic neurotransmission in adult Schistosoma mansoni.

    PubMed

    Mendonça-Silva, D L; Gardino, P F; Kubrusly, R C C; De Mello, F G; Noël, F

    2004-08-01

    The neuromuscular systems of parasitic helminths are targets that are particularly amenable for anthelmintics. In this study, we describe a GABAergic neurotransmission in adult Schistosoma mansoni, the trematode responsible for high levels of morbidity in people living in developing countries. GABA immunoreactivity (GABA-IR) was detected in nerve cells and fibres of the cerebral ganglia and longitudinal nerve cords and the nerve plexuses ramifying throughout the parenchyma of male adult worms. In addition, strong GABA-IR was also found associated with the oral and ventral suckers as well as in testes indicating a role for GABA in fixation to the host vascular wall and spermatogenesis. The capacity to synthesize GABA from glutamate was confirmed by measurement of a glutamate decarboxylase (GAD) activity. Supporting these data, a single band with an apparent molecular weight of about 67 kDa was detected using an antibody raised against mammalian GAD. In vivo studies revealed that picrotoxin, a non-competitive antagonist of the GABAA receptor, produced a modification of the motility and locomotory behaviour of adult worms, suggesting that GABAergic signalling pathway may play a physiological role in the motonervous system of S. mansoni and could be considered as a potential target for the development of new drugs.

  11. Dynamic GABAergic afferent modulation of AgRP neurons

    PubMed Central

    Garfield, Alastair S; Shah, Bhavik P; Burgess, Christian R; Li, Monica M; Li, Chia; Steger, Jennifer S; Madara, Joseph C; Campbell, John N; Kroeger, Daniel; Scammell, Thomas E; Tannous, Bakhos A; Myers, Martin G; Andermann, Mark L; Krashes, Michael J; Lowell, Bradford B

    2017-01-01

    Agouti-related peptide (AgRP) neurons of the arcuate nucleus of the hypothalamus (ARC) promote homeostatic feeding at times of caloric insufficiency, yet they are rapidly suppressed by food-related sensory cues prior to ingestion. Here we identify a highly selective inhibitory afferent to AgRP neurons that serves as a neural determinant of this rapid modulation. Specifically, GABAergic projections arising from the ventral compartment of the dorsomedial nucleus of the hypothalamus (vDMH) contribute to the pre-consummatory modulation of ARCAgRP neurons. In a manner reciprocal to ARCAgRP neurons, ARC-projecting leptin receptor (LepR)-expressing GABAergic DMH neurons exhibit rapid activation upon availability of food that additionally reflects the relative value of the food. Thus, DMHLepR neurons form part of the sensory network that relays real-time information about the nature and availability of food to dynamically modulate ARCAgRP neuron activity and feeding behavior. PMID:27643429

  12. Using Multiple Whole-Cell Recordings to Study Spike-Timing-Dependent Plasticity in Acute Neocortical Slices

    PubMed Central

    Lalanne, Txomin; Abrahamsson, Therese; Sjöström, P. Jesper

    2017-01-01

    This protocol provides a method for quadruple whole-cell recording to study synaptic plasticity of neocortical connections, with a special focus on spike-timing-dependent plasticity (STDP). It also describes how to morphologically identify recorded cells from two-photon laser-scanning microscopy (2PLSM) stacks. PMID:27250948

  13. Target-specific effects of somatostatin-expressing interneurons on neocortical visual processing.

    PubMed

    Cottam, James C H; Smith, Spencer L; Häusser, Michael

    2013-12-11

    A diverse array of interneuron types regulates activity in the mammalian neocortex. Two of the most abundant are the fast-spiking, parvalbumin-positive (PV(+)) interneurons, which target the axosomatic region of pyramidal cells, and the somatostatin-positive (SOM(+)) interneurons, which target the dendrites. Recent work has focused on the influence of PV(+) and SOM(+) interneurons on pyramidal cells. However, the connections among PV(+) and SOM(+) interneurons are poorly understood and could play an important role in cortical circuitry, since their interactions may alter the net influence on pyramidal cell output. We used an optogenetic approach to investigate the effect of SOM(+) interneurons on pyramidal cells and PV(+) interneurons during visual stimulation in mouse primary visual cortex. We find that SOM(+) interneuron activation suppresses PV(+) cell spiking at least twice as potently as pyramidal cell spiking during visual stimulation. This differential effect of SOM(+) cell stimulation is detectable even when only two to three SOM(+) cells are activated. Importantly, the remaining responses to oriented gratings in PV(+) cells are more orientation tuned and temporally modulated, suggesting that SOM(+) activity unmasks this tuning by suppressing untuned input. Our results highlight the importance of SOM(+) inhibition of PV(+) interneurons during sensory processing. This prominent competitive inhibition between interneuron types leads to a reconfiguration of inhibition along the somatodendritic axis of pyramidal cells, and enhances the orientation selectivity of PV(+) cells.

  14. Role of tonic GABAergic currents during pre- and early postnatal rodent development

    PubMed Central

    Kilb, Werner; Kirischuk, Sergei; Luhmann, Heiko J.

    2013-01-01

    In the last three decades it became evident that the GABAergic system plays an essential role for the development of the central nervous system, by influencing the proliferation of neuronal precursors, neuronal migration and differentiation, as well as by controlling early activity patterns and thus formation of neuronal networks. GABA controls neuronal development via depolarizing membrane responses upon activation of ionotropic GABA receptors. However, many of these effects occur before the onset of synaptic GABAergic activity and thus require the presence of extrasynaptic tonic currents in neuronal precursors and immature neurons. This review summarizes our current knowledge about the role of tonic GABAergic currents during early brain development. In this review we compare the temporal sequence of the expression and functional relevance of different GABA receptor subunits, GABA synthesizing enzymes and GABA transporters. We also refer to other possible endogenous agonists of GABAA receptors. In addition, we describe functional consequences mediated by the GABAergic system during early developmental periods and discuss current models about the origin of extrasynaptic GABA and/or other endogenous GABAergic agonists during early developmental states. Finally, we present evidence that tonic GABAergic activity is also critically involved in the generation of physiological as well as pathophysiological activity patterns before and after the establishment of functional GABAergic synaptic connections. PMID:24027498

  15. Modulation of GABAergic and glutamatergic transmission by ethanol in the developing neocortex: an in vitro test of the excessive inhibition hypothesis of Fetal Alcohol Spectrum Disorder

    PubMed Central

    Sanderson, Jennifer L.; Partridge, L. Donald; Valenzuela, C. Fernando

    2010-01-01

    Summary Exposure to ethanol during development triggers neuronal cell death and this is thought to play a central role in the pathophysiology of fetal alcohol spectrum disorder (FASD). Studies suggest that ethanol-induced neurodegeneration during the period of synaptogenesis results from widespread potentiation of GABAA receptors and inhibition of NMDA receptors throughout the brain, with neocortical layer II being particularly sensitive. Here, we tested whether ethanol modulates the function of these receptors during this developmental period using patch-clamp electrophysiological and Ca2+ imaging techniques in acute slices from postnatal day 7–9 rats. We focused on pyramidal neurons in layer II of the parietal cortex (with layer III as a control). Ethanol (70 mM) increased spontaneous action potential-dependent GABA release in layer II (but not layer III) neurons without affecting postsynaptic GABAA receptors. Protein and mRNA expression for both the Cl− importer, NKCC1, and the Cl− exporter KCC2, were detected in layer II/III neurons. Perforated-patch experiments demonstrated that ECl− is shifted to the right of Em; activation of GABAA receptors with muscimol depolarized Em, decreased action potential firing, and minimally increased [Ca2+]i. However, the ethanol-induced increase of GABAergic transmission did not affect neuronal excitability. Ethanol had no effect on currents exogenously evoked by NMDA or AMPA receptor-mediated spontaneous excitatory postsynaptic currents. Acute application of ethanol in the absence of receptor antagonists minimally increased [Ca2+]i. These findings are inconsistent with the excessive inhibition model of ethanol-induced neurodegeneration, supporting the view that ethanol damages developing neurons via more complex mechanisms that vary among specific neuronal populations. PMID:19027758

  16. GABAergic and glycinergic pathways to goldfish retinal ganglion cells: an ultrastructural double label study

    SciTech Connect

    Muller, J.F.

    1987-01-01

    An ultrastructural double label has been employed to compare GABAergic and glycinergic systems in the inner plexiform layer (IPL) of the goldfish retina. Electron microscope autoradiography of /sup 3/H-GABA and /sup 3/H-glycine uptake was combined with retrograde HRP-labeling of ganglion cells. When surveyed for distribution, GABAergic and glycinergic synapses were found onto labeled ganglion cells throughout the IPL. This reinforces previous physiological work that described GABAergic and glycinergic influences on a variety of ganglion cells in goldfish and carp; These physiological effects often reflect direct inputs.

  17. Neocortical synchronization

    PubMed Central

    Timofeev, Igor; Bazhenov, Maksim; Seigneur, Joseé; Sejnowski, Terrence

    2011-01-01

    Summary Neuronal synchronization occurs when two or more neuronal events are coordinated across time. Local synchronization produces field potentials. Long-range synchronization between distant brain sites contributes to the electroencephalogram. Neuronal synchronization depends on synaptic (chemical/electrical), ephaptic, and extracellular interactions. For an expanded treatment of this topic see Jasper’s Basic Mechanisms of the Epilepsies, Fourth Edition (Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, eds) published by Oxford University Press (available on the National Library of Medicine Bookshelf [NCBI] at www.ncbi.nlm.nih.gov/books). PMID:24850952

  18. Functional switching of GABAergic synapses by ryanodine receptor activation

    NASA Astrophysics Data System (ADS)

    Sun, Miao-Kun; Nelson, Thomas J.; Alkon, Daniel L.

    2000-10-01

    The role of the ryanodine receptor (RyR) in modifiability of synapses made by the basket interneurons onto the hippocampal CA1 pyramidal cells was examined in rats. Associating single-cell RyR activation with postsynaptic depolarization increased intracellular free Ca2+ concentrations and reversed the basket interneuron-CA1 inhibitory postsynaptic potential into an excitatory postsynaptic potential. This synaptic transformation was accompanied by a shift of the reversal potential from that of chloride toward that of bicarbonate. This inhibitory postsynaptic potential-excitatory postsynaptic potential transformation was prevented by blocking RyR or carbonic anhydrase. Associated postsynaptic depolarization and RyR activation, therefore, changes GABAergic synapses from excitation filters to amplifier and, thereby, shapes information flow through the hippocampal network.

  19. Abnormal GABAergic function and negative affect in schizophrenia.

    PubMed

    Taylor, Stephan F; Demeter, Elise; Phan, K Luan; Tso, Ivy F; Welsh, Robert C

    2014-03-01

    Deficits in the γ-aminobutyric acid (GABA) system have been reported in postmortem studies of schizophrenia, and therapeutic interventions in schizophrenia often involve potentiation of GABA receptors (GABAR) to augment antipsychotic therapy and treat negative affect such as anxiety. To map GABAergic mechanisms associated with processing affect, we used a benzodiazepine challenge while subjects viewed salient visual stimuli. Fourteen stable, medicated schizophrenia/schizoaffective patients and 13 healthy comparison subjects underwent functional magnetic resonance imaging using the blood oxygenation level-dependent (BOLD) technique while they viewed salient emotional images. Subjects received intravenous lorazepam (LRZ; 0.01 mg/kg) or saline in a single-blinded, cross-over design (two sessions separated by 1-3 weeks). A predicted group by drug interaction was noted in the dorsal medial prefrontal cortex (dmPFC) as well as right superior frontal gyrus and left and right occipital regions, such that psychosis patients showed an increased BOLD signal to LRZ challenge, rather than the decreased signal exhibited by the comparison group. A main effect of reduced BOLD signal in bilateral occipital areas was noted across groups. Consistent with the role of the dmPFC in processing emotion, state negative affect positively correlated with the response to the LRZ challenge in the dmPFC for the patients and comparison subjects. The altered response to LRZ challenge is consistent with altered inhibition predicted by postmortem findings of altered GABAR in schizophrenia. These results also suggest that negative affect in schizophrenia/schizoaffective disorder is associated-directly or indirectly-with GABAergic function on a continuum with normal behavior.

  20. Steroid influences on GABAergic neurotransmission: A behavioral and biochemical approach

    SciTech Connect

    McCarthy, M.M.

    1989-01-01

    Steroid influences on GABAergic neurotransmission are varied and complex. However, there has been little investigation into the behavioral relevance of steroid effects on GABA. GABA had been implicated in the control of lordosis, a steroid dependent posture exhibited by sexually receptive female rats, but with conflicting results. This data demonstrated that GABA plays a dual role in the regulation of lordosis; stimulation of GABAergic transmission in the medial hypothalamus enhances lordosis whereas stimulation of GABA in the preoptic area inhibits lordosis. In separate experiments it was determined that progesterone enhances binding of the GABA{sub A} agonist, muscimol, in an in vitro exchange assay utilizing synaptic membranes prepared from the hypothalamus of ovariectomized rats. Scatchard analysis revealed a difference in affinity of the GABA{sub A} receptor between ovariectomized, receptive and post receptive females. In the preoptic area there was a significant decrease in the binding of {sup 3}H-muscimol in receptive females versus post-receptive and ovariectomized rats. In other behavioral experiments, the influence of estrogen and progesterone on GABA-induced analgesia was assessed. Intrathecal infusion of a low dose of muscimol at the lumbar level of the spinal cord did not alter nociceptive thresholds in ovariectomized rats. However, when intact females were administered the same dose of muscimol, they exhibited differential responses over the estrous cycle. Females in estrus were analgesic after muscimol, whereas diestrus females did not differ from ovariectomized controls. Ovariectomized rats injected s.c. with progesterone (2mg) exhibited a pronounced analgesia after intrathecal muscimol beginning 15 minutes after steroid treatment, whereas similar treatment with estrogen (10ug) was without effect.

  1. Dendritic channelopathies contribute to neocortical and sensory hyperexcitability in Fmr1(-/y) mice.

    PubMed

    Zhang, Yu; Bonnan, Audrey; Bony, Guillaume; Ferezou, Isabelle; Pietropaolo, Susanna; Ginger, Melanie; Sans, Nathalie; Rossier, Jean; Oostra, Ben; LeMasson, Gwen; Frick, Andreas

    2014-12-01

    Hypersensitivity in response to sensory stimuli and neocortical hyperexcitability are prominent features of Fragile X Syndrome (FXS) and autism spectrum disorders, but little is known about the dendritic mechanisms underlying these phenomena. We found that the primary somatosensory neocortex (S1) was hyperexcited in response to tactile sensory stimulation in Fmr1(-/y) mice. This correlated with neuronal and dendritic hyperexcitability of S1 pyramidal neurons, which affect all major aspects of neuronal computation, from the integration of synaptic input to the generation of action potential output. Using dendritic electrophysiological recordings, calcium imaging, pharmacology, biochemistry and a computer model, we found that this defect was, at least in part, attributable to the reduction and dysfunction of dendritic h- and BKCa channels. We pharmacologically rescued several core hyperexcitability phenomena by targeting BKCa channels. Our results provide strong evidence pointing to the utility of BKCa channel openers for the treatment of the sensory hypersensitivity aspects of FXS.

  2. Target cell-dependent normalization of transmitter release at neocortical synapses.

    PubMed

    Koester, Helmut J; Johnston, Daniel

    2005-05-06

    The efficacy and short-term modification of neocortical synaptic connections vary with the type of target neuron. We investigated presynaptic Ca2+ and release probability at single synaptic contacts between pairs of neurons in layer 2/3 of the rat neocortex. The amplitude of Ca2+ signals in boutons of pyramids contacting bitufted or multipolar interneurons or other pyramids was dependent on the target cell type. Optical quantal analysis at single synaptic contacts suggested that release probabilities are also target cell-specific. Both the Ca2+ signal and the release probability of different boutons of a pyramid contacting the same target cell varied little. We propose that the mechanisms that regulate the functional properties of boutons of a pyramid normalize the presynaptic Ca2+ influx and release probability for all those boutons that innervate the same target cell.

  3. Alterations of Neocortical Pyramidal Neurons: Turning Points in the Genesis of Mental Retardation

    PubMed Central

    Granato, Alberto; De Giorgio, Andrea

    2014-01-01

    Pyramidal neurons (PNs) represent the majority of neocortical cells and their involvement in cognitive functions is decisive. Therefore, they are the most obvious target of developmental disorders characterized by mental retardation. Genetic and non-genetic forms of intellectual disability share a few basic pathogenetic signatures that result in the anomalous function of PNs. Here, we review the key mechanisms impairing these neurons and their participation in the cortical network, with special focus on experimental models of fetal exposure to alcohol. Due to the heterogeneity of PNs, some alterations affect selectively a given cell population, which may also differ depending on the considered pathology. These specific features open new possibilities for the interpretation of cognitive defects observed in mental retardation syndromes, as well as for novel therapeutic interventions. PMID:25157343

  4. SOX6 controls dorsal progenitor identity and interneuron diversity during neocortical development.

    PubMed

    Azim, Eiman; Jabaudon, Denis; Fame, Ryann M; Macklis, Jeffrey D

    2009-10-01

    The neuronal diversity of the CNS emerges largely from controlled spatial and temporal segregation of cell type-specific molecular regulators. We found that the transcription factor SOX6 controls the molecular segregation of dorsal (pallial) from ventral (subpallial) telencephalic progenitors and the differentiation of cortical interneurons, regulating forebrain progenitor and interneuron heterogeneity. During corticogenesis in mice, SOX6 and SOX5 were largely mutually exclusively expressed in pallial and subpallial progenitors, respectively, and remained mutually exclusive in a reverse pattern in postmitotic neuronal progeny. Loss of SOX6 from pallial progenitors caused their inappropriate expression of normally subpallium-restricted developmental controls, conferring mixed dorsal-ventral identity. In postmitotic cortical interneurons, loss of SOX6 disrupted the differentiation and diversity of cortical interneuron subtypes, analogous to SOX5 control over cortical projection neuron development. These data indicate that SOX6 is a central regulator of both progenitor and cortical interneuron diversity during neocortical development.

  5. In vivo rapid gene delivery into postmitotic neocortical neurons using iontoporation.

    PubMed

    De la Rossa, Andres; Jabaudon, Denis

    2015-01-01

    This protocol describes a method for directing the expression of genes of interest into postmitotic neocortical neurons in vivo. Microinjection of a DNA plasmid-amphiphilic molecule mix into the neocortex followed by delivery of an ad hoc electric pulse protocol during the first few days of life in mice allows rapid, focal and efficient expression of genes in postmitotic neurons. Compared with other gene delivery techniques such as in utero electroporation and viral infection, this method allows rapid (12 h), focal (50-200 μm), mosaic-like (50 to several hundred neurons) targeting of postmitotic neurons within existing circuits. This 'iontoporation' protocol, which can be completed within ∼20 min per mouse, allows straightforward assessment of genetic constructs in postmitotic cortical neurons and subsequent genetic, histological and physiological investigations of gene function.

  6. Imaging the Dynamics of Neocortical Population Activity in Behaving and Freely Moving Mammals.

    PubMed

    Grinvald, Amiram; Petersen, Carl C H

    2015-01-01

    The development of functional imaging techniques applicable to neuroscience and covering a wide range of spatial and temporal scales has greatly facilitated the exploration of the relationships between cognition, behaviour and electrical brain activity. For mammals, the neocortex plays a particularly profound role in generating sensory perception, controlling voluntary movement, higher cognitive functions and planning goal-directed behaviours. Since these remarkable functions of the neocortex cannot be explored in simple model preparations or in anesthetised animals, the neural basis of behaviour must be explored in awake behaving subjects. Because neocortical function is highly distributed across many rapidly interacting regions, it is essential to measure spatiotemporal dynamics of cortical activity in real-time. Extensive work in anesthetised mammals has shown that in vivo Voltage-Sensitive Dye Imaging (VSDI) reveals the neocortical population membrane potential dynamics at millisecond temporal resolution and subcolumnar spatial resolution. Here, we describe recent advances indicating that VSDI is also already well-developed for exploring cortical function in behaving monkeys and mice. The first animal model, the non-human primate, is well-suited for fundamental exploration of higher-level cognitive function and behavior. The second animal model, the mouse, benefits from a rich arsenal of molecular and genetic technologies. In the monkey, imaging from the same patch of cortex, repeatedly, is feasible for a long period of time, up to a year. In the rodent, VSDI is applicable to freely moving and awake head-restrained mice. Interactions between different cortical areas and different cortical columns can therefore now be dynamically mapped through VSDI and related to the corresponding behaviour. Thus by applying VSDI to mice and monkeys one can begin to explore how behaviour emerges from neuronal activity in neuronal networks residing in different cortical areas.

  7. Prdm8 regulates the morphological transition at multipolar phase during neocortical development.

    PubMed

    Inoue, Mayuko; Kuroda, Takao; Honda, Aya; Komabayashi-Suzuki, Mariko; Komai, Tae; Shinkai, Yoichi; Mizutani, Ken-ichi

    2014-01-01

    Here, we found that the PR domain protein Prdm8 serves as a key regulator of the length of the multipolar phase by controlling the timing of morphological transition. We used a mouse line with expression of Prdm8-mVenus reporter and found that Prdm8 is predominantly expressed in the middle and upper intermediate zone during both the late and terminal multipolar phases. Prdm8 expression was almost coincident with Unc5D expression, a marker for the late multipolar phase, although the expression of Unc5D was found to be gradually down-regulated to the point at which mVenus expression was gradually up-regulated. This expression pattern suggests the possible involvement of Prdm8 in the control of the late and terminal multipolar phases, which controls the timing for morphological transition. To test this hypothesis, we performed gain- and loss-of-function analysis of neocortical development by using in utero electroporation. We found that the knockdown of Prdm8 results in premature change from multipolar to bipolar morphology, whereas the overexpression of Prdm8 maintained the multipolar morphology. Additionally, the postnatal analysis showed that the Prdm8 knockdown stimulated the number of early born neurons, and differentiated neurons located more deeply in the neocortex, however, majority of those cells could not acquire molecular features consistent with laminar location. Furthermore, we found the candidate genes that were predominantly utilized in both the late and terminal multipolar phases, and these candidate genes included those encoding for guidance molecules. In addition, we also found that the expression level of these guidance molecules was inhibited by the introduction of the Prdm8 expression vector. These results indicate that the Prdm8-mediated regulation of morphological changes that normally occur during the late and terminal multipolar phases plays an important role in neocortical development.

  8. Synchronized changes to relative neuron populations in postnatal human neocortical development

    PubMed Central

    Cooper, David L.; Gentle, James E.; Barreto, Ernest

    2010-01-01

    Mammalian prenatal neocortical development is dominated by the synchronized formation of the laminae and migration of neurons. Postnatal development likewise contains “sensitive periods” during which functions such as ocular dominance emerge. Here we introduce a novel neuroinformatics approach to identify and study these periods of active development. Although many aspects of the approach can be used in other studies, some specific techniques were chosen because of a legacy dataset of human histological data (Conel in The postnatal development of the human cerebral cortex, vol 1–8. Harvard University Press, Cambridge, 1939–1967). Our method calculates normalized change vectors from the raw histological data, and then employs k-means cluster analysis of the change vectors to explore the population dynamics of neurons from 37 neocortical areas across eight postnatal developmental stages from birth to 72 months in 54 subjects. We show that the cortical “address” (Brodmann area/sub-area and layer) provides the necessary resolution to segregate neuron population changes into seven correlated “k-clusters” in k-means cluster analysis. The members in each k-cluster share a single change interval where the relative share of the cortex by the members undergoes its maximum change. The maximum change occurs in a different change interval for each k-cluster. Each k-cluster has at least one totally connected maximal “clique” which appears to correspond to cortical function. Electronic supplementary material The online version of this article (doi:10.1007/s11571-010-9103-3) contains supplementary material, which is available to authorized users. PMID:21629587

  9. Kv2 subunits underlie slowly inactivating potassium current in rat neocortical pyramidal neurons

    PubMed Central

    Guan, D; Tkatch, T; Surmeier, D J; Armstrong, W E; Foehring, R C

    2007-01-01

    We determined the expression of Kv2 channel subunits in rat somatosensory and motor cortex and tested for the contributions of Kv2 subunits to slowly inactivating K+ currents in supragranular pyramidal neurons. Single cell RT-PCR showed that virtually all pyramidal cells expressed Kv2.1 mRNA and ∼80% expressed Kv2.2 mRNA. Immunocytochemistry revealed striking differences in the distribution of Kv2.1 and Kv2.2 subunits. Kv2.1 subunits were clustered and located on somata and proximal dendrites of all pyramidal cells. Kv2.2 subunits were primarily distributed on large apical dendrites of a subset of pyramidal cells from deep layers. We used two methods for isolating currents through Kv2 channels after excluding contributions from Kv1 subunits: intracellular diffusion of Kv2.1 antibodies through the recording pipette and extracellular application of rStromatoxin-1 (ScTx). The Kv2.1 antibody specifically blocked the slowly inactivating K+ current by 25–50% (at 8 min), demonstrating that Kv2.1 subunits underlie much of this current in neocortical pyramidal neurons. ScTx (300 nm) also inhibited ∼40% of the slowly inactivating K+ current. We observed occlusion between the actions of Kv2.1 antibody and ScTx. In addition, Kv2.1 antibody- and ScTx-sensitive currents demonstrated similar recovery from inactivation and voltage dependence and kinetics of activation and inactivation. These data indicate that both agents targeted the same channels. Considering the localization of Kv2.1 and 2.2 subunits, currents from truncated dissociated cells are probably dominated by Kv2.1 subunits. Compared with Kv2.1 currents in expression systems, the Kv2.1 current in neocortical pyramidal cells activated and inactivated at relatively negative potentials and was very sensitive to holding potential. PMID:17379638

  10. Encoding of High Frequencies Improves with Maturation of Action Potential Generation in Cultured Neocortical Neurons

    PubMed Central

    Nikitin, Evgeny S.; Bal, Natalia V.; Malyshev, Aleksey; Ierusalimsky, Victor N.; Spivak, Yulia; Balaban, Pavel M.; Volgushev, Maxim

    2017-01-01

    The ability of neocortical neurons to detect and encode rapid changes at their inputs is crucial for basic neuronal computations, such as coincidence detection, precise synchronization of activity and spike-timing dependent plasticity. Indeed, populations of cortical neurons can respond to subtle changes of the input very fast, on a millisecond time scale. Theoretical studies and model simulations linked the encoding abilities of neuronal populations to the fast onset dynamics of action potentials (APs). Experimental results support this idea, however mechanisms of fast onset of APs in cortical neurons remain elusive. Studies in neuronal cultures, that are allowing for accurate control over conditions of growth and microenvironment during the development of neurons and provide better access to the spike initiation zone, may help to shed light on mechanisms of AP generation and encoding. Here we characterize properties of AP encoding in neocortical neurons grown for 11–25 days in culture. We show that encoding of high frequencies improves upon culture maturation, which is accompanied by the development of passive electrophysiological properties and AP generation. The onset of APs becomes faster with culture maturation. Statistical analysis using correlations and linear model approaches identified the onset dynamics of APs as a major predictor of age-dependent changes of encoding. Encoding of high frequencies strongly correlated also with the input resistance of neurons. Finally, we show that maturation of encoding properties of neurons in cultures is similar to the maturation of encoding in neurons studied in slices. These results show that maturation of AP generators and encoding is, to a large extent, determined genetically and takes place even without normal micro-environment and activity of the whole brain in vivo. This establishes neuronal cultures as a valid experimental model for studying mechanisms of AP generation and encoding, and their maturation. PMID

  11. Characterization of thalamocortical responses of regular-spiking and fast-spiking neurons of the mouse auditory cortex in vitro and in silico

    PubMed Central

    Reyes, Alex D.

    2012-01-01

    We use a combination of in vitro whole cell recordings and computer simulations to characterize the cellular and synaptic properties that contribute to processing of auditory stimuli. Using a mouse thalamocortical slice preparation, we record the intrinsic membrane properties and synaptic properties of layer 3/4 regular-spiking (RS) pyramidal neurons and fast-spiking (FS) interneurons in primary auditory cortex (AI). We find that postsynaptic potentials (PSPs) evoked in FS cells are significantly larger and depress more than those evoked in RS cells after thalamic stimulation. We use these data to construct a simple computational model of the auditory thalamocortical circuit and find that the differences between FS and RS cells observed in vitro generate model behavior similar to that observed in vivo. We examine how feedforward inhibition and synaptic depression affect cortical responses to time-varying inputs that mimic sinusoidal amplitude-modulated tones. In the model, the balance of cortical inhibition and thalamic excitation evolves in a manner that depends on modulation frequency (MF) of the stimulus and determines cortical response tuning. PMID:22090462

  12. Ablation of fast-spiking interneurons in the dorsal striatum, recapitulating abnormalities seen post-mortem in Tourette syndrome, produces anxiety and elevated grooming.

    PubMed

    Xu, M; Li, L; Pittenger, C

    2016-06-02

    Tic disorders, including Tourette syndrome (TS), are thought to involve pathology of cortico-basal ganglia loops, but their pathology is not well understood. Post-mortem studies have shown a reduced number of several populations of striatal interneurons, including the parvalbumin-expressing fast-spiking interneurons (FSIs), in individuals with severe, refractory TS. We tested the causal role of this interneuronal deficit by recapitulating it in an otherwise normal adult mouse using a combination transgenic-viral cell ablation approach. FSIs were reduced bilaterally by ∼40%, paralleling the deficit found post-mortem. This did not produce spontaneous stereotypies or tic-like movements, but there was increased stereotypic grooming after acute stress in two validated paradigms. Stereotypy after amphetamine, in contrast, was not elevated. FSI ablation also led to increased anxiety-like behavior in the elevated plus maze, but not to alterations in motor learning on the rotorod or to alterations in prepulse inhibition, a measure of sensorimotor gating. These findings indicate that a striatal FSI deficit can produce stress-triggered repetitive movements and anxiety. These repetitive movements may recapitulate aspects of the pathophysiology of tic disorders.

  13. Effect of gap junctions on the firing patterns and synchrony for different external inputs in the striatal fast-spiking neuron network.

    PubMed

    Zhang, Mingming; Zhao, Zongya; He, Ping; Wang, Jue

    2014-01-01

    Gap junctions are the mechanism for striatal fast-spiking interneurons (FSIs) to interconnect with each other and play an important role in determining the physiological functioning of the FSIs. To investigate the effect of gap junctions on the firing activities and synchronization of the network for different external inputs, a simple network with least connections and a Newman-Watts small-world network were constructed. Our research shows that both properties of neural networks are related to the conductance of the gap junctions, as well as the frequency and correlation of the external inputs. The effect of gap junctions on the synchronization of network is different for inputs with different frequencies and correlations. The addition of gap junctions can promote the network synchrony in some conditions but suppress it in others, and they can inhibit the firing activities in most cases. Both the firing rate and synchronization of the network increase along with the increase of the electrical coupling strength for inputs with low frequency and high correlation. Thus, the network of coupled FSIs can act as a detector for synchronous synaptic input from cortex and thalamus.

  14. Multiple facets of GABAergic neurons and synapses: multiple fates of GABA signalling in epilepsies.

    PubMed

    Cossart, Rosa; Bernard, Christophe; Ben-Ari, Yehezkel

    2005-02-01

    Because blocking GABAergic neurotransmission in control tissue generates seizures and because GABA boosters control epilepsy in many patients, studies on epilepsies have been dominated by the axiom that seizures are generated by a failure of GABA-mediated inhibition. However, GABAergic interneurons and synapses are heterogeneous and have many roles that go beyond the straightforward concept of "inhibition of the target". Operation of such a diversified system cannot be ascribed to a single mechanism. In epileptic tissue, GABAergic networks undergo complex rewiring at the anatomical, physiological and functional levels; GABAergic synapses are still operative but show unique features, including excitatory effects. Therefore, inhibition is not a uniform notion and the concept of "failure" of inhibition in epilepsies must be reassessed. Seizures are not generated in a normal circuit in which GABA-mediated inhibition is simply impaired, but in a profoundly rewired network in which several properties of GABA function are altered. This review is part of the TINS Interneuron Diversity series.

  15. GABAergic Projections from Lateral Hypothalamus to Paraventricular Hypothalamic Nucleus Promote Feeding

    PubMed Central

    Wu, Zhaofei; Kim, Eun Ran; Sun, Hao; Xu, Yuanzhong; Mangieri, Leandra R.; Li, De-Pei; Pan, Hui-Lin; Xu, Yong; Arenkiel, Benjamin R.

    2015-01-01

    Lesions of the lateral hypothalamus (LH) cause hypophagia. However, activation of glutamatergic neurons in LH inhibits feeding. These results suggest a potential importance for other LH neurons in stimulating feeding. Our current study in mice showed that disruption of GABA release from adult LH GABAergic neurons reduced feeding. LH GABAergic neurons project extensively to the paraventricular hypothalamic nucleus (PVH), and optogenetic stimulation of GABAergic LH → PVH fibers induced monosynaptic IPSCs in PVH neurons, and potently increased feeding, which depended on GABA release. In addition, disruption of GABA-A receptors in the PVH reduced feeding. Thus, we have identified a new feeding pathway in which GABAergic projections from the LH to the PVH promote feeding. PMID:25716832

  16. Neocortical inhibitory activities and long-range afferents contribute to the synchronous onset of silent states of the neocortical slow oscillation

    PubMed Central

    Lemieux, Maxime; Chauvette, Sylvain

    2014-01-01

    During slow-wave sleep, neurons of the thalamocortical network are engaged in a slow oscillation (<1 Hz), which consists of an alternation between the active and the silent states. Several studies have provided insights on the transition from the silent, which are essentially periods of disfacilitation, to the active states. However, the conditions leading to the synchronous onset of the silent state remain elusive. We hypothesized that a synchronous input to local inhibitory neurons could contribute to the transition to the silent state in the cat suprasylvian gyrus during natural sleep and under ketamine-xylazine anesthesia. After partial and complete deafferentation of the cortex, we found that the silent state onset was more variable among remote sites. We found that the transition to the silent state was preceded by a reduction in excitatory postsynaptic potentials and firing probability in cortical neurons. We tested the impact of chloride-mediated inhibition in the silent-state onset. We uncovered a long-duration (100–300 ms) inhibitory barrage occurring about 250 ms before the silent state onset in 3–6% of neurons during anesthesia and in 12–15% of cases during natural sleep. These inhibitory activities caused a decrease in cortical firing that reduced the excitatory drive in the neocortical network. That chain reaction of disfacilitation ends up on the silent state. Electrical stimuli could trigger a network silent state with a maximal efficacy in deep cortical layers. We conclude that long-range afferents to the neocortex and chloride-mediated inhibition play a role in the initiation of the silent state. PMID:25392176

  17. Neocortical inhibitory activities and long-range afferents contribute to the synchronous onset of silent states of the neocortical slow oscillation.

    PubMed

    Lemieux, Maxime; Chauvette, Sylvain; Timofeev, Igor

    2015-02-01

    During slow-wave sleep, neurons of the thalamocortical network are engaged in a slow oscillation (<1 Hz), which consists of an alternation between the active and the silent states. Several studies have provided insights on the transition from the silent, which are essentially periods of disfacilitation, to the active states. However, the conditions leading to the synchronous onset of the silent state remain elusive. We hypothesized that a synchronous input to local inhibitory neurons could contribute to the transition to the silent state in the cat suprasylvian gyrus during natural sleep and under ketamine-xylazine anesthesia. After partial and complete deafferentation of the cortex, we found that the silent state onset was more variable among remote sites. We found that the transition to the silent state was preceded by a reduction in excitatory postsynaptic potentials and firing probability in cortical neurons. We tested the impact of chloride-mediated inhibition in the silent-state onset. We uncovered a long-duration (100-300 ms) inhibitory barrage occurring about 250 ms before the silent state onset in 3-6% of neurons during anesthesia and in 12-15% of cases during natural sleep. These inhibitory activities caused a decrease in cortical firing that reduced the excitatory drive in the neocortical network. That chain reaction of disfacilitation ends up on the silent state. Electrical stimuli could trigger a network silent state with a maximal efficacy in deep cortical layers. We conclude that long-range afferents to the neocortex and chloride-mediated inhibition play a role in the initiation of the silent state.

  18. GABA-ergic Cell Therapy for Epilepsy: Advances, Limitations and Challenges

    PubMed Central

    Shetty, Ashok K.; Upadhya, Dinesh

    2016-01-01

    Diminution in the number of gamma-amino butyric acid positive (GABA-ergic) interneurons and their axon terminals, and/or alterations in functional inhibition are conspicuous brain alterations believed to contribute to the persistence of seizures in acquired epilepsies such as temporal lobe epilepsy. This has steered a perception that replacement of lost GABA-ergic interneurons would improve inhibitory synaptic neurotransmission in the epileptic brain region and thereby reduce the occurrence of seizures. Indeed, studies using animal prototypes have reported that grafting of GABA-ergic progenitors derived from multiple sources into epileptic regions can reduce seizures. This review deliberates recent advances, limitations and challenges concerning the development of GABA-ergic cell therapy for epilepsy. The efficacy and limitations of grafts of primary GABA-ergic progenitors from the embryonic lateral ganglionic eminence and medial ganglionic eminence (MGE), neural stem/progenitor cells expanded from MGE, and MGE-like progenitors generated from human pluripotent stem cells for alleviating seizures and co-morbidities of epilepsy are conferred. Additional studies required for possible clinical application of GABA-ergic cell therapy for epilepsy are also summarized. PMID:26748379

  19. Response Patterns of GABAergic Neurons in the Anterior Piriform Cortex of Awake Mice.

    PubMed

    Hu, Rongfeng; Zhang, Juen; Luo, Minmin; Hu, Ji

    2016-06-01

    Local inhibition by γ-amino butyric acid (GABA)-containing neurons is of vital importance for the operation of sensory cortices. However, the physiological response patterns of cortical GABAergic neurons are poorly understood, especially in the awake condition. Here, we utilized the recently developed optical tagging technique to specifically record GABAergic neurons in the anterior piriform cortex (aPC) in awake mice. The identified aPC GABAergic neurons were stimulated with robotic delivery of 32 distinct odorants, which covered a broad range of functional groups. We found that aPC GABAergic neurons could be divided into 4 types based on their response patterns. Type I, type II, and type III neurons displayed broad excitatory responses to test odorants with different dynamics. Type I neurons were constantly activated during odorant stimulation, whereas type II neurons were only transiently activated at the onset of odorant delivery. In addition, type III neurons displayed transient excitatory responses both at the onset and termination of odorant presentation. Interestingly, type IV neurons were broadly inhibited by most of the odorants. Taken together, aPC GABAergic neurons adopt different strategies to affect the cortical circuitry. Our results will allow for better understanding of the role of cortical GABAergic interneurons in sensory information processing.

  20. GABAergic interneuron development and function is modulated by the Tsc1 gene.

    PubMed

    Fu, Cary; Cawthon, Bryan; Clinkscales, William; Bruce, Adrienne; Winzenburger, Peggy; Ess, Kevin C

    2012-09-01

    Tuberous sclerosis complex (TSC) is a genetic disease with severe neurologic and psychiatric manifestations including epilepsy, developmental delay, and autism. Despite much progress in defining abnormal signaling pathways including the contribution of increased mTORC1 signaling, specific abnormalities that underlie the severe neurologic features in TSC remain poorly understood. We hypothesized that epilepsy and autism in TSC result from abnormalities of γ-aminobutyric acidergic (GABAergic) interneurons. To test this hypothesis, we generated conditional knockout mice with selective deletion of the Tsc1 gene in GABAergic interneuron progenitor cells. These interneuron-specific Tsc1 conditional knockout (CKO) mice have impaired growth and decreased survival. Cortical and hippocampal GABAergic interneurons of CKO mice are enlarged and show increased mTORC1 signaling. Total numbers of GABAergic cells are reduced in the cortex with differential reduction of specific GABAergic subtypes. Ectopic clusters of cells with increased mTORC1 signaling are also seen suggesting impaired interneuron migration. The functional consequences of these cellular changes are evident in the decreased seizure threshold on exposure to the proconvulsant flurothyl. These findings support an important role for the Tsc1 gene during GABAergic interneuron development, function, and possibly migration.

  1. Behavior‐dependent activity patterns of GABAergic long‐range projecting neurons in the rat hippocampus

    PubMed Central

    Micklem, Ben; Borhegyi, Zsolt; Swiejkowski, Daniel A.; Valenti, Ornella; Viney, Tim J.; Kotzadimitriou, Dimitrios; Klausberger, Thomas

    2017-01-01

    ABSTRACT Long‐range glutamatergic and GABAergic projections participate in temporal coordination of neuronal activity in distributed cortical areas. In the hippocampus, GABAergic neurons project to the medial septum and retrohippocampal areas. Many GABAergic projection cells express somatostatin (SOM+) and, together with locally terminating SOM+ bistratified and O‐LM cells, contribute to dendritic inhibition of pyramidal cells. We tested the hypothesis that diversity in SOM+ cells reflects temporal specialization during behavior using extracellular single cell recording and juxtacellular neurobiotin‐labeling in freely moving rats. We have demonstrated that rare GABAergic projection neurons discharge rhythmically and are remarkably diverse. During sharp wave‐ripples, most projection cells, including a novel SOM+ GABAergic back‐projecting cell, increased their activity similar to bistratified cells, but unlike O‐LM cells. During movement, most projection cells discharged along the descending slope of theta cycles, but some fired at the trough jointly with bistratified and O‐LM cells. The specialization of hippocampal SOM+ projection neurons complements the action of local interneurons in differentially phasing inputs from the CA3 area to CA1 pyramidal cell dendrites during sleep and wakefulness. Our observations suggest that GABAergic projection cells mediate the behavior‐ and network state‐dependent binding of neuronal assemblies amongst functionally‐related brain regions by transmitting local rhythmic entrainment of neurons in CA1 to neuronal populations in other areas. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc. PMID:27997999

  2. Culturing Layer-Specific Neocortical Neurons as a Cell Replacement Therapy Following Traumatic Brain Injury

    PubMed Central

    Cramer, Nathan Peter; Chatterjee, Mitali; Lischka, Fritz Walter; Juliano, Sharon L.

    2014-01-01

    Neurophysiological changes resulting from traumatic brain injury (TBI) can result in adverse changes in behavior including mood instability and cognitive dysfunction. Cell death following TBI likely contributes to these altered behaviors and remains an elusive but attractive target for therapies aiming at functional recovery. Previously we demonstrated that neural progenitor cells derived from embryonic rats can be transplanted into donor neonatal rat brain slices and, over the course of 2 weeks in culture, mature into neurons that express neuronal immunohistochemical markers and develop electrophysiological profiles consistent with excitatory and inhibitory interneurons. Here we examine the potential of generating electrophysiologically mature neurons with a layer-specific phenotype as a next step in developing a therapy designed to rebuild a damaged cortical column with the functionally appropriate neuronal subtypes. Preliminary results suggest that neurons derived from passaged neurospheres and grown in dissociated cell culture develop GABAergic and presumed glutamatergic phenotypes and that the percentage of GABAergic cells increases as a function of passage. After 2 weeks in culture, the neurons have a mix of immature and mature neuronal electrophysiological profiles and receive synaptic inputs from surrounding neurons. Subsets of cells expressing neuron specific markers also express layer-specific markers such as Cux1, ER81, and RORβ. Future studies will investigate the potential of transplanting layer-specific neurons generated and isolated in vitro into the neocortex of neonatal brain slices and their potential to maintain their phenotype and integrate into the host tissue. PMID:24432011

  3. "Small axonless neurons": postnatally generated neocortical interneurons with delayed functional maturation.

    PubMed

    Le Magueresse, Corentin; Alfonso, Julieta; Khodosevich, Konstantin; Arroyo Martín, Angel A; Bark, Christine; Monyer, Hannah

    2011-11-16

    GABAergic interneurons of the mouse cortex are generated embryonically in the ventral telencephalon. Recent evidence, however, indicated that a subset of cortical cells expressing interneuronal markers originate in the neonatal subventricular zone. This has raised interest in the functional development and incorporation of these postnatally generated cells into cortical circuits. Here we demonstrate that these cells integrate in the cortex, and that they constitute two distinct GABAergic interneuronal classes. Whereas one class reflects the tail end of embryonic interneuron genesis, the other class comprises interneurons that are exclusively generated perinatally and postnatally. The latter constitute a novel subclass of interneurons. They are preferentially located in the deeper layers of the olfactory and orbital cortices, exhibit a unique firing pattern and slow functional maturation. Based on their distinct morphology we termed them "small axonless neurons" and indeed, unlike other cortical neurons, they communicate with their neuronal partners via dendrodendritic synapses. Finally, we provide evidence that the number of small axonless neurons is enhanced by odor enrichment, a further indication that they integrate into neural circuits and participate to olfactory processing.

  4. Extracellular pH modulates GABAergic neurotransmission in rat hypothalamus.

    PubMed

    Chen, Z L; Huang, R Q

    2014-06-20

    Changes in extracellular pH have a modulatory effect on GABAA receptor function. It has been reported that pH sensitivity of the GABA receptor is dependent on subunit composition and GABA concentration. Most of previous investigations focused on GABA-evoked currents, which only reflect the postsynaptic receptors. The physiological relevance of pH modulation of GABAergic neurotransmission is not fully elucidated. In the present studies, we examined the influence of extracellular pH on the GABAA receptor-mediated inhibitory neurotransmission in rat hypothalamic neurons. The inhibitory postsynaptic currents (IPSCs), tonic currents, and the GABA-evoked currents were recorded with whole-cell patch techniques on the hypothalamic slices from Sprague-Dawley rats at 15-26 postnatal days. The amplitude and frequency of spontaneous GABA IPSCs were significantly increased while the external pH was changed from 7.3 to 8.4. In the acidic pH (6.4), the spontaneous GABA IPSCs were reduced in amplitude and frequency. The pH induced changes in miniature GABA IPSCs (mIPSCs) similar to that in spontaneous IPSCs. The pH effect on the postsynaptic GABA receptors was assessed with exogenously applied varying concentrations of GABA. The tonic currents and the currents evoked by sub-saturating concentration of GABA ([GABA]) (10 μM) were inhibited by acidic pH and potentiated by alkaline pH. In contrast, the currents evoked by saturating [GABA] (1mM) were not affected by pH changes. We also investigated the influence of pH buffers and buffering capacity on pH sensitivity of GABAA receptors on human recombinant α1β2γ2 GABAA receptors stably expressed in HEK 293 cells. The pH influence on GABAA receptors was similar in HEPES- and MES-buffered media, and not dependent on protonated buffers, suggesting that the observed pH effect on GABA response is a specific consequence of changes in extracellular protons. Our data suggest that the hydrogen ions suppress the GABAergic neurotransmission

  5. Conical expansion of the outer subventricular zone and the role of neocortical folding in evolution and development

    PubMed Central

    Lewitus, Eric; Kelava, Iva; Huttner, Wieland B.

    2013-01-01

    There is a basic rule to mammalian neocortical expansion: as it expands, so does it fold. The degree to which it folds, however, cannot strictly be attributed to its expansion. Across species, cortical volume does not keep pace with cortical surface area, but rather folds appear more rapidly than expected. As a result, larger brains quickly become disproportionately more convoluted than smaller brains. Both the absence (lissencephaly) and presence (gyrencephaly) of cortical folds is observed in all mammalian orders and, while there is likely some phylogenetic signature to the evolutionary appearance of gyri and sulci, there are undoubtedly universal trends to the acquisition of folds in an expanding neocortex. Whether these trends are governed by conical expansion of neocortical germinal zones, the distribution of cortical connectivity, or a combination of growth- and connectivity-driven forces remains an open question. But the importance of cortical folding for evolution of the uniquely mammalian neocortex, as well as for the incidence of neuropathologies in humans, is undisputed. In this hypothesis and theory article, we will summarize the development of cortical folds in the neocortex, consider the relative influence of growth- vs. connectivity-driven forces for the acquisition of cortical folds between and within species, assess the genetic, cell-biological, and mechanistic implications for neocortical expansion, and discuss the significance of these implications for human evolution, development, and disease. We will argue that evolutionary increases in the density of neuron production, achieved via maintenance of a basal proliferative niche in the neocortical germinal zones, drive the conical migration of neurons toward the cortical surface and ultimately lead to the establishment of cortical folds in large-brained mammal species. PMID:23914167

  6. Statistical mechanics of neocortical interactions: High-resolution path-integral calculation of short-term memory

    NASA Astrophysics Data System (ADS)

    Ingber, Lester; Nunez, Paul L.

    1995-05-01

    We present high-resolution path-integral calculations of a previously developed model of short-term memory in neocortex. These calculations, made possible with supercomputer resources, supplant similar calculations made by Ingber [Phys. Rev. E 49, 4652 (1994)] and support coarser estimates made by Ingber [Phys. Rev. A 29, 3346 (1984)]. We also present a current experimental context for the relevance of these calculations using the approach of statistical mechanics of neocortical interactions, especially in the context of electroencephalographic data.

  7. Correlation between stimulation strength and onset time of signal traveling within the neocortical neural circuits under caffeine application.

    PubMed

    Yoshimura, Hiroshi; Honjo, Miho; Sugai, Tokio; Kaneyama, Keiseki; Segami, Natsuki; Kato, Nobuo

    2011-08-01

    In general, strength of input to neocortical neural circuits affects the amplitude of postsynaptic potentials (PSPs), thereby modulating the way signals are transmitted within the circuits. Caffeine is one of the pharmacological agents able to modulate synaptic activities. The present study investigated how strength of input affects signal propagation in neocortical circuits under the application of caffeine. Spatio-temporal neural activities were observed from visual cortical slices of rats using optical recording methods with voltage-sensitive dye. Electrical stimulations were applied to white matter in the primary visual cortex with bath-application of caffeine. When the strength of stimulation was 0.3mA, signals propagated from the site of stimulation in the primary visual cortex toward the secondary visual cortex along vertical and horizontal pathways. When stimulation strength was reduced from 0.3mA to 0.07mA, start of signal propagation was delayed about 25ms without affecting field PSP amplitude or the manner of signal propagation. Conversely, co-application of caffeine and d-2-amino-5-phosphonovaleric acid (d-AP5) did not induce delays in signal start. These findings suggest that conversion of neural code from amplitude code to temporal code is inducible at the level of neocortical circuits in an N-methyl-d-aspartate (NMDA) receptor activity-dependent manner.

  8. Cntnap4 differentially contributes to GABAergic and dopaminergic synaptic transmission.

    PubMed

    Karayannis, T; Au, E; Patel, J C; Kruglikov, I; Markx, S; Delorme, R; Héron, D; Salomon, D; Glessner, J; Restituito, S; Gordon, A; Rodriguez-Murillo, L; Roy, N C; Gogos, J A; Rudy, B; Rice, M E; Karayiorgou, M; Hakonarson, H; Keren, B; Huguet, G; Bourgeron, T; Hoeffer, C; Tsien, R W; Peles, E; Fishell, G

    2014-07-10

    Although considerable evidence suggests that the chemical synapse is a lynchpin underlying affective disorders, how molecular insults differentially affect specific synaptic connections remains poorly understood. For instance, Neurexin 1a and 2 (NRXN1 and NRXN2) and CNTNAP2 (also known as CASPR2), all members of the neurexin superfamily of transmembrane molecules, have been implicated in neuropsychiatric disorders. However, their loss leads to deficits that have been best characterized with regard to their effect on excitatory cells. Notably, other disease-associated genes such as BDNF and ERBB4 implicate specific interneuron synapses in psychiatric disorders. Consistent with this, cortical interneuron dysfunction has been linked to epilepsy, schizophrenia and autism. Using a microarray screen that focused upon synapse-associated molecules, we identified Cntnap4 (contactin associated protein-like 4, also known as Caspr4) as highly enriched in developing murine interneurons. In this study we show that Cntnap4 is localized presynaptically and its loss leads to a reduction in the output of cortical parvalbumin (PV)-positive GABAergic (γ-aminobutyric acid producing) basket cells. Paradoxically, the loss of Cntnap4 augments midbrain dopaminergic release in the nucleus accumbens. In Cntnap4 mutant mice, synaptic defects in these disease-relevant neuronal populations are mirrored by sensory-motor gating and grooming endophenotypes; these symptoms could be pharmacologically reversed, providing promise for therapeutic intervention in psychiatric disorders.

  9. Muscarinic presynaptic modulation in GABAergic pallidal synapses of the rat.

    PubMed

    Hernández-Martínez, Ricardo; Aceves, José J; Rueda-Orozco, Pavel E; Hernández-Flores, Teresa; Hernández-González, Omar; Tapia, Dagoberto; Galarraga, Elvira; Bargas, José

    2015-02-01

    The external globus pallidus (GPe) is central for basal ganglia processing. It expresses muscarinic cholinergic receptors and receives cholinergic afferents from the pedunculopontine nuclei (PPN) and other regions. The role of these receptors and afferents is unknown. Muscarinic M1-type receptors are expressed by synapses from striatal projection neurons (SPNs). Because axons from SPNs project to the GPe, one hypothesis is that striatopallidal GABAergic terminals may be modulated by M1 receptors. Alternatively, some M1 receptors may be postsynaptic in some pallidal neurons. Evidence of muscarinic modulation in any of these elements would suggest that cholinergic afferents from the PPN, or other sources, could modulate the function of the GPe. In this study, we show this evidence using striatopallidal slice preparations: after field stimulation in the striatum, the cholinergic muscarinic receptor agonist muscarine significantly reduced the amplitude of inhibitory postsynaptic currents (IPSCs) from synapses that exhibited short-term synaptic facilitation. This inhibition was associated with significant increases in paired-pulse facilitation, and quantal content was proportional to IPSC amplitude. These actions were blocked by atropine, pirenzepine, and mamba toxin-7, suggesting that receptors involved were M1. In addition, we found that some pallidal neurons have functional postsynaptic M1 receptors. Moreover, some evoked IPSCs exhibited short-term depression and a different kind of modulation: they were indirectly modulated by muscarine via the activation of presynaptic cannabinoid CB1 receptors. Thus pallidal synapses presenting distinct forms of short-term plasticity were modulated differently.

  10. Alterations of GABAergic Signaling in Autism Spectrum Disorders

    PubMed Central

    Pizzarelli, Rocco; Cherubini, Enrico

    2011-01-01

    Autism spectrum disorders (ASDs) comprise a heterogeneous group of pathological conditions, mainly of genetic origin, characterized by stereotyped behavior, marked impairment in verbal and nonverbal communication, social skills, and cognition. Interestingly, in a small number of cases, ASDs are associated with single mutations in genes encoding for neuroligin-neurexin families. These are adhesion molecules which, by regulating transsynaptic signaling, contribute to maintain a proper excitatory/inhibitory (E/I) balance at the network level. Furthermore, GABA, the main inhibitory neurotransmitter in adult life, at late embryonic/early postnatal stages has been shown to depolarize and excite targeted cell through an outwardly directed flux of chloride. The depolarizing action of GABA and associated calcium influx regulate a variety of developmental processes from cell migration and differentiation to synapse formation. Here, we summarize recent data concerning the functional role of GABA in building up and refining neuronal circuits early in development and the molecular mechanisms regulating the E/I balance. A dysfunction of the GABAergic signaling early in development leads to a severe E/I unbalance in neuronal circuits, a condition that may account for some of the behavioral deficits observed in ASD patients. PMID:21766041

  11. Alterations of GABAergic signaling in autism spectrum disorders.

    PubMed

    Pizzarelli, Rocco; Cherubini, Enrico

    2011-01-01

    Autism spectrum disorders (ASDs) comprise a heterogeneous group of pathological conditions, mainly of genetic origin, characterized by stereotyped behavior, marked impairment in verbal and nonverbal communication, social skills, and cognition. Interestingly, in a small number of cases, ASDs are associated with single mutations in genes encoding for neuroligin-neurexin families. These are adhesion molecules which, by regulating transsynaptic signaling, contribute to maintain a proper excitatory/inhibitory (E/I) balance at the network level. Furthermore, GABA, the main inhibitory neurotransmitter in adult life, at late embryonic/early postnatal stages has been shown to depolarize and excite targeted cell through an outwardly directed flux of chloride. The depolarizing action of GABA and associated calcium influx regulate a variety of developmental processes from cell migration and differentiation to synapse formation. Here, we summarize recent data concerning the functional role of GABA in building up and refining neuronal circuits early in development and the molecular mechanisms regulating the E/I balance. A dysfunction of the GABAergic signaling early in development leads to a severe E/I unbalance in neuronal circuits, a condition that may account for some of the behavioral deficits observed in ASD patients.

  12. 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.

  13. Impact of network activity on the integrative properties of neocortical pyramidal neurons in vivo.

    PubMed

    Destexhe, A; Paré, D

    1999-04-01

    During wakefulness, neocortical neurons are subjected to an intense synaptic bombardment. To assess the consequences of this background activity for the integrative properties of pyramidal neurons, we constrained biophysical models with in vivo intracellular data obtained in anesthetized cats during periods of intense network activity similar to that observed in the waking state. In pyramidal cells of the parietal cortex (area 5-7), synaptic activity was responsible for an approximately fivefold decrease in input resistance (Rin), a more depolarized membrane potential (Vm), and a marked increase in the amplitude of Vm fluctuations, as determined by comparing the same cells before and after microperfusion of tetrodotoxin (TTX). The model was constrained by measurements of Rin, by the average value and standard deviation of the Vm measured from epochs of intense synaptic activity recorded with KAc or KCl-filled pipettes as well as the values measured in the same cells after TTX. To reproduce all experimental results, the simulated synaptic activity had to be of relatively high frequency (1-5 Hz) at excitatory and inhibitory synapses. In addition, synaptic inputs had to be significantly correlated (correlation coefficient approximately 0.1) to reproduce the amplitude of Vm fluctuations recorded experimentally. The presence of voltage-dependent K+ currents, estimated from current-voltage relations after TTX, affected these parameters by <10%. The model predicts that the conductance due to synaptic activity is 7-30 times larger than the somatic leak conductance to be consistent with the approximately fivefold change in Rin. The impact of this massive increase in conductance on dendritic attenuation was investigated for passive neurons and neurons with voltage-dependent Na+/K+ currents in soma and dendrites. In passive neurons, correlated synaptic bombardment had a major influence on dendritic attenuation. The electrotonic attenuation of simulated synaptic inputs was

  14. Long-range correlation of the membrane potential in neocortical neurons during slow oscillation

    PubMed Central

    Volgushev, Maxim; Chauvette, Sylvain; Timofeev, Igor

    2012-01-01

    Large amplitude slow waves are characteristic for the summary brain activity, recorded as electroencephalogram (EEG) or local field potentials (LFP), during deep stages of sleep and some types of anesthesia. Slow rhythm of the synchronized EEG reflects an alternation of active (depolarized, UP) and silent (hyperpolarized, DOWN) states of neocortical neurons. In neurons, involvement in the generalized slow oscillation results in a long-range synchronization of changes of their membrane potential as well as their firing. Here, we aimed at intracellular analysis of details of this synchronization. We asked which components of neuronal activity exhibit long-range correlations during the synchronized EEG? To answer this question, we made simultaneous intracellular recordings from two to four neocortical neurons in cat neocortex. We studied how correlated is the occurrence of active and silent states, and how correlated are fluctuations of the membrane potential in pairs of neurons located close one to the other or separated by up to 13 mm. We show that strong long-range correlation of the membrane potential was observed only (i) during the slow oscillation but not during periods without the oscillation, (ii) during periods which included transitions between the states but not during within-the-state periods, and (iii) for the low-frequency (<5 Hz) components of membrane potential fluctuations but not for the higher-frequency components (>10 Hz). In contrast to the neurons located several millimeters one from the other, membrane potential fluctuations in neighboring neurons remain strongly correlated during periods without slow oscillation. We conclude that membrane potential correlation in distant neurons is brought about by synchronous transitions between the states, while activity within the states is largely uncorrelated. The lack of the generalized fine-scale synchronization of membrane potential changes in neurons during the active states of slow oscillation may

  15. Molecular Mechanisms Underlying Activity-Dependent GABAergic Synapse Development and Plasticity and Its Implications for Neurodevelopmental Disorders

    PubMed Central

    Chattopadhyaya, Bidisha

    2011-01-01

    GABAergic interneurons are critical for the normal function and development of neural circuits, and their dysfunction is implicated in a large number of neurodevelopmental disorders. Experience and activity-dependent mechanisms play an important role in GABAergic circuit development, also recent studies involve a number of molecular players involved in the process. Emphasizing the molecular mechanisms of GABAergic synapse formation, in particular basket cell perisomatic synapses, this paper draws attention to the links between critical period plasticity, GABAergic synapse maturation, and the consequences of its dysfunction on the development of the nervous system. PMID:21826279

  16. Nicotine increases GABAergic input on rat dorsal raphe serotonergic neurons through alpha7 nicotinic acetylcholine receptor.

    PubMed

    Hernández-Vázquez, F; Chavarría, K; Garduño, J; Hernández-López, S; Mihailescu, S P

    2014-12-15

    The dorsal raphe nucleus (DRN) contains large populations of serotonergic (5-HT) neurons. This nucleus receives GABAergic inhibitory afferents from many brain areas and from DRN interneurons. Both GABAergic and 5-HT DRN neurons express functional nicotinic acetylcholine receptors (nAChRs). Previous studies have demonstrated that nicotine increases 5-HT release and 5-HT DRN neuron discharge rate by stimulating postsynaptic nAChRs and by increasing glutamate and norepinephrine release inside DRN. However, the influence of nicotine on the GABAergic input to 5-HT DRN neurons was poorly investigated. Therefore, the aim of this work was to determine the effect of nicotine on GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs) of 5-HT DRN neurons and the subtype of nAChR(s) involved in this response. Experiments were performed in coronal slices obtained from young Wistar rats. GABAergic sIPSCs were recorded from post hoc-identified 5-HT DRN neurons with the whole cell voltage patch-clamp technique. Administration of nicotine (1 μM) increased sIPSC frequency in 72% of identified 5-HT DRN neurons. This effect was not reproduced by the α4β2 nAChR agonist RJR-2403 and was not influenced by TTX (1 μM). It was mimicked by the selective agonist for α7 nAChR, PNU-282987, and exacerbated by the positive allosteric modulator of the same receptor, PNU-120596. The nicotine-induced increase in sIPSC frequency was independent on voltage-gated calcium channels and dependent on Ca(2+)-induced Ca(2+) release (CICR). These results demonstrate that nicotine increases the GABAergic input to most 5-HT DRN neurons, by activating α7 nAChRs and producing CICR in DRN GABAergic terminals.

  17. Enrichment of mGluR7a in the presynaptic active zones of GABAergic and non-GABAergic terminals on interneurons in the rat somatosensory cortex.

    PubMed

    Dalezios, Yannis; Luján, Rafael; Shigemoto, Ryuichi; Roberts, J David B; Somogyi, Peter

    2002-09-01

    The release of glutamate and GABA is modulated by presynaptic metabotropic glutamate receptors (mGluRs). We used immunocytochemical methods to define the location of the group III receptor mGluR7a in glutamatergic and GABAergic terminals innervating GABAergic interneurons and pyramidal cells. Immunoreactivity for mGluR7a was localized in the presynaptic active zone of both identified GABAergic and presumed glutamatergic terminals. Terminals innervating dendritic spines showed a variable level of receptor immunoreactivity, ranging from immunonegative to strongly immunopositive. The frequency of strongly mGluR7a positive terminals innervating the soma and dendrites of mGluR1 alpha/somatostatin-expressing interneurons was very high relative to other neurons. On dendrites that received mGluR7a-enriched glutamatergic innervation, at least 80% of GABAergic terminals were immunopositive for mGluR7a. On such dendrites virtually all (95%) vasoactive intestinal polypeptide (VIP) positive (GABAergic) terminals were enriched in mGluR7a. The targets of VIP/mGluR7a-expressing terminals were mainly (88%) mGluR1 alpha-expressing interneurons, which were mostly somatostatin immunopositive. Parvalbumin positive terminals were immunonegative for mGluR7a. Some parvalbumin immunoreactive dendrites received strongly mGluR7a positive terminals. The subcellular location, as well as the cell type and synapse-specific distribution of mGluR7a in isocortical neuronal circuits, is homologous to its distribution in the hippocampus. The specific location of mGluR7a in the presynaptic active zone of both glutamatergic and GABAergic synapses may be related to the proximity of calcium channels and the vesicle fusion machinery. The enrichment of mGluR7a in the main GABAergic, as well as in the glutamatergic, innervation of mGluR1 alpha/somatostatin-expressing interneurons suggests that their activation is under unique regulation by extracellular glutamate.

  18. Increased gamma- and decreased delta-oscillations in a mouse deficient for a potassium channel expressed in fast-spiking interneurons.

    PubMed

    Joho, R H; Ho, C S; Marks, G A

    1999-10-01

    Kv3.1 is a voltage-gated, fast activating/deactivating potassium (K(+)) channel with a high-threshold of activation and a large unit conductance. Kv3.1 K(+) channels are expressed in fast-spiking, parvalbumin-containing interneurons in cortex, hippocampus, striatum, the thalamic reticular nucleus (TRN), and in several nuclei of the brain stem. A high density of Kv3.1 channels contributes to short-duration action potentials, fast afterhyperpolarizations, and brief refractory periods enhancing the capability in these neurons for high-frequency firing. Kv3.1 K(+) channel expression in the TRN and cortex also suggests a role in thalamocortical and cortical function. Here we show that fast gamma and slow delta oscillations recorded from the somatomotor cortex are altered in the freely behaving Kv3.1 mutant mouse. Electroencephalographic (EEG) recordings from homozygous Kv3.1(-/-) mice show a three- to fourfold increase in both absolute and relative spectral power in the gamma frequency range (20-60 Hz). In contrast, Kv3.1-deficient mice have a 20-50% reduction of power in the slow delta range (2-3 Hz). The increase in gamma power is most prominent during waking in the 40- to 55-Hz range, whereas the decrease in delta power occurs equally across all states of arousal. Our findings suggest that Kv3. 1-expressing neurons are involved in the generation and maintenance of cortical fast gamma and slow delta oscillations. Hence the Kv3. 1-mutant mouse could serve as a model to study the generation and maintenance of fast gamma and slow delta rhythms and their involvement in behavior and cognition.

  19. Functional and molecular differences between voltage-gated K+ channels of fast-spiking interneurons and pyramidal neurons of rat hippocampus.

    PubMed

    Martina, M; Schultz, J H; Ehmke, H; Monyer, H; Jonas, P

    1998-10-15

    We have examined gating and pharmacological characteristics of somatic K+ channels in fast-spiking interneurons and regularly spiking principal neurons of hippocampal slices. In nucleated patches isolated from basket cells of the dentate gyrus, a fast delayed rectifier K+ current component that was highly sensitive to tetraethylammonium (TEA) and 4-aminopyridine (4-AP) (half-maximal inhibitory concentrations <0.1 mM) predominated, contributing an average of 58% to the total K+ current in these cells. By contrast, in pyramidal neurons of the CA1 region a rapidly inactivating A-type K+ current component that was TEA-resistant prevailed, contributing 61% to the total K+ current. Both types of neurons also showed small amounts of the K+ current component mainly found in the other type of neuron and, in addition, a slow delayed rectifier K+ current component with intermediate properties (slow inactivation, intermediate sensitivity to TEA). Single-cell RT-PCR analysis of mRNA revealed that Kv3 (Kv3.1, Kv3.2) subunit transcripts were expressed in almost all (89%) of the interneurons but only in 17% of the pyramidal neurons. In contrast, Kv4 (Kv4.2, Kv4.3) subunit mRNAs were present in 87% of pyramidal neurons but only in 55% of interneurons. Selective block of fast delayed rectifier K+ channels, presumably assembled from Kv3 subunits, by 4-AP reduced substantially the action potential frequency in interneurons. These results indicate that the differential expression of Kv3 and Kv4 subunits shapes the action potential phenotypes of principal neurons and interneurons in the cortex.

  20. Closed-Loop Brain Model of Neocortical Information-Based Exchange

    PubMed Central

    Kozloski, James

    2016-01-01

    Here we describe an “information-based exchange” model of brain function that ascribes to neocortex, basal ganglia, and thalamus distinct network functions. The model allows us to analyze whole brain system set point measures, such as the rate and heterogeneity of transitions in striatum and neocortex, in the context of neuromodulation and other perturbations. Our closed-loop model is grounded in neuroanatomical observations, proposing a novel “Grand Loop” through neocortex, and invokes different forms of plasticity at specific tissue interfaces and their principle cell synapses to achieve these transitions. By implementing a system for maximum information-based exchange of action potentials between modeled neocortical areas, we observe changes to these measures in simulation. We hypothesize that similar dynamic set points and modulations exist in the brain's resting state activity, and that different modifications to information-based exchange may shift the risk profile of different component tissues, resulting in different neurodegenerative diseases. This model is targeted for further development using IBM's Neural Tissue Simulator, which allows scalable elaboration of networks, tissues, and their neural and synaptic components toward ever greater complexity and biological realism. PMID:26834573

  1. Thalamic input to distal apical dendrites in neocortical layer 1 is massive and highly convergent.

    PubMed

    Rubio-Garrido, Pablo; Pérez-de-Manzo, Flor; Porrero, César; Galazo, Maria J; Clascá, Francisco

    2009-10-01

    Input to apical dendritic tufts is now deemed crucial for associative learning, attention, and similar "feedback" interactions in the cerebral cortex. Excitatory input to apical tufts in neocortical layer 1 has been traditionally assumed to be predominantly cortical, as thalamic pathways directed to this layer were regarded relatively scant and diffuse. However, the sensitive tracing methods used in the present study show that, throughout the rat neocortex, large numbers (mean approximately 4500/mm(2)) of thalamocortical neurons converge in layer 1 and that this convergence gives rise to a very high local density of thalamic terminals. Moreover, we show that the layer 1-projecting neurons are present in large numbers in most, but not all, motor, association, limbic, and sensory nuclei of the rodent thalamus. Some layer 1-projecting axons branch to innervate large swaths of the cerebral hemisphere, whereas others arborize within only a single cortical area. Present data imply that realistic modeling of cortical circuitry should factor in a dense axonal canopy carrying highly convergent thalamocortical input to pyramidal cell apical tufts. In addition, they are consistent with the notion that layer 1-projecting axons may be a robust anatomical substrate for extensive "feedback" interactions between cortical areas via the thalamus.

  2. Layer Specific Development of Neocortical Pyramidal to Fast Spiking Cell Synapses

    PubMed Central

    Voinova, Olga; Valiullina, Fliza; Zakharova, Yulia; Mukhtarov, Marat; Draguhn, Andreas; Rozov, Andrei

    2016-01-01

    All cortical neurons are engaged in inhibitory feedback loops which ensure excitation-inhibition balance and are key elements for the development of coherent network activity. The resulting network patterns are strongly dependent on the strength and dynamic properties of these excitatory-inhibitory loops which show pronounced regional and developmental diversity. Therefore we compared the properties and postnatal maturation of two different synapses between rat neocortical pyramidal cells (layer 2/3 and layer 5, respectively) and fast spiking (FS) interneurons in the corresponding layer. At P14, both synapses showed synaptic depression upon repetitive activation. Synaptic release properties between layer 2/3 pyramidal cells and FS cells were stable from P14 to P28. In contrast, layer 5 pyramidal to FS cell connections showed a significant increase in paired pulse ratio by P28. Presynaptic calcium dynamics also changed at these synapses, including sensitivity to exogenously loaded calcium buffers and expression of presynaptic calcium channel subtypes. These results underline the large variety of properties at different, yet similar, synapses in the neocortex. They also suggest that postnatal maturation of the brain goes along with increasing differences between synaptically driven network activity in layer 5 and layer 2/3. PMID:26834564

  3. Dynamics of centrosome translocation and microtubule organization in neocortical neurons during distinct modes of polarization.

    PubMed

    Sakakibara, Akira; Sato, Toshiyuki; Ando, Ryota; Noguchi, Namiko; Masaoka, Makoto; Miyata, Takaki

    2014-05-01

    Neuronal migration and process formation require cytoskeletal organization and remodeling. Recent studies suggest that centrosome translocation is involved in initial axon outgrowth, while the role of centrosomal positioning is not clear. Here, we examine relations between centrosomal positioning, axonogenesis, and microtubule (MT) polarization in multipolar and bipolar neocortical neurons. We monitored dynamic movements of centrosomes and MT plus ends in migratory neurons in embryonic mouse cerebral slices. In locomoting bipolar neurons, the centrosome oriented toward the pia-directed leading process. Bipolar neurons displayed dense MT plus end dynamics in leading processes, while trailing processes showed clear bidirectional MTs. In migrating multipolar neurons, new processes emerged irrespective of centrosome localization, followed by centrosome reorientations toward the dominant process. Anterograde movements of MT plus ends occurred in growing processes and retrograde movements were observed after retraction of the distal tip. In multipolar neurons, axon formed by tangential extension of a dominant process and the centrosome oriented toward the growing axon, while in locomoting neurons, an axon formed opposite to the direction of migration and the centrosome localized to the base of the leading process. Our data suggest that MT organization may alter centrosomal localization and that centrosomal positioning does not necessarily direct process formation.

  4. Neocortical dynamics at multiple scales: EEG standing waves, statistical mechanics, and physical analogs.

    PubMed

    Ingber, Lester; Nunez, Paul L

    2011-02-01

    The dynamic behavior of scalp potentials (EEG) is apparently due to some combination of global and local processes with important top-down and bottom-up interactions across spatial scales. In treating global mechanisms, we stress the importance of myelinated axon propagation delays and periodic boundary conditions in the cortical-white matter system, which is topologically close to a spherical shell. By contrast, the proposed local mechanisms are multiscale interactions between cortical columns via short-ranged non-myelinated fibers. A mechanical model consisting of a stretched string with attached nonlinear springs demonstrates the general idea. The string produces standing waves analogous to large-scale coherent EEG observed in some brain states. The attached springs are analogous to the smaller (mesoscopic) scale columnar dynamics. Generally, we expect string displacement and EEG at all scales to result from both global and local phenomena. A statistical mechanics of neocortical interactions (SMNI) calculates oscillatory behavior consistent with typical EEG, within columns, between neighboring columns via short-ranged non-myelinated fibers, across cortical regions via myelinated fibers, and also derives a string equation consistent with the global EEG model.

  5. SOX6 controls dorsal-ventral progenitor parcellation and interneuron diversity during neocortical development

    PubMed Central

    Azim, Eiman; Jabaudon, Denis; Fame, Ryann; Macklis, Jeffrey D.

    2010-01-01

    Summary The extraordinary neuronal diversity of the central nervous system emerges largely from controlled spatial and temporal segregation of cell type-specific molecular regulators. Here, we report that the transcription factor SOX6 controls the molecular segregation of dorsal (pallial) from ventral (subpallial) telencephalic progenitors, and the differentiation of cortical interneurons, regulating forebrain progenitor and interneuron heterogeneity. During corticogenesis in mice, SOX6 and highly related SOX5 expression is largely mutually exclusive in pallial and subpallial progenitors, respectively, and remains mutually exclusive in a reverse pattern in postmitotic neuronal progeny. Loss of SOX6 from pallial progenitors causes their inappropriate expression of normally subpallium-restricted developmental controls, conferring mixed dorsal-ventral identity. In postmitotic cortical interneurons, loss of SOX6 dramatically disrupts the differentiation and diversity of cortical interneuron subtypes, analogous to SOX5 control over cortical projection neuron development. These data reveal SOX6 as a novel transcription factor regulator of both progenitor and cortical interneuron diversity during neocortical development. PMID:19657336

  6. Probabilistic inference of short-term synaptic plasticity in neocortical microcircuits

    PubMed Central

    Costa, Rui P.; Sjöström, P. Jesper; van Rossum, Mark C. W.

    2013-01-01

    Short-term synaptic plasticity is highly diverse across brain area, cortical layer, cell type, and developmental stage. Since short-term plasticity (STP) strongly shapes neural dynamics, this diversity suggests a specific and essential role in neural information processing. Therefore, a correct characterization of short-term synaptic plasticity is an important step towards understanding and modeling neural systems. Phenomenological models have been developed, but they are usually fitted to experimental data using least-mean-square methods. We demonstrate that for typical synaptic dynamics such fitting may give unreliable results. As a solution, we introduce a Bayesian formulation, which yields the posterior distribution over the model parameters given the data. First, we show that common STP protocols yield broad distributions over some model parameters. Using our result we propose a experimental protocol to more accurately determine synaptic dynamics parameters. Next, we infer the model parameters using experimental data from three different neocortical excitatory connection types. This reveals connection-specific distributions, which we use to classify synaptic dynamics. Our approach to demarcate connection-specific synaptic dynamics is an important improvement on the state of the art and reveals novel features from existing data. PMID:23761760

  7. Maternal-fetal unit interactions and eutherian neocortical development and evolution

    PubMed Central

    Montiel, Juan F.; Kaune, Heidy; Maliqueo, Manuel

    2013-01-01

    The conserved brain design that primates inherited from early mammals differs from the variable adult brain size and species-specific brain dominances observed across mammals. This variability relies on the emergence of specialized cerebral cortical regions and sub-compartments, triggering an increase in brain size, areal interconnectivity and histological complexity that ultimately lies on the activation of developmental programs. Structural placental features are not well correlated with brain enlargement; however, several endocrine pathways could be tuned with the activation of neuronal progenitors in the proliferative neocortical compartments. In this article, we reviewed some mechanisms of eutherians maternal–fetal unit interactions associated with brain development and evolution. We propose a hypothesis of brain evolution where proliferative compartments in primates become activated by “non-classical” endocrine placental signals participating in different steps of corticogenesis. Changes in the inner placental structure, along with placenta endocrine stimuli over the cortical proliferative activity would allow mammalian brain enlargement with a concomitant shorter gestation span, as an evolutionary strategy to escape from parent-offspring conflict. PMID:23882189

  8. Cerebral cortex development: From progenitors patterning to neocortical size during evolution.

    PubMed

    Pierani, Alessandra; Wassef, Marion

    2009-04-01

    The central nervous system is composed of thousands of distinct neurons that are assembled in a highly organized structure. In order to form functional neuronal networks, distinct classes of cells have to be generated in a precise number, in a spatial and temporal hierarchy and to be positioned at specific coordinates. An exquisite coordination of appropriate growth of competent territories and their patterning is required for regionalization and neurogenesis along both the anterior-posterior and dorso-ventral axis of the developing nervous system. The neocortex represents the brain territory that has undergone a major increase in its relative size during the course of mammalian evolution. In this review we will discuss how the fine tuning of growth and cell fate patterning plays a crucial role in the achievement of the final size of central nervous system structures and how divergence might have contributed to the surface increase of the cerebral cortex in mammals. In particular, we will describe how lack of precision might have been instrumental to neocortical evolution.

  9. Blood metabolite markers of neocortical amyloid-β burden: discovery and enrichment using candidate proteins

    PubMed Central

    Voyle, N; Kim, M; Proitsi, P; Ashton, N J; Baird, A L; Bazenet, C; Hye, A; Westwood, S; Chung, R; Ward, M; Rabinovici, G D; Lovestone, S; Breen, G; Legido-Quigley, C; Dobson, R J B; Kiddle, S J

    2016-01-01

    We believe this is the first study to investigate associations between blood metabolites and neocortical amyloid burden (NAB) in the search for a blood-based biomarker for Alzheimer's disease (AD). Further, we present the first multi-modal analysis of blood markers in this field. We used blood plasma samples from 91 subjects enrolled in the University of California, San Francisco Alzheimer's Disease Research Centre. Non-targeted metabolomic analysis was used to look for associations with NAB using both single and multiple metabolic feature models. Five metabolic features identified subjects with high NAB, with 72% accuracy. We were able to putatively identify four metabolites from this panel and improve the model further by adding fibrinogen gamma chain protein measures (accuracy=79%). One of the five metabolic features was studied in the Alzheimer's Disease Neuroimaging Initiative cohort, but results were inconclusive. If replicated in larger, independent studies, these metabolic features and proteins could form the basis of a blood test with potential for enrichment of amyloid pathology in anti-amyloid trials. PMID:26812040

  10. Differential effects of phosphonic analogues of GABA on GABA(B) autoreceptors in rat neocortical slices.

    PubMed

    Ong, J; Marino, V; Parker, D A; Kerr, D I

    1998-04-01

    The effects of five phosphonic derivatives of GABA on the release of [3H]-GABA from rat neocortical slices, preloaded with [3H]-GABA, were investigated. Phaclofen and 4-aminobutylphosphonic acid (4-ABPA) increased the overflow of [3H] evoked by electrical stimulation (2 Hz) in a concentration-dependent manner, with similar potencies (phaclofen EC50=0.3 mmol/l, 4-ABPA EC50=0.4 mmol/l). At 3 mmol/l, phaclofen increased the release of [3H]-GABA by 82.6+/-8.6%, and 4-ABPA increased the release by 81.3+/-9.0%. 2-Amino-ethylphosphonic acid (2-AEPA) increased the overflow of [3H] by 46.8+/-10.9% at the highest concentration tested (3 mmol/l). In contrast, the lower phosphonic homologue 3-aminopropylphosphonic acid (3-APPA), and 2-amino-2-(p-chlorophenyl)-ethylphosphonic acid (2-CPEPA), a baclofen analogue, did not modify the stimulated overflow. These results suggest that phaclofen, 4-ABPA and 2-AEPA are antagonists at GABA(B) autoreceptors, the latter being the weakest antagonist, whilst neither 3-APPA nor 2-CPEPA are active at these receptors. Since phaclofen, 4-ABPA and 2-CPEPA are antagonists and 3-APPA a partial agonist/antagonist on GABA(B) heteroreceptors, the lack of effect of 3-APPA and 2-CPEPA on [3H]-GABA release in this study suggests that GABA(B) autoreceptors may be pharmacologically distinct from the heteroreceptors.

  11. Medial temporal and neocortical contributions to remote memory for semantic narratives: evidence from amnesia.

    PubMed

    Verfaellie, Mieke; Bousquet, Kathryn; Keane, Margaret M

    2014-08-01

    Studies of remote memory for semantic facts and concepts suggest that hippocampal lesions lead to a temporally graded impairment that extends no more than ten years prior to the onset of amnesia. Such findings have led to the notion that once consolidated, semantic memories are represented neocortically and are no longer dependent on the hippocampus. Here, we examined the fate of well-established semantic narratives following medial temporal lobe (MTL) lesions. Seven amnesic patients, five with lesions restricted to the MTL and two with lesions extending into lateral temporal cortex (MTL+), were asked to recount fairy tales and bible stories that they rated as familiar. Narratives were scored for number and type of details, number of main thematic elements, and order in which the main thematic elements were recounted. In comparison to controls, patients with MTL lesions produced fewer details, but the number and order of main thematic elements generated was intact. By contrast, patients with MTL+ lesions showed a pervasive impairment, affecting not only the generation of details, but also the generation and ordering of main steps. These findings challenge the notion that, once consolidated, semantic memories are no longer dependent on the hippocampus for retrieval. Possible hippocampal contributions to the retrieval of detailed semantic narratives are discussed.

  12. Medial Temporal and Neocortical Contributions to Remote Memory for Semantic Narratives: Evidence from Amnesia

    PubMed Central

    Verfaellie, Mieke; Bousquet, Kathryn; Keane, Margaret M.

    2014-01-01

    Studies of remote memory for semantic facts and concepts suggest that hippocampal lesions lead to a temporally graded impairment that extends no more than ten years prior to the onset of amnesia. Such findings have led to the notion that once consolidated, semantic memories are represented neocortically and are no longer dependent on the hippocampus. Here, we examined the fate of well-established semantic narratives following medial temporal lobe (MTL) lesions. Seven amnesic patients, five with lesions restricted to the MTL and two with lesions extending into lateral temporal cortex (MTL+), were asked to recount fairy tales and bible stories that they rated as familiar. Narratives were scored for number and type of details, number of main thematic elements, and order in which the main thematic elements were recounted. In comparison to controls, patients with MTL lesions produced fewer details, but the number and order of main thematic elements generated was intact. By contrast, patients with MTL+ lesions showed a pervasive impairment, affecting not only the generation of details, but also the generation and ordering of main steps. These findings challenge the notion that, once consolidated, semantic memories are no longer dependent on the hippocampus for retrieval. Possible hippocampal contributions to the retrieval of detailed semantic narratives are discussed. PMID:24953960

  13. Involvement of JNK and Caspase Activation in Hoiamide A-Induced Neurotoxicity in Neocortical Neurons

    PubMed Central

    Cao, Zhengyu; Li, Xichun; Zou, Xiaohan; Greenwood, Michael; Gerwick, William H.; Murray, Thomas F.

    2015-01-01

    The frequent occurrence of Moorea producens (formerly Lyngbya majuscula) blooms has been associated with adverse effects on human health. Hoiamide A is a structurally unique cyclic depsipeptide isolated from an assemblage of the marine cyanobacteria M. producens and Phormidium gracile. We examined the influence of hoiamide A on neurite outgrowth in neocortical neurons and found that it suppressed neurite outgrowth with an IC50 value of 4.89 nM. Further study demonstrated that hoiamide A stimulated lactic acid dehydrogenase (LDH) efflux, nuclear condensation and caspase-3 activity with EC50 values of 3.66, 2.55 and 4.33 nM, respectively. These data indicated that hoiamide A triggered a unique neuronal death profile that involves both necrotic and apoptotic mechanisms. The similar potencies and similar time-response relationships between LDH efflux and caspase-3 activation/nuclear condensation suggested that both necrosis and apoptosis may derive from interaction with a common molecular target. The broad-spectrum caspase inhibitor, Z-VAD-FMK completely inhibited hoiamide A-induced neurotoxicity. Additionally, hoiamide A stimulated JNK phosphorylation, and a JNK inhibitor attenuated hoiamide A-induced neurotoxicity. Collectively, these data demonstrate that hoiamide A-induced neuronal death requires both JNK and caspase signaling pathways. The potent neurotoxicity and unique neuronal cell death profile of hoiamide A represents a novel neurotoxic chemotype from marine cyanobacteria. PMID:25675001

  14. The GABAergic septohippocampal connection is impaired in a mouse model of tauopathy.

    PubMed

    Soler, Helena; Dorca-Arévalo, Jonatan; González, Marta; Rubio, Sara Esmeralda; Ávila, Jesús; Soriano, Eduardo; Pascual, Marta

    2017-01-01

    Alzheimer's disease (AD), the most common cause of dementia nowadays, has been linked to alterations in the septohippocampal pathway (SHP), among other circuits in the brain. In fact, the GABAergic component of the SHP, which controls hippocampal rhythmic activity crucial for learning and memory, is altered in the J20 mouse model of AD-a model that mimics the amyloid pathology of this disease. However, AD is characterized by another pathophysiological hallmark: the hyperphosphorylation and aggregation of the microtubule-associated protein Tau. To evaluate whether tauopathies alter the GABAergic SHP, we analyzed transgenic mice expressing human mutated Tau (mutations G272V, P301L, and R406W, VLW transgenic strain). We show that pyramidal neurons, mossy cells, and some parvalbumin (PARV)-positive hippocampal interneurons in 2- and 8-month-old (mo) VLW mice accumulate phosphorylated forms of Tau (P-Tau). By tract-tracing studies of the GABAergic SHP, we describe early-onset deterioration of GABAergic septohippocampal (SH) innervation on PARV-positive interneurons in 2-mo VLW mice. In 8-mo animals, this alteration was more severe and affected mainly P-Tau-accumulating PARV-positive interneurons. No major loss of GABAergic SHP neurons or PARV-positive hippocampal interneurons was observed, thereby indicating that this decline is not caused by neuronal loss but by the reduced number and complexity of GABAergic SHP axon terminals. The decrease in GABAergic SHP described in this study, targeted onto the PARV-positive/P-Tau-accumulating inhibitory neurons in the hippocampus, establishes a cellular correlation with the dysfunctions in rhythmic neuronal activity and excitation levels in the hippocampus. These dysfunctions are associated with the VLW transgenic strain in particular and with AD human pathology in general. These data, together with our previous results in the J20 mouse model, indicate that the GABAergic SHP is impaired in response to both amyloid-β and P

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

    PubMed Central

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

    2016-01-01

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

  16. Dopamine synapse is a neuroligin-2-mediated contact between dopaminergic presynaptic and GABAergic postsynaptic structures.

    PubMed

    Uchigashima, Motokazu; Ohtsuka, Toshihisa; Kobayashi, Kazuto; Watanabe, Masahiko

    2016-04-12

    Midbrain dopamine neurons project densely to the striatum and form so-called dopamine synapses on medium spiny neurons (MSNs), principal neurons in the striatum. Because dopamine receptors are widely expressed away from dopamine synapses, it remains unclear how dopamine synapses are involved in dopaminergic transmission. Here we demonstrate that dopamine synapses are contacts formed between dopaminergic presynaptic and GABAergic postsynaptic structures. The presynaptic structure expressed tyrosine hydroxylase, vesicular monoamine transporter-2, and plasmalemmal dopamine transporter, which are essential for dopamine synthesis, vesicular filling, and recycling, but was below the detection threshold for molecules involving GABA synthesis and vesicular filling or for GABA itself. In contrast, the postsynaptic structure of dopamine synapses expressed GABAergic molecules, including postsynaptic adhesion molecule neuroligin-2, postsynaptic scaffolding molecule gephyrin, and GABAA receptor α1, without any specific clustering of dopamine receptors. Of these, neuroligin-2 promoted presynaptic differentiation in axons of midbrain dopamine neurons and striatal GABAergic neurons in culture. After neuroligin-2 knockdown in the striatum, a significant decrease of dopamine synapses coupled with a reciprocal increase of GABAergic synapses was observed on MSN dendrites. This finding suggests that neuroligin-2 controls striatal synapse formation by giving competitive advantage to heterologous dopamine synapses over conventional GABAergic synapses. Considering that MSN dendrites are preferential targets of dopamine synapses and express high levels of dopamine receptors, dopamine synapse formation may serve to increase the specificity and potency of dopaminergic modulation of striatal outputs by anchoring dopamine release sites to dopamine-sensing targets.

  17. Coordinated Plasticity between Barrel Cortical Glutamatergic and GABAergic Neurons during Associative Memory

    PubMed Central

    Yan, Fenxia; Gao, Zilong; Chen, Pin; Huang, Li; Wang, Dangui; Chen, Na; Wu, Ruixiang; Feng, Jing; Cui, Shan; Lu, Wei

    2016-01-01

    Neural plasticity is associated with memory formation. The coordinated refinement and interaction between cortical glutamatergic and GABAergic neurons remain elusive in associative memory, which we examine in a mouse model of associative learning. In the mice that show odorant-induced whisker motion after pairing whisker and odor stimulations, the barrel cortical glutamatergic and GABAergic neurons are recruited to encode the newly learnt odor signal alongside the innate whisker signal. These glutamatergic neurons are functionally upregulated, and GABAergic neurons are refined in a homeostatic manner. The mutual innervations between these glutamatergic and GABAergic neurons are upregulated. The analyses by high throughput sequencing show that certain microRNAs related to regulating synapses and neurons are involved in this cross-modal reflex. Thus, the coactivation of the sensory cortices through epigenetic processes recruits their glutamatergic and GABAergic neurons to be the associative memory cells as well as drive their coordinated refinements toward the optimal state for the storage of the associated signals. PMID:28070425

  18. Interplay between glutamatergic and GABAergic neurotransmission alterations in cognitive and motor impairment in minimal hepatic encephalopathy.

    PubMed

    Llansola, Marta; Montoliu, Carmina; Agusti, Ana; Hernandez-Rabaza, Vicente; Cabrera-Pastor, Andrea; Gomez-Gimenez, Belen; Malaguarnera, Michele; Dadsetan, Sherry; Belghiti, Majedeline; Garcia-Garcia, Raquel; Balzano, Tiziano; Taoro, Lucas; Felipo, Vicente

    2015-09-01

    The cognitive and motor alterations in hepatic encephalopathy (HE) are the final result of altered neurotransmission and communication between neurons in neuronal networks and circuits. Different neurotransmitter systems cooperate to modulate cognitive and motor function, with a main role for glutamatergic and GABAergic neurotransmission in different brain areas and neuronal circuits. There is an interplay between glutamatergic and GABAergic neurotransmission alterations in cognitive and motor impairment in HE. This interplay may occur: (a) in different brain areas involved in specific neuronal circuits; (b) in the same brain area through cross-modulation of glutamatergic and GABAergic neurotransmission. We will summarize some examples of the (1) interplay between glutamatergic and GABAergic neurotransmission alterations in different areas in the basal ganglia-thalamus-cortex circuit in the motor alterations in minimal hepatic encephalopathy (MHE); (2) interplay between glutamatergic and GABAergic neurotransmission alterations in cerebellum in the impairment of cognitive function in MHE through altered function of the glutamate-nitric oxide-cGMP pathway. We will also comment the therapeutic implications of the above studies and the utility of modulators of glutamate and GABA receptors to restore cognitive and motor function in rats with hyperammonemia and hepatic encephalopathy.

  19. Divergent Modulation of Nociception by Glutamatergic and GABAergic Neuronal Subpopulations in the Periaqueductal Gray

    PubMed Central

    Grajales-Reyes, Jose G.; Copits, Bryan A.; O’Brien, Daniel E.; Trigg, Sarah L.; Gomez, Adrian M.

    2017-01-01

    Abstract The ventrolateral periaqueductal gray (vlPAG) constitutes a major descending pain modulatory system and is a crucial site for opioid-induced analgesia. A number of previous studies have demonstrated that glutamate and GABA play critical opposing roles in nociceptive processing in the vlPAG. It has been suggested that glutamatergic neurotransmission exerts antinociceptive effects, whereas GABAergic neurotransmission exert pronociceptive effects on pain transmission, through descending pathways. The inability to exclusively manipulate subpopulations of neurons in the PAG has prevented direct testing of this hypothesis. Here, we demonstrate the different contributions of genetically defined glutamatergic and GABAergic vlPAG neurons in nociceptive processing by employing cell type-specific chemogenetic approaches in mice. Global chemogenetic manipulation of vlPAG neuronal activity suggests that vlPAG neural circuits exert tonic suppression of nociception, consistent with previous pharmacological and electrophysiological studies. However, selective modulation of GABAergic or glutamatergic neurons demonstrates an inverse regulation of nociceptive behaviors by these cell populations. Selective chemogenetic activation of glutamatergic neurons, or inhibition of GABAergic neurons, in vlPAG suppresses nociception. In contrast, inhibition of glutamatergic neurons, or activation of GABAergic neurons, in vlPAG facilitates nociception. Our findings provide direct experimental support for a model in which excitatory and inhibitory neurons in the PAG bidirectionally modulate nociception. PMID:28374016

  20. Pin1-dependent signalling negatively affects GABAergic transmission by modulating neuroligin2/gephyrin interaction

    PubMed Central

    Antonelli, Roberta; Pizzarelli, Rocco; Pedroni, Andrea; Fritschy, Jean-Marc; Del Sal, Giannino; Cherubini, Enrico; Zacchi, Paola

    2014-01-01

    The cell adhesion molecule Neuroligin2 (NL2) is localized selectively at GABAergic synapses, where it interacts with the scaffolding protein gephyrin in the post-synaptic density. However, the role of this interaction for formation and plasticity of GABAergic synapses is unclear. Here, we demonstrate that endogenous NL2 undergoes proline-directed phosphorylation at its unique S714-P consensus site, leading to the recruitment of the peptidyl-prolyl cis–trans isomerase Pin1. This signalling cascade negatively regulates NL2’s ability to interact with gephyrin at GABAergic post-synaptic sites. As a consequence, enhanced accumulation of NL2, gephyrin and GABAA receptors was detected at GABAergic synapses in the hippocampus of Pin1-knockout mice (Pin1−/−) associated with an increase in amplitude of spontaneous GABAA-mediated post-synaptic currents. Our results suggest that Pin1-dependent signalling represents a mechanism to modulate GABAergic transmission by regulating NL2/gephyrin interaction. PMID:25297980

  1. Regulation of GABAergic synapse formation and plasticity by GSK3β-dependent phosphorylation of gephyrin

    PubMed Central

    Tyagarajan, Shiva K.; Ghosh, Himanish; Yévenes, Gonzalo E.; Nikonenko, Irina; Ebeling, Claire; Schwerdel, Cornelia; Sidler, Corinne; Zeilhofer, Hanns Ulrich; Gerrits, Bertran; Muller, Dominique; Fritschy, Jean-Marc

    2011-01-01

    Postsynaptic scaffolding proteins ensure efficient neurotransmission by anchoring receptors and signaling molecules in synapse-specific subcellular domains. In turn, posttranslational modifications of scaffolding proteins contribute to synaptic plasticity by remodeling the postsynaptic apparatus. Though these mechanisms are operant in glutamatergic synapses, little is known about regulation of GABAergic synapses, which mediate inhibitory transmission in the CNS. Here, we focused on gephyrin, the main scaffolding protein of GABAergic synapses. We identify a unique phosphorylation site in gephyrin, Ser270, targeted by glycogen synthase kinase 3β (GSK3β) to modulate GABAergic transmission. Abolishing Ser270 phosphorylation increased the density of gephyrin clusters and the frequency of miniature GABAergic postsynaptic currents in cultured hippocampal neurons. Enhanced, phosphorylation-dependent gephyrin clustering was also induced in vitro and in vivo with lithium chloride. Lithium is a GSK3β inhibitor used therapeutically as mood-stabilizing drug, which underscores the relevance of this posttranslational modification for synaptic plasticity. Conversely, we show that gephyrin availability for postsynaptic clustering is limited by Ca2+-dependent gephyrin cleavage by the cysteine protease calpain-1. Together, these findings identify gephyrin as synaptogenic molecule regulating GABAergic synaptic plasticity, likely contributing to the therapeutic action of lithium. PMID:21173228

  2. Cannabinoids inhibit hippocampal GABAergic transmission and network oscillations.

    PubMed

    Hájos, N; Katona, I; Naiem, S S; MacKie, K; Ledent, C; Mody, I; Freund, T F

    2000-09-01

    Using a new antibody developed against the C-terminus of the cannabinoid receptor (CB1), the immunostaining in the hippocampus revealed additional axon terminals relative to the pattern reported previously with an N-terminus antibody. Due to a greater sensitivity of this antibody, a large proportion of boutons in the dendritic layers displaying symmetrical (GABAergic) synapses were also strongly immunoreactive for CB1 receptors, as were axon terminals of perisomatic inhibitory cells containing cholecystokinin. Asymmetrical (glutamatergic) synapses, however, were always negative for CB1. To investigate the effect of presynaptic CB1 receptor activation on hippocampal inhibition, we recorded inhibitory postsynaptic currents (IPSCs) from principal cells. Bath application of CB1 receptor agonists (WIN55,212-2 and CP55,940) suppressed IPSCs evoked by local electrical stimulation, which could be prevented or reversed by the CB1 receptor antagonist SR141716A. Action potential-driven IPSCs, evoked by pharmacological stimulation of a subset of interneurons, were also decreased by CB1 receptor activation. We also examined the effects of CB1 receptor agonists on Ca2+-independent miniature IPSCs (mIPSC). Both agonists were without significant effect on the frequency or amplitude of mIPSCs. Synchronous gamma oscillations induced by kainic acid in the CA3 region of hippocampal slices were reversibly reduced in amplitude by the CB1 receptor agonist CP 55,940, which is consistent with an action on IPSCs. We used CB1-/- knock-out mice to confirm the specificity of the antibody and of the agonist (WIN55,212-2) action. We conclude that activation of presynaptic CB1 receptors decreases Ca2+-dependent GABA release, and thereby reduces the power of hippocampal network oscillations.

  3. Postnatal development of intrinsic GABAergic rhythms in mouse hippocampus.

    PubMed

    Wong, T; Zhang, X L; Asl, M Nassiri; Wu, C P; Carlen, P L; Zhang, L

    2005-01-01

    recurrent circuitry and associated GABAergic inhibitory interneurons.

  4. 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.

  5. Unitary GABAergic volume transmission from individual interneurons to astrocytes in the cerebral cortex.

    PubMed

    Rózsa, Márton; Baka, Judith; Bordé, Sándor; Rózsa, Balázs; Katona, Gergely; Tamás, Gábor

    2017-01-01

    Communication between individual GABAergic cells and their target neurons is mediated by synapses and, in the case of neurogliaform cells (NGFCs), by unitary volume transmission. Effects of non-synaptic volume transmission might involve non-neuronal targets, and astrocytes not receiving GABAergic synapses but expressing GABA receptors are suitable for evaluating this hypothesis. Testing several cortical interneuron types in slices of the rat cerebral cortex, we show selective unitary transmission from NGFCs to astrocytes with an early, GABAA receptor and GABA transporter-mediated component and a late component that results from the activation of GABA transporters and neuronal GABAB receptors. We could not detect Ca(2+) influx in astrocytes associated with unitary GABAergic responses. Our experiments identify a presynaptic cell-type-specific, GABA-mediated communication pathway from individual neurons to astrocytes, assigning a role for unitary volume transmission in the control of ionic and neurotransmitter homeostasis.

  6. An extrasynaptic GABAergic signal modulates a pattern of forward movement in Caenorhabditis elegans

    PubMed Central

    Shen, Yu; Wen, Quan; Liu, He; Zhong, Connie; Qin, Yuqi; Harris, Gareth; Kawano, Taizo; Wu, Min; Xu, Tianqi; Samuel, Aravinthan DT; Zhang, Yun

    2016-01-01

    As a common neurotransmitter in the nervous system, γ-aminobutyric acid (GABA) modulates locomotory patterns in both vertebrates and invertebrates. However, the signaling mechanisms underlying the behavioral effects of GABAergic modulation are not completely understood. Here, we demonstrate that a GABAergic signal in C. elegans modulates the amplitude of undulatory head bending through extrasynaptic neurotransmission and conserved metabotropic receptors. We show that the GABAergic RME head motor neurons generate undulatory activity patterns that correlate with head bending and the activity of RME causally links with head bending amplitude. The undulatory activity of RME is regulated by a pair of cholinergic head motor neurons SMD, which facilitate head bending, and inhibits SMD to limit head bending. The extrasynaptic neurotransmission between SMD and RME provides a gain control system to set head bending amplitude to a value correlated with optimal efficiency of forward movement. DOI: http://dx.doi.org/10.7554/eLife.14197.001 PMID:27138642

  7. The Memory-Impairing Effects of Septal GABA Receptor Activation Involve GABAergic Septo-Hippocampal Projection Neurons

    ERIC Educational Resources Information Center

    Krebs-Kraft, Desiree L.; Wheeler, Marina G.; Parent, Marise B.

    2007-01-01

    Septal infusions of the [gamma]-aminobutyric acid (GABA)[subscript A] agonist muscimol impair memory, and the effect likely involves the hippocampus. GABA[subscript A] receptors are present on the perikarya of cholinergic and GABAergic septo-hippocampal (SH) projections. The current experiments determined whether GABAergic SH projections are…

  8. Differential synaptic organization of GABAergic bipolar cells and non-GABAergic (glutamatergic) bipolar cells in the tiger salamander retina.

    PubMed

    Yang, Chen-Yu; Zhang, Jun; Yazulla, Stephen

    2003-01-06

    The synaptic organizations of gamma-aminobutyric acid-immunoreactive (GABA-IR, GABAergic) and non-GABA-IR (non-IR, glutamatergic) bipolar cells in salamander retina were compared by postembedding immunoelectron microscopy. A total of 238 presynaptic bipolar cell synapses were studied; 61 were GABA-IR and 177 were non-IR. Both groups were similar in that (1). they made asymmetrical ribbon synapses as well as asymmetrical non-ribbon synapses; (2). they made ribbon synapses at dyads, triads, and monads; and (3). the vast majority of ribbon synapses ( approximately 90%) were with dyads. The differences were that synapses of GABA-IR bipolar cells had a higher proportion of (1). direct contact with ganglion cells, (2). non-ribbon synapses, (3). output to GABA-IR amacrine cells, and (4). output in sublamina a. Overall, the output of GABA-IR ribbons was equally split between amacrine and ganglion cell processes, whereas for non-IR ribbons, it was approximately 2:1 in favor of amacrine cells. The ribbon:non-ribbon synapse ratio was approximately 1.2:1 (33:28) for GABA-IR but approximately 2:1 (118:59) for non-IR terminals. Thus, GABA-IR bipolar cells made more direct contacts with ganglion cells and used a higher proportion of non-ribbon synapses. GABA-IR dyads were more likely to contact GABA-IR amacrine profiles (52% vs. 38%). Finally, GABA-IR ribbon synapses were more common in sublamina a than sublamina b (2:1), whereas non-IR synapses were equally present in sublaminas a and b. This differential targeting of ganglion cells and amacrine cells in the OFF vs. ON layers indicates a difference in the role of bipolar cells in the generation of receptive field properties, depending on whether or not they use GABA as well as glutamate for their transmitter.

  9. Immunocytochemical characterization of hippocamposeptal projecting GABAergic nonprincipal neurons in the mouse brain: a retrograde labeling study.

    PubMed

    Jinno, Shozo; Kosaka, Toshio

    2002-08-02

    The neurochemical contents of hippocamposeptal projecting nonprincipal neurons were examined in the mouse brain by using retrograde labeling techniques. We used the immunofluorescent multiple labeling method with a confocal laser-scanning microscope. First of all, the hippocamposeptal projecting nonprincipal neurons were glutamic acid decarboxylase 67-immunoreactive (IR), i.e., these hippocamposeptal projecting nonprincipal neurons were immunocytochemically GABAergic in the mouse brain. Next, most (93.0%) of the hippocamposeptal projecting GABAergic neurons were somatostatin-like immunoreactive (SS-LIR). The SS-LIR hippocamposeptal projecting neurons were frequently found in the stratum oriens of the CA1 and CA3 regions, and were also occasionally found in the stratum radiatum, stratum lucidum, and stratum pyramidale of the CA3 region. They were also frequently found in the dentate hilus. On the other hand, at least 40.6% of SS-LIR neurons in the hippocampus projected to the medial septum. Next, 38.0% of hippocamposeptal projecting GABAergic neurons were calbindin D28K (CB)-IR. Although the distribution of the CB-IR hippocamposeptal projecting neurons was generally similar to that of the SS-LIR projecting neurons in Ammon's horn, they were never seen in the dentate hilus. At least 22.1% of CB-IR GABAergic neurons in the hippocampus projected to the medial septum. Furthermore, 5.8% of hippocamposeptal projecting GABAergic neurons were parvalbumin-IR, which were most always found in Ammon's horn. Finally, no hippocamposeptal projecting GABAergic neurons were neuronal nitric oxide synthase-IR nor calretinin-IR. These results indicate that the SS-LIR neurons play a crucial role in the hippocamposeptal projection of the mouse brain, and they are also assumed to be involved in the theta oscillation of the mouse hippocampus.

  10. Altered postnatal maturation of striatal GABAergic interneurons in a phenotypic animal model of dystonia.

    PubMed

    Bode, Christoph; Richter, Franziska; Spröte, Christine; Brigadski, Tanja; Bauer, Anne; Fietz, Simone; Fritschy, Jean-Marc; Richter, Angelika

    2017-01-01

    GABAergic disinhibition has been suggested to play a critical role in the pathophysiology of several basal ganglia disorders, including dystonia, a common movement disorder. Previous studies have shown a deficit of striatal GABAergic interneurons (IN) in the dt(sz) mutant hamster, one of the few phenotypic animal models of dystonia. However, mechanisms underlying this deficit are largely unknown. In the present study, we investigated the migration and maturation of striatal IN during postnatal development (18days of age) and at age of highest severity of dystonia (33days of age) in this hamster model. In line with previous findings, the density of GAD67-positive IN and the level of parvalbumin mRNA, a marker for fast spiking GABAergic IN, were lower in the dt(sz) mutant than in control hamsters. However, an unaltered density of Nkx2.1 labeled cells and Nkx2.1 mRNA level suggested that the migration of GABAergic IN into the striatum was not retarded. Therefore, different factors that indicate maturation of GABAergic IN were determined. While mRNA of the KCC2 cation/chloride transporters and the cytosolic carboanhydrase VII, used as markers for the so called GABA switch, as well as BDNF were unaltered, we found a reduced number of IN expressing the alpha1 subunit of the GABAA-receptor (37.5%) in dt(sz) hamsters at an age of 33days, but not after spontaneous remission of dystonia at an age of 90days. Since IN shift expression from alpha2 to alpha1 subunits during postnatal maturation, this result together with a decreased parvalbumin mRNA expression suggest a delayed maturation of striatal GABAergic IN in this animal model, which might underlie abnormal neuronal activity and striatal plasticity.

  11. Functional Hallmarks of GABAergic Synapse Maturation and the Diverse Roles of Neurotrophins

    PubMed Central

    Grantyn, Rosemarie; Henneberger, Christian; Jüttner, René; Meier, Jochen C.; Kirischuk, Sergei

    2011-01-01

    Functional impairment of the adult brain can result from deficits in the ontogeny of GABAergic synaptic transmission. Gene defects underlying autism spectrum disorders, Rett’s syndrome or some forms of epilepsy, but also a diverse set of syndromes accompanying perinatal trauma, hormonal imbalances, intake of sleep-inducing or mood-improving drugs or, quite common, alcohol intake during pregnancy can alter GABA signaling early in life. The search for therapeutically relevant endogenous molecules or exogenous compounds able to alleviate the consequences of dysfunction of GABAergic transmission in the embryonic or postnatal brain requires a clear understanding of its site- and state-dependent development. At the level of single synapses, it is necessary to discriminate between presynaptic and postsynaptic alterations, and to define parameters that can be regarded as both suitable and accessible for the quantification of developmental changes. Here we focus on the performance of GABAergic synapses in two brain structures, the hippocampus and the superior colliculus, describe some novel aspects of neurotrophin effects during the development of GABAergic synaptic transmission and examine the applicability of the following rules: (1) synaptic transmission starts with GABA, (2) nascent/immature GABAergic synapses operate in a ballistic mode (multivesicular release), (3) immature synaptic terminals release vesicles with higher probability than mature synapses, (4) immature GABAergic synapses are prone to paired pulse and tetanic depression, (5) synapse maturation is characterized by an increasing dominance of synchronous over asynchronous release, (6) in immature neurons GABA acts as a depolarizing transmitter, (7) synapse maturation implies inhibitory postsynaptic current shortening due to an increase in alpha1 subunit expression, (8) extrasynaptic (tonic) conductances can inhibit the development of synaptic (phasic) GABA actions. PMID:21772813

  12. GABA transporter 1 tunes GABAergic synaptic transmission at output neurons of the mouse neostriatum

    PubMed Central

    Kirmse, Knut; Dvorzhak, Anton; Kirischuk, Sergei; Grantyn, Rosemarie

    2008-01-01

    GABAergic medium-sized striatal output neurons (SONs) provide the principal output for the neostriatum. In vitro and in vivo data indicate that spike discharge of SONs is tightly controlled by effective synaptic inhibition. Although phasic GABAergic transmission critically depends on ambient GABA levels, the role of GABA transporters (GATs) in neostriatal GABAergic synaptic transmission is largely unknown. In the present study we aimed at elucidating the role of GAT-1 in the developing mouse neostriatum (postnatal day (P) 7–34). We recorded GABAergic postsynaptic currents (PSCs) using the whole-cell patch-clamp technique. Based on the effects of NO-711, a specific GAT-1 blocker, we demonstrate that GAT-1 is operative at this age and influences GABAergic synaptic transmission by presynaptic and postsynaptic mechanisms. Presynaptic GABABR-mediated suppression of GABA release was found to be functional at all ages tested; however, there was no evidence for persistent GABABR activity under control conditions, unless GAT-1 was blocked (P12–34). In addition, whereas no tonic GABAAR-mediated conductances were detected in SONs until P14, application of a specific GABAAR antagonist caused distinct tonic outward currents later in development (P19–34). In the presence of NO-711, tonic GABAAR-mediated currents were also observed at P7–14 and were dramatically increased at more mature stages. Furthermore, GAT-1 block reduced the median amplitude of GABAergic miniature PSCs indicating a decrease in quantal size. We conclude that in the murine neostriatum GAT-1 operates in a net uptake mode. It prevents the persistent activation of presynaptic GABABRs (P12–34) and prevents (P7–14) or reduces (P19–34) tonic postsynaptic GABAAR activity. PMID:18832421

  13. Physiological and morphological characterization of GABAergic neurons in the medial amygdala.

    PubMed

    Bian, Xiling

    2013-05-06

    GABAergic neurons in the medial amygdala (MeA) have been indicated in information processing in reproductive behavior and fear/anxiety. However, basic knowledge of their physiological and morphological properties is still very limited, probably due to the technical challenge to selectively record the GABAergic neurons. In this study, I characterized properties of the MeA GABAergic neurons by performing whole-cell patch clamp recordings from brain slices of adult knock-in mice selectively expressing green fluorescence protein (GFP) in GABAergic neurons. The majority (73%) of GABAergic neurons exhibiting low threshold calcium spike were classified as type I neurons, with morphological properties of being bitufted or stellate, and dendrites either aspiny or covered by various shapes of spines. Axonal collaterals of some neurons were observed near somata as well as in other amygdaloid nuclei. Neurons incapable of generate low threshold calcium spikes were divided into two types. Type II neurons (11%) exhibited hyperpolarization-activated sag and higher input resistance (>400 MΩ). Most Type II neurons exhibited asymmetric dendritic trees extending towards the superficial layer covered with long neck dendritic spines. The axons of type II neurons formed large collaterals and projected to other amygdaloid nuclei. Type III neurons (16%) lack prominent hyperpolarization-activated sag and possessed lower input resistance (<400 MΩ). These neurons were local interneurons with smooth multipolar dendritic trees. Since both MeA and nearby amygdaloid nuclei are involved in fear/anxiety processing, two types of MeA GABAergic projection neurons and a third type of interneurons that might participate in anxiety-related behavior were revealed by my present study.

  14. A developmental shift from GABAergic to glycinergic transmission in the central auditory system.

    PubMed

    Kotak, V C; Korada, S; Schwartz, I R; Sanes, D H

    1998-06-15

    GABAergic and glycinergic circuits are found throughout the auditory brainstem, and it is generally assumed that transmitter phenotype is established early in development. The present study documents a profound transition from GABAergic to glycinergic transmission in the gerbil lateral superior olive (LSO) during the first 2 postnatal weeks. Whole-cell voltage-clamp recordings were obtained from LSO neurons in a brain slice preparation, and IPSCs were evoked by electrical stimulation of the medial nucleus of the trapezoid body (MNTB), a known glycinergic projection in adult animals. GABAergic and glycinergic components were identified by blocking transmission with bicuculline and strychnine (SN), respectively. In the medial limb of LSO, there was a dramatic change in the GABAergic IPSC component, decreasing from 78% at postnatal day 3 (P3)-P5 to 12% at P12-P16. There was an equal and opposite increase in the glycinergic component during this same period. Direct application of GABA also elicited significantly larger amplitude and longer duration responses in P3-P5 neurons compared with glycine-evoked responses. In contrast, MNTB-evoked IPSCs in lateral limb neurons were more sensitive to SN throughout development. Consistent with the electrophysiological observations, there was a reduction in staining for the beta2,3-GABAA receptor subunit from P4 to P14, whereas staining for the glycine receptor-associated protein gephyrin increased. Brief exposure to baclofen depressed transmission at excitatory and inhibitory synapses for approximately 15 min, suggesting a GABAB-mediated metabotropic signal. Collectively, these data demonstrate a striking switch from GABAergic to glycinergic transmission during postnatal development. Although GABA and glycine elicit similar postsynaptic ionotropic responses, our results raise the possibility that GABAergic transmission in neonates may play a developmental role distinct from that of glycine.

  15. GABAergic Somatostatin-immunoreactive Neurons in the Amygdala Project to the Entorhinal Cortex

    PubMed Central

    McDonald, Alexander J.; Zaric, Violeta

    2015-01-01

    The entorhinal cortex and other hippocampal and parahippocampal cortices are interconnected by a small number of GABAergic nonpyramidal neurons in addition to glutamatergic pyramidal cells. Since the cortical and basolateral amygdalar nuclei have cortex-like cell types and have robust projections to the entorhinal cortex, we hypothesized that a small number of amygdalar GABAergic nonpyramidal neurons might participate in amygdalo-entorhinal projections. To test this hypothesis we combined Fluorogold (FG) retrograde tract tracing with immunohistochemistry for the amygdalar nonpyramidal cell markers glutamic acid decarboxylase (GAD), parvalbumin (PV), somatostatin (SOM), neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), and the m2 muscarinic cholinergic receptor (M2R). Injections of FG into the rat entorhinal cortex labeled numerous neurons that were mainly located in the cortical and basolateral nuclei of the amygdala. Although most of these amygdalar FG+ neurons labeled by entorhinal injections were large pyramidal cells, 1–5% were smaller long-range nonpyramidal neurons (LRNP neurons) that expressed SOM, or both SOM and NPY. No amygdalar FG+ neurons in these cases were PV+ or VIP+. Cell counts revealed that LRNP neurons labeled by injections into the entorhinal cortex constituted about 10–20% of the total SOM+ population, and 20–40% of the total NPY population in portions of the lateral amygdalar nucleus that exhibited a high density of FG+ neurons. Sixty-two percent of amygdalar FG+/SOM+ neurons were GAD+, and 51% were M2R+. Since GABAergic projection neurons typically have low perikaryal levels of GABAergic markers, it is actually possible that most or all of the amygdalar LRNP neurons are GABAergic. Like GABAergic LRNP neurons in hippocampal/parahippocampal regions, amygdalar LRNP neurons that project to the entorhinal cortex are most likely involved in synchronizing oscillatory activity between the two regions. These oscillations could entrain

  16. 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.

  17. Regulation of GABAergic inputs to CA1 pyramidal neurons by nicotinic receptors and kynurenic acid.

    PubMed

    Banerjee, Jyotirmoy; Alkondon, Manickavasagom; Pereira, Edna F R; Albuquerque, Edson X

    2012-05-01

    Impaired α7 nicotinic acetylcholine receptor (nAChR) function and GABAergic transmission in the hippocampus and elevated brain levels of kynurenic acid (KYNA), an astrocyte-derived metabolite of the kynurenine pathway, are key features of schizophrenia. KYNA acts as a noncompetitive antagonist with respect to agonists at both α7 nAChRs and N-methyl-D-aspartate receptors. Here, we tested the hypothesis that in hippocampal slices tonically active α7 nAChRs control GABAergic transmission to CA1 pyramidal neurons and are sensitive to inhibition by rising levels of KYNA. The α7 nAChR-selective antagonist α-bungarotoxin (α-BGT; 100 nM) and methyllycaconitine (MLA; 10 nM), an antagonist at α7 and other nAChRs, reduced by 51.3 ± 1.3 and 65.2 ± 1.5%, respectively, the frequency of GABAergic postsynaptic currents (PSCs) recorded from CA1 pyramidal neurons. MLA had no effect on miniature GABAergic PSCs. Thus, GABAergic synaptic activity in CA1 pyramidal neurons is maintained, in part, by tonically active α7 nAChRs located on the preterminal region of axons and/or the somatodendritic region of interneurons that synapse onto the neurons under study. L-Kynurenine (20 or 200 μM) or KYNA (20-200 μM) suppressed concentration-dependently the frequency of GABAergic PSCs; the inhibitory effect of 20 μM L-kynurenine had an onset time of approximately 35 min and could not be detected in the presence of 100 nM α-BGT. These results suggest that KYNA levels generated from 20 μM kynurenine inhibit tonically active α7 nAChR-dependent GABAergic transmission to the pyramidal neurons. Disruption of nAChR-dependent GABAergic transmission by mildly elevated levels of KYNA can be an important determinant of the cognitive deficits presented by patients with schizophrenia.

  18. D1/D5 dopamine receptors stimulate intracellular calcium release in primary cultures of neocortical and hippocampal neurons.

    PubMed

    Lezcano, Nelson; Bergson, Clare

    2002-04-01

    D1/D5 dopamine receptors in basal ganglia, hippocampus, and cerebral cortex modulate motor, reward, and cognitive behavior. Previous work with recombinant proteins revealed that in cells primed with heterologous G(q/11)-coupled G-protein-coupled receptor (GPCR) agonists, the typically G(s)-linked D1/D5 receptors can stimulate robust release of calcium from internal stores when coexpressed with calcyon. To learn more about the intracellular signaling mechanisms underlying these D1/D5 receptor regulated behaviors, we explored the possibility that endogenous receptors stimulate internal release of calcium in neurons. We have identified a population of neurons in primary cultures of hippocampus and neocortex that respond to D1/D5 dopamine receptor agonists with a marked increase in intracellular calcium (Ca) levels. The D1/D5 receptor stimulated responses occurred in the absence of extracellular Ca(2+) indicating the rises in Ca involve release from internal stores. In addition, the responses were blocked by D1/D5 receptor antagonists. Further, the D1/D5 agonist-evoked responses were state dependent, requiring priming with agonists of G(q/11)-coupled glutamate, serotonin, muscarinic, and adrenergic receptors or with high external K(+) solution. In contrast, D1/D5 receptor agonist-evoked Ca(2+) responses were not detected in neurons derived from striatum. However, D1/D5 agonists elevated cAMP levels in striatal cultures as effectively as in neocortical and hippocampal cultures. Further, neither forskolin nor 8-Br-cAMP stimulation following priming was able to mimic the D1/D5 agonist-evoked Ca(2+) response in neocortical neurons indicating that increased cAMP levels are not sufficient to stimulate Ca release. Our data suggest that D1-like dopamine receptors likely modulate neocortical and hippocampal neuronal excitability and synaptic function via Ca(2+) as well as cAMP-dependent signaling.

  19. Neocortical neuron types in Xenarthra and Afrotheria: implications for brain evolution in mammals.

    PubMed

    Sherwood, Chet C; Stimpson, Cheryl D; Butti, Camilla; Bonar, Christopher J; Newton, Alisa L; Allman, John M; Hof, Patrick R

    2009-02-01

    Interpreting the evolution of neuronal types in the cerebral cortex of mammals requires information from a diversity of species. However, there is currently a paucity of data from the Xenarthra and Afrotheria, two major phylogenetic groups that diverged close to the base of the eutherian mammal adaptive radiation. In this study, we used immunohistochemistry to examine the distribution and morphology of neocortical neurons stained for nonphosphorylated neurofilament protein, calbindin, calretinin, parvalbumin, and neuropeptide Y in three xenarthran species-the giant anteater (Myrmecophaga tridactyla), the lesser anteater (Tamandua tetradactyla), and the two-toed sloth (Choloepus didactylus)-and two afrotherian species-the rock hyrax (Procavia capensis) and the black and rufous giant elephant shrew (Rhynchocyon petersi). We also studied the distribution and morphology of astrocytes using glial fibrillary acidic protein as a marker. In all of these species, nonphosphorylated neurofilament protein-immunoreactive neurons predominated in layer V. These neurons exhibited diverse morphologies with regional variation. Specifically, high proportions of atypical neurofilament-enriched neuron classes were observed, including extraverted neurons, inverted pyramidal neurons, fusiform neurons, and other multipolar types. In addition, many projection neurons in layers II-III were found to contain calbindin. Among interneurons, parvalbumin- and calbindin-expressing cells were generally denser compared to calretinin-immunoreactive cells. We traced the evolution of certain cortical architectural traits using phylogenetic analysis. Based on our reconstruction of character evolution, we found that the living xenarthrans and afrotherians show many similarities to the stem eutherian mammal, whereas other eutherian lineages display a greater number of derived traits.

  20. Unsupervised classification of neocortical activity patterns in neonatal and pre-juvenile rodents

    PubMed Central

    Cichon, Nicole B.; Denker, Michael; Grün, Sonja; Hanganu-Opatz, Ileana L.

    2014-01-01

    Flexible communication within the brain, which relies on oscillatory activity, is not confined to adult neuronal networks. Experimental evidence has documented the presence of discontinuous patterns of oscillatory activity already during early development. Their highly variable spatial and time-frequency organization has been related to region specificity. However, it might be equally due to the absence of unitary criteria for classifying the early activity patterns, since they have been mainly characterized by visual inspection. Therefore, robust and unbiased methods for categorizing these discontinuous oscillations are needed for increasingly complex data sets from different labs. Here, we introduce an unsupervised detection and classification algorithm for the discontinuous activity patterns of rodents during early development. For this, in a first step time windows with discontinuous oscillations vs. epochs of network “silence” were identified. In a second step, the major features of detected events were identified and processed by principal component analysis for deciding on their contribution to the classification of different oscillatory patterns. Finally, these patterns were categorized using an unsupervised cluster algorithm. The results were validated on manually characterized neonatal spindle bursts (SB), which ubiquitously entrain neocortical areas of rats and mice, and prelimbic nested gamma spindle bursts (NG). Moreover, the algorithm led to satisfactory results for oscillatory events that, due to increased similarity of their features, were more difficult to classify, e.g., during the pre-juvenile developmental period. Based on a linear classification, the optimal number of features to consider increased with the difficulty of detection. This algorithm allows the comparison of neonatal and pre-juvenile oscillatory patterns in their spatial and temporal organization. It might represent a first step for the unbiased elucidation of activity patterns

  1. Morphologic evidence for spatially clustered spines in apical dendrites of monkey neocortical pyramidal cells.

    PubMed

    Yadav, Aniruddha; Gao, Yuan Z; Rodriguez, Alfredo; Dickstein, Dara L; Wearne, Susan L; Luebke, Jennifer I; Hof, Patrick R; Weaver, Christina M

    2012-09-01

    The general organization of neocortical connectivity in rhesus monkey is relatively well understood. However, mounting evidence points to an organizing principle that involves clustered synapses at the level of individual dendrites. Several synaptic plasticity studies have reported cooperative interaction between neighboring synapses on a given dendritic branch, which may potentially induce synapse clusters. Additionally, theoretical models have predicted that such cooperativity is advantageous, in that it greatly enhances a neuron's computational repertoire. However, largely because of the lack of sufficient morphologic data, the existence of clustered synapses in neurons on a global scale has never been established. The majority of excitatory synapses are found within dendritic spines. In this study, we demonstrate that spine clusters do exist on pyramidal neurons by analyzing the three-dimensional locations of ∼40,000 spines on 280 apical dendritic branches in layer III of the rhesus monkey prefrontal cortex. By using clustering algorithms and Monte Carlo simulations, we quantify the probability that the observed extent of clustering does not occur randomly. This provides a measure that tests for spine clustering on a global scale, whenever high-resolution morphologic data are available. Here we demonstrate that spine clusters occur significantly more frequently than expected by pure chance and that spine clustering is concentrated in apical terminal branches. These findings indicate that spine clustering is driven by systematic biological processes. We also found that mushroom-shaped and stubby spines are predominant in clusters on dendritic segments that display prolific clustering, independently supporting a causal link between spine morphology and synaptic clustering.

  2. Neocortical axon arbors trade-off material and conduction delay conservation.

    PubMed

    Budd, Julian M L; Kovács, Krisztina; Ferecskó, Alex S; Buzás, Péter; Eysel, Ulf T; Kisvárday, Zoltán F

    2010-03-12

    The brain contains a complex network of axons rapidly communicating information between billions of synaptically connected neurons. The morphology of individual axons, therefore, defines the course of information flow within the brain. More than a century ago, Ramón y Cajal proposed that conservation laws to save material (wire) length and limit conduction delay regulate the design of individual axon arbors in cerebral cortex. Yet the spatial and temporal communication costs of single neocortical axons remain undefined. Here, using reconstructions of in vivo labelled excitatory spiny cell and inhibitory basket cell intracortical axons combined with a variety of graph optimization algorithms, we empirically investigated Cajal's conservation laws in cerebral cortex for whole three-dimensional (3D) axon arbors, to our knowledge the first study of its kind. We found intracortical axons were significantly longer than optimal. The temporal cost of cortical axons was also suboptimal though far superior to wire-minimized arbors. We discovered that cortical axon branching appears to promote a low temporal dispersion of axonal latencies and a tight relationship between cortical distance and axonal latency. In addition, inhibitory basket cell axonal latencies may occur within a much narrower temporal window than excitatory spiny cell axons, which may help boost signal detection. Thus, to optimize neuronal network communication we find that a modest excess of axonal wire is traded-off to enhance arbor temporal economy and precision. Our results offer insight into the principles of brain organization and communication in and development of grey matter, where temporal precision is a crucial prerequisite for coincidence detection, synchronization and rapid network oscillations.

  3. Neocortical neuronal morphology in the Siberian Tiger (Panthera tigris altaica) and the clouded leopard (Neofelis nebulosa).

    PubMed

    Johnson, Cameron B; Schall, Matthew; Tennison, Mackenzie E; Garcia, Madeleine E; Shea-Shumsky, Noah B; Raghanti, Mary Ann; Lewandowski, Albert H; Bertelsen, Mads F; Waller, Leona C; Walsh, Timothy; Roberts, John F; Hof, Patrick R; Sherwood, Chet C; Manger, Paul R; Jacobs, Bob

    2016-12-01

    Despite extensive investigations of the neocortex in the domestic cat, little is known about neuronal morphology in larger felids. To this end, the present study characterized and quantified the somatodendritic morphology of neocortical neurons in prefrontal, motor, and visual cortices of the Siberian tiger (Panthera tigris altaica) and clouded leopard (Neofelis nebulosa). After neurons were stained with a modified Golgi technique (N = 194), dendritic branching and spine distributions were analyzed using computer-assisted morphometry. Qualitatively, aspiny and spiny neurons in both species appeared morphologically similar to those observed in the domestic cat. Although the morphology of spiny neurons was diverse, with the presence of extraverted, inverted, horizontal, and multiapical pyramidal neurons, the most common variant was the typical pyramidal neuron. Gigantopyramidal neurons in the motor cortex were extremely large, confirming the observation of Brodmann ([1909] Vergleichende Lokalisationlehre der Grosshirnrinde in ihren Prinzipien dargestellt auf Grund des Zellenbaues. Leipzig, Germany: J.A. Barth), who found large somata for these neurons in carnivores in general, and felids in particular. Quantitatively, a MARSplines analysis of dendritic measures differentiated typical pyramidal neurons between the Siberian tiger and the clouded leopard with 93% accuracy. In general, the dendrites of typical pyramidal neurons were more complex in the tiger than in the leopards. Moreover, dendritic measures in tiger pyramidal neurons were disproportionally large relative to body/brain size insofar as they were nearly as extensive as those observed in much larger mammals (e.g., African elephant). Comparison of neuronal morphology in a more diverse collection of larger felids may elucidate the comparative context for the relatively large size of the pyramidal neurons observed in the present study. J. Comp. Neurol. 524:3641-3665, 2016. © 2016 Wiley Periodicals, Inc.

  4. Neocortical neuronal morphology in the newborn giraffe (Giraffa camelopardalis tippelskirchi) and African elephant (Loxodonta africana).

    PubMed

    Jacobs, Bob; Lee, Laura; Schall, Matthew; Raghanti, Mary Ann; Lewandowski, Albert H; Kottwitz, Jack J; Roberts, John F; Hof, Patrick R; Sherwood, Chet C

    2016-02-01

    Although neocortical neuronal morphology has been documented in the adult giraffe (Giraffa camelopardalis tippelskirchi) and African elephant (Loxodonta africana), no research has explored the cortical architecture in newborns of these species. To this end, the current study examined the morphology of neurons from several cortical areas in the newborn giraffe and elephant. After cortical neurons were stained with a modified Golgi technique (N = 153), dendritic branching and spine distributions were analyzed by using computer-assisted morphometry. The results showed that newborn elephant neurons were considerably larger in terms of all dendritic and spine measures than newborn giraffe neurons. Qualitatively, neurons in the newborns appeared morphologically comparable to those in their adult counterparts. Neurons in the newborn elephant differed considerably from those observed in other placental mammals, including the giraffe, particularly with regard to the morphology of spiny projection neurons. Projection neurons were observed in both species, with a much larger variety in the elephant (e.g., flattened pyramidal, nonpyramidal multipolar, and inverted pyramidal neurons). Although local circuit neurons (i.e., interneurons, neurogliaform, Cajal-Retzius neurons) resembled those observed in other eutherian mammals, these were usually spiny, which contrasts with their adult, aspiny equivalents. Newborn projection neurons were smaller than the adult equivalents in both species, but newborn interneurons were approximately the same size as their adult counterparts. Cortical neuromorphology in the newborn giraffe is thus generally consistent with what has been observed in other cetartiodactyls, whereas newborn and adult elephant morphology appears to deviate substantially from what is commonly observed in other placental mammals.

  5. Changes in neurotransmitter sensitivity in the mouse neocortical slice following propranolol and theophylline administration.

    PubMed Central

    Mally, J.; Connick, J. H.; Stone, T. W.

    1991-01-01

    1. The mouse neocortical slice has been used to examine the sensitivity of neurones to isoprenaline, 5-hydroxytryptamine (5-HT) and adenosine acutely and following chronic treatment of animals with propranolol or theophylline. 2. While having little effect alone, all three agonists enhanced the d.c. depolarizing potential produced by N-methyl-D-aspartate (NMDA). The effect of (-)-isoprenaline (0.2 microM) was shared by (+)-isoprenaline at the much higher concentration of 10 microM. 3. Superfusion of slices with theophylline or 8-phenyltheophylline blocked responses to adenosine with evidence of selectivity. A single injection of theophylline 24 h before slice preparation did not alter agonist sensitivity, but when administered daily at 100 mg kg-1 for 14 days, the xanthine caused a loss of sensitivity to adenosine and (-)-isoprenaline but not 5-HT. The lower dose of theophylline, 10 mg kg-1 daily, also led to a loss of adenosine responses but no change of sensitivity to the amines. 4. Following the 14 day treatment with theophylline at 100 mg kg-1 daily in two groups of mice, responses to adenosine recovered to control levels after 20 days. 5. Propranolol superfusion blocked responses to both isomers of isoprenaline and 5-HT but did not affect sensitivity to adenosine. 6. Chronic treatment with propranolol at 25 mg kg-1 daily for 14 days induced a loss of sensitivity to (-)-isoprenaline and 5-HT but not adenosine. A lower dose of 5 mg kg-1 daily caused no change in responses to adenosine or 5-HT, but yielded an increased sensitivity to (-)-isoprenaline.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1364843

  6. Electroconvulsive therapy and structural neuroplasticity in neocortical, limbic and paralimbic cortex

    PubMed Central

    Pirnia, T; Joshi, S H; Leaver, A M; Vasavada, M; Njau, S; Woods, R P; Espinoza, R; Narr, K L

    2016-01-01

    Electroconvulsive therapy (ECT) is a highly effective and rapidly acting treatment for severe depression. To understand the biological bases of therapeutic response, we examined variations in cortical thickness from magnetic resonance imaging (MRI) data in 29 patients scanned at three time points during an ECT treatment index series and in 29 controls at two time points. Changes in thickness across time and with symptom improvement were evaluated at high spatial resolution across the cortex and within discrete cortical regions of interest. Patients showed increased thickness over the course of ECT in the bilateral anterior cingulate cortex (ACC), inferior and superior temporal, parahippocampal, entorhinal and fusiform cortex and in distributed prefrontal areas. No changes across time occurred in controls. In temporal and fusiform regions showing significant ECT effects, thickness differed between patients and controls at baseline and change in thickness related to therapeutic response in patients. In the ACC, these relationships occurred in treatment responders only, and thickness measured soon after treatment initiation predicted the overall ECT response. ECT leads to widespread neuroplasticity in neocortical, limbic and paralimbic regions and changes relate to the extent of antidepressant response. Variations in ACC thickness, which discriminate treatment responders and predict response early in the course of ECT, may represent a biomarker of overall clinical outcome. Because post-mortem studies show focal reductions in glial density and neuronal size in patients with severe depression, ECT-related increases in thickness may be attributable to neuroplastic processes affecting the size and/or density of neurons and glia and their connections. PMID:27271858

  7. Layer-specific endocannabinoid-mediated long-term depression of GABAergic neurotransmission onto principal neurons in mouse visual cortex.

    PubMed

    Sun, Wenjuan; Wang, Laijian; Li, Shuo; Tie, Xiaoxiu; Jiang, Bin

    2015-08-01

    Visually induced endocannabinoid-mediated long-term depression of GABAergic neurotransmission (iLTD) mediates the maturation of GABAergic release in layer 2/3 of visual cortex. Here we examined whether the maturation of GABAergic transmission in other layers of visual cortex also requires endocannabinoids. The developmental plasticity of GABAergic neurotransmission onto the principal neurons in different layers of mouse visual cortex was examined in cortical slices by whole-cell recordings of inhibitory postsynaptic currents evoked by presynaptic inhibitory inputs. Theta burst stimulation of GABAergic inputs induced an endocannabinoid-mediated long-term depression of GABAergic neurotransmission onto pyramidal cells in layer 2/3 from postnatal day (P)10 to 30 and in layer 5 from P10 to 40, whereas that of GABAergic inputs did not induce iLTD onto star pyramidal neurons in layer 4 at any time postnatally, indicating that this plasticity is laminar-specific. The developmental loss of iLTD paralleled the maturation of GABAergic inhibition in both layer 2/3 and layer 5. Visual deprivation delayed the developmental loss of iLTD in layers 3 and 5 during a critical period, while 2 days of light exposure eliminated iLTD in both layers. Furthermore, the GABAergic synapses in layers 2/3 and 5 did not normally mature in the type 1 cannabinoid receptor knock-out mice, whereas those in layer 4 did not require endocannabinoid receptor for maturation. These results suggest that visually induced endocannabinoid-dependent iLTD mediates the maturation of GABAergic release in extragranular layer rather than in granular layer of mouse visual cortex.

  8. Dense and overlapping innervation of pyramidal neurons by neocortical chandelier cells

    PubMed Central

    Inan, Melis; Blázquez-Llorca, Lidia; Merchán-Perez, Angel; Anderson, Stewart A.; DeFelipe, Javier; Yuste, Rafael

    2013-01-01

    Chandelier (or axo-axonic) cells are a distinct group of GABAergic interneurons that innervate the axon initial segments of pyramidal cells and thus could have an important role controlling the activity of cortical circuits. To understand their connectivity we labeled upper layers chandelier cells (ChCs) from mouse neocortex with a genetic strategy and studied how their axons contact local populations of pyramidal neurons, using immunohistochemical detection of axon initial segments. We studied ChCs located in the border of layers 1 and 2 from primary somatosensory cortex and find that practically all ChC axon terminals contact axon initial segments with an average of 3–5 boutons per cartridge. By measuring the number of putative synapses in initial segments we estimate that each pyramidal neuron is innervated, on average, by at least 4 ChCs. Additionally, each individual ChC contacts 35–50% of pyramidal neurons within its axonal arbor, with pockets of high innervation density. Finally, we find that ChC axons seems to have a conserved innervation pattern at different postnatal ages (P18–90), with only relatively small lateral expansions of their arbor and increases in the total number of their cartridges during the developmental period analyzed. We conclude that ChCs innervate neighboring pyramidal neurons in a dense and overlapping manner, an innervation pattern which could enable ChCs exert a widespread influence on their local circuits. PMID:23365230

  9. Instructing Perisomatic Inhibition by Direct Lineage Reprogramming of Neocortical Projection Neurons.

    PubMed

    Ye, Zhanlei; Mostajo-Radji, Mohammed A; Brown, Juliana R; Rouaux, Caroline; Tomassy, Giulio Srubek; Hensch, Takao K; Arlotta, Paola

    2015-11-04

    During development of the cerebral cortex, local GABAergic interneurons recognize and pair with excitatory projection neurons to ensure the fine excitatory-inhibitory balance essential for proper circuit function. Whether the class-specific identity of projection neurons has a role in the establishment of afferent inhibitory synapses is debated. Here, we report that direct in vivo lineage reprogramming of layer 2/3 (L2/3) callosal projection neurons (CPNs) into induced corticofugal projection neurons (iCFuPNs) increases inhibitory input onto the converted neurons to levels similar to that of endogenous CFuPNs normally found in layer 5 (L5). iCFuPNs recruit increased numbers of inhibitory perisomatic synapses from parvalbumin (PV)-positive interneurons, with single-cell precision and despite their ectopic location in L2/3. The data show that individual reprogrammed excitatory projection neurons extrinsically modulate afferent input by local PV(+) interneurons, suggesting that projection neuron class-specific identity can actively control the wiring of the cortical microcircuit.

  10. Recruitment of early postnatal parvalbumin-positive hippocampal interneurons by GABAergic excitation.

    PubMed

    Sauer, Jonas-Frederic; Bartos, Marlene

    2010-01-06

    GABAergic synaptic inputs targeting cortical principal cells undergo marked changes in their functional properties from depolarizing at early postnatal life to hyperpolarizing at mature stages. In contrast, the nature of GABA(A) receptor-mediated signaling in interneurons during maturation of neuronal networks is controversial. By using gramicidin perforated-patch and whole-cell recordings from LIM homeobox 6 (Lhx6)-positive dentate gyrus perisomatic-targeting parvalbumin-expressing interneurons (PV-INs), we show that signaling at first formed GABAergic synapses at postnatal day 3 (P3) is excitatory and switches to shunting during the course of the first to second postnatal week. GABAergic synaptic inputs at P3-P6 reliably evoke action potentials in 65% of Lhx6-EGFP-expressing perisomatic-targeting cells and boost spike induction upon conjoint activation of glutamatergic fibers. Thus, GABAergic inputs change their functional role during maturation. They facilitate the recruitment of perisomatic-targeting INs in early postnatal circuits when network connectivity and synaptic glutamate receptor-mediated excitation are low and control spike timing at later stages when connectivity and glutamate-mediated drive are high.

  11. Monoacylglycerol lipase inhibitors produce pro- or antidepressant responses via hippocampal CA1 GABAergic synapses

    PubMed Central

    Wang, Y; Gu, N; Duan, T; Kesner, P; Blaskovits, F; Liu, J; Lu, Y; Tong, L; Gao, F; Harris, C; Mackie, K; Li, J; Tan, Q; Hill, M N; Yuan, Z; Zhang, X

    2017-01-01

    The probability of suffering the mood disorder depression is up to 30% in women and 15% in men during their life span. Pharmacological options for depression are limited: conventional antidepressants have low efficacy and a delayed onset of action (several weeks). Here we investigate the antidepressant actions of inhibitors of monoacylglycerol lipase (MAGL), the major degradative enzyme of the endocannabinoid 2-arachidonoylglycerol. A low-dose of MAGL inhibitors produces antidepressant effects on acute stress-exposed mice, through glutamatergic synaptic long-term depression (LTD), without significant effects on chronic corticosterone-exposed mice. In contrast, a high-dose of MAGL inhibitors produces pro- or antidepressant effects on acute stress- or chronic corticosterone-exposed mice, respectively, through GABAergic synaptic disinhibition. In the hippocampus, in vivo inhibition of MAGL induces a CB1 cannabinoid receptor (CB1R)-dependent suppression of inhibitory GABAergic synapses and an in vivo LTD of excitatory glutamatergic synapses. LTD induction requires CB1R in astroglial cells (but not in GABAergic or glutamatergic neurons) and postsynaptic glutamate receptors. The conventional antidepressant fluoxetine produces rapid or delayed antidepressant effects in acute stress- or chronic corticosterone-exposed mice, respectively. We propose that depression-like behavior of animals in response to acute stress is the normal behavioral response, and thus, MAGL inhibitors, which produce antidepressant effects in chronic corticosterone-exposed animals through GABAergic synaptic disinhibition, represent a new class of rapidly-acting and long-lasting antidepressants. PMID:27001616

  12. GABAergic agents prevent alpha-melanocyte stimulating hormone induced anxiety and anorexia in rats.

    PubMed

    Rao, T Lakshmi; Kokare, Dadasaheb M; Sarkar, Sumit; Khisti, Rahul T; Chopde, Chandrabhan T; Subhedar, Nishikant

    2003-12-01

    Alpha-melanocyte stimulating hormone (alpha-MSH) is a hypothalamic peptide believed to play a tonic inhibitory role in feeding and energy homeostasis. Systemic administration of alpha-MSH is known to produce anorexia and anxiety. Since synaptic contacts between gamma-aminobutyric acid (GABA)ergic terminals and alpha-MSH neurons in the hypothalamus have been reported, the present work was undertaken to refine our knowledge on the role of GABAergic systems in anxiety and anorexia induced by intracerebroventricular (icv) administration of alpha-MSH in rats. The anxiety was assessed by elevated plus maze, and spontaneous food consumption was monitored during dark cycle. Prior administration of diazepam and muscimol that promote the function of GABA(A) receptors reversed the anxiogenic response and decreased food intake elicited by alpha-MSH. In contrast, bicuculline, the GABA(A) receptor antagonist, not only enhanced the effects of alpha-MSH but also prevented the influence of GABAergic drugs on alpha-MSH-induced anorexia and anxiety. These findings suggest that alpha-MSH-induced anxiety and anorexia are due to its negative influence on GABAergic system.

  13. Profound regulation of neonatal CA1 rat hippocampal GABAergic transmission by functionally distinct kainate receptor populations

    PubMed Central

    Maingret, François; Lauri, Sari E; Taira, Tomi; Isaac, John TR

    2005-01-01

    Neonatal hippocampus exhibits distinct patterns of network activity that are dependent on the interaction between inhibitory and excitatory transmission. Kainate receptors are ideally positioned to regulate this activity by virtue of their ability to regulate presynaptic function in GABAergic interneurones. Indeed, kainate receptors are highly expressed in neonatal hippocampal interneurones, yet the role and mechanisms by which they might regulate neonatal circuitry are unexplored. To address this we investigated the kainate receptor-dependent regulation of GABAergic transmission onto neonatal CA1 pyramidal neurones. Kainate receptor activation produced two distinct opposing effects, a very large increase in the frequency of spontaneous IPSCs, and a robust depression of evoked GABAergic transmission. The up-regulation of spontaneous transmission was due to activation of somatodendritic and axonal receptors while the depression of evoked transmission could be fully accounted for by a direct regulation of GABA release by kainate receptors located at the terminals. None of the effects of kainate receptor agonists were sensitive to GABAB receptor antagonists, nor was there any postsynaptic kainate receptor-dependent effects observed in CA1 pyramidal cells that could account for our findings. Our data demonstrate that kainate receptors profoundly regulate neonatal CA1 GABAergic circuitry by two distinct opposing mechanisms, and indicate that these two effects are mediated by functionally distinct populations of receptors. Thus kainate receptors are strategically located to play a critical role in shaping early hippocampal network activity and by virtue of this have a key role in hippocampal development. PMID:15946969

  14. Caffeine-Induced Suppression of GABAergic Inhibition and Calcium-Independent Metaplasticity

    PubMed Central

    Isokawa, Masako

    2016-01-01

    GABAergic inhibition plays a critical role in the regulation of neuron excitability; thus, it is subject to modulations by many factors. Recent evidence suggests the elevation of intracellular calcium ([Ca2+]i) and calcium-dependent signaling molecules underlie the modulations. Caffeine induces a release of calcium from intracellular stores. We tested whether caffeine modulated GABAergic transmission by increasing [Ca2+]i. A brief local puff-application of caffeine to hippocampal CA1 pyramidal cells transiently suppressed GABAergic inhibitory postsynaptic currents (IPSCs) by 73.2 ± 6.98%. Time course of suppression and the subsequent recovery of IPSCs resembled DSI (depolarization-induced suppression of inhibition), mediated by endogenous cannabinoids that require a [Ca2+]i rise. However, unlike DSI, caffeine-induced suppression of IPSCs (CSI) persisted in the absence of a [Ca2+]i rise. Intracellular applications of BAPTA and ryanodine (which blocks caffeine-induced calcium release from intracellular stores) failed to prevent the generation of CSI. Surprisingly, ruthenium red, an inhibitor of multiple calcium permeable/release channels including those of stores, induced metaplasticity by amplifying the magnitude of CSI independently of calcium. This metaplasticity was accompanied with the generation of a large inward current. Although ionic basis of this inward current is undetermined, the present result demonstrates that caffeine has a robust Ca2+-independent inhibitory action on GABAergic inhibition and causes metaplasticity by opening plasma membrane channels. PMID:26998364

  15. Caffeine-Induced Suppression of GABAergic Inhibition and Calcium-Independent Metaplasticity.

    PubMed

    Isokawa, Masako

    2016-01-01

    GABAergic inhibition plays a critical role in the regulation of neuron excitability; thus, it is subject to modulations by many factors. Recent evidence suggests the elevation of intracellular calcium ([Ca(2+)]i) and calcium-dependent signaling molecules underlie the modulations. Caffeine induces a release of calcium from intracellular stores. We tested whether caffeine modulated GABAergic transmission by increasing [Ca(2+)]i. A brief local puff-application of caffeine to hippocampal CA1 pyramidal cells transiently suppressed GABAergic inhibitory postsynaptic currents (IPSCs) by 73.2 ± 6.98%. Time course of suppression and the subsequent recovery of IPSCs resembled DSI (depolarization-induced suppression of inhibition), mediated by endogenous cannabinoids that require a [Ca(2+)]i rise. However, unlike DSI, caffeine-induced suppression of IPSCs (CSI) persisted in the absence of a [Ca(2+)]i rise. Intracellular applications of BAPTA and ryanodine (which blocks caffeine-induced calcium release from intracellular stores) failed to prevent the generation of CSI. Surprisingly, ruthenium red, an inhibitor of multiple calcium permeable/release channels including those of stores, induced metaplasticity by amplifying the magnitude of CSI independently of calcium. This metaplasticity was accompanied with the generation of a large inward current. Although ionic basis of this inward current is undetermined, the present result demonstrates that caffeine has a robust Ca(2+)-independent inhibitory action on GABAergic inhibition and causes metaplasticity by opening plasma membrane channels.

  16. Orexin (hypocretin)/dynorphin neurons control GABAergic inputs to tuberomammillary neurons.

    PubMed

    Eriksson, Krister S; Sergeeva, Olga A; Selbach, Oliver; Haas, Helmut L

    2004-03-01

    High activity of the histaminergic neurons in the tuberomammillary (TM) nucleus increases wakefulness, and their firing rate is highest during waking and lowest during rapid eye movement sleep. The TM neurons receive a prominent innervation from sleep-active gamma-aminobutyric acidergic (GABAergic) neurons in the ventrolateral preoptic nucleus, which inhibits them during sleep. They also receive an excitatory input from the orexin- and dynorphin-containing neurons in the lateral hypothalamus, which are critically involved in sleep regulation and whose dysfunction causes narcolepsy. We have used intracellular recordings and immunohistochemistry to study if orexin neurons exert control over the GABAergic inputs to TM neurons in rat hypothalamic slices. Dynorphin suppressed GABAergic inputs and thus disinhibits the TM neurons, acting in concert with orexin to increase the excitability of these neurons. In contrast, both orexin-A and orexin-B markedly increased the frequency of GABAergic potentials, while co-application of orexin and dynorphin produced responses similar to dynorphin alone. Thus, orexins excite TM neurons directly and by disinhibition, gated by dynorphin. These data might explain some of the neuropathology of narcolepsy.

  17. Neonatal DSP-4 treatment modifies GABAergic neurotransmission in the prefrontal cortex of adult rats.

    PubMed

    Bortel, Aleksandra; Nowak, Przemyslaw; Brus, Ryszard

    2008-01-01

    N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) is a noradrenergic neurotoxin which selectively damages noradrenergic projections originating from the locus coeruleus (LC). DSP-4 treatment of rats on the first and third days after birth produces a long-lasting lesion of noradrenergic neurons in the prefrontal cortex (PFC). In DSP-4-lesioned rats, studied as adults, we observed a decrease in norepinephrine content, with no significant change in the levels of dopamine, 5-hydroxytryptamine, and gamma-aminobutyric acid (GABA). There is now a well established interaction between noradrenergic and GABAergic systems, whereby the noradrenergic system is involved in the regulation of basal GABA release, while GABAergic neurons simultaneously exert tonic inhibitory regulation of LC norepinephrine neurons. We examined GABAergic neurotransmission in the norepinephrine-denervated PFC for a better appreciation of the interaction between these two systems. Treatment with the GABA transaminase inhibitor vigabatrine (VGB) increased the GABA level of PFC (tissue content) in both intact and lesioned groups. Additionally, VGB increased extracellular GABA concentration in the PFC in both control and DSP-4-lesioned animals, but the elevation of GABA was 2-fold higher in DSP-4 lesioned rats. These findings indicate that neonatal DSP-4 treatment increases GABAergic neurotransmission in the PFC of rats in adulthood, perhaps by decreasing reactivity of central GABA(A) receptors.

  18. Participation of a GABA-ergic system in the processes of neuroimmunomodulation.

    PubMed

    Devoino, L; Idova, G; Beletskaya, I

    1992-01-01

    Participation of a GABA-ergic system in neuroimmunomodulation was established through the use of a large number of chemical compounds which selectively modulate the activity of the GABA-BD-receptor-ionophore complex. Activation of the GABA-receptors with muscimol or activation of the BD-receptors with diazepam or tazepam had stimulatory effects upon immunogenesis. A decrease in the GABA-BD-receptor-ionophore complex activity led to a suppression of the immune response. The effect was achieved with: a blockade of the complex with bicuculline--a competitive inhibitor of the GABA-receptors: administration of a specific antagonist of the BD-receptors flumazenil or Ro 15-3505: or with blockade of chloride channels with picrotoxin. Activation of the GABA-ergic system causes an increase in bone marrow content of T-helper cells marked by L3T4. The immunomodulatory action of the GABA-ergic system is of central origin and can occur only when the hypothalamo-pituitary system is intact. Section of the pituitary stalk prevents accumulation of the T-helper cells in the bone marrow. The result show that the influence of GABA-ergic system on immunogenesis requires participation of both dopaminergic and serotoninergic systems.

  19. Intraspinal transplantation of GABAergic neural progenitors attenuates neuropathic pain in rats: a pharmacologic and neurophysiological evaluation

    PubMed Central

    Jergova, Stanislava; Hentall, Ian D.; Gajavelli, Shyam; Varghese, Mathew S.; Sagen, Jacqueline

    2012-01-01

    Dysfunctional γ-aminobutyric acid (GABA)-ergic inhibitory neurotransmission is hypothesized to underlie chronic neuropathic pain. Intraspinal transplantation of GABAergic neural progenitor cells (NPCs) may reduce neuropathic pain by restoring dorsal horn inhibition. Rat NPCs pre-differentiated to a GABAergic phenotype were transplanted into the dorsal horn of rats with unilateral chronic constriction injury (CCI) of the sciatic nerve. GABA signaling in antinociceptive effects of NPC grafts was tested with the GABAA receptor antagonist bicuculline (BIC), GABAB receptor antagonist CGP35348 (CGP) and GABA reuptake inhibitor SKF 89976A (SKF). NPC-treated animals showed decreased hyperalgesia and allodynia 1-3 week post-transplantation; vehicle-injected CCI rats continued displaying pain behaviors. Intrathecal application of BIC or CGP attenuated the antinociceptive effects of the NPC transplants while SKF injection induced analgesia in control rats. Electrophysiological recordings in NPC treated rats showed reduced responses of wide dynamic range (WDR) neurons to peripheral stimulation compared to controls. A spinal application of BIC or CGP increased wind-up response and post-discharges of WDR neurons in NPC treated animals. Results suggest that transplantation of GABAergic NPCs attenuate pain behaviors and reduce exaggerated dorsal horn neuronal firing induced by CCI. The effects of GABA receptor inhibitors suggest participation of continuously released GABA in the grafted animals. PMID:22193109

  20. Chronic GABAergic blockade in the spinal cord in vivo induces motor alterations and neurodegeneration.

    PubMed

    Ramírez-Jarquín, Uri Nimrod; Tapia, Ricardo

    2017-05-01

    Inhibitory GABAergic and glycinergic neurotransmission in the spinal cord play a central role in the regulation of neuronal excitability, by maintaining a balance with the glutamate-mediated excitatory transmission. Glutamatergic agonists infusion in the spinal cord induce motor neuron death by excitotoxicity, leading to motor deficits and paralysis, but little is known on the effect of the blockade of inhibitory transmission. In this work we studied the effects of GABAergic and glycinergic blockade, by means of microdialysis perfusion (acute administration) and osmotic minipumps infusion (chronic administration) of GABA and glycine receptors antagonists directly in the lumbar spinal cord. We show that acute glycinergic blockade with strychnine or GABAergic blockade with bicuculline had no significant effects on motor activity and on motor neuron survival. However, chronic bicuculline infusion, but not strychnine, induced ipsilateral gait alterations, phalange flaccidity and significant motor neuron loss, and these effects were prevented by AMPA receptor blockade with CNQX but not by NMDA receptor blockade with MK801. In addition, we demonstrate that the chronic infusion of bicuculline enhanced the excitotoxic effect of AMPA, causing faster bilateral paralysis and increasing motor neuron loss. These findings indicate a relevant role of GABAergic inhibitory circuits in the regulation of motor neuron excitability and suggest that their alterations may be involved in the neurodegeneration processes characteristic of motor neuron diseases such as amyotrophic lateral sclerosis.

  1. VTA glutamatergic inputs to nucleus accumbens drive aversion by acting on GABAergic interneurons

    PubMed Central

    Qi, Jia; Zhang, Shiliang; Wang, Hui-Ling; Barker, David J.; Miranda-Barrientos, Jorge; Morales, Marisela

    2016-01-01

    The ventral tegmental area (VTA) is best known for its dopamine neurons, some of which project to nucleus accumbens (nAcc). However, the VTA also has glutamatergic neurons that project to nAcc. The function of the mesoaccumbens-glutamatergic pathway remains unknown. Here, we report that nAcc photoactivation of mesoaccumbens-glutamatergic fibers promotes aversion. Although we found that these mesoaccumbens-glutamate-fibers lack GABA, the aversion evoked by their photoactivation depends on glutamate and GABA receptor signaling, and not on dopamine receptor signaling. We found that mesoaccumbens-glutamatergic-fibers establish multiple asymmetric synapses on single parvalbumin-GABAergic interneurons, and that nAcc photoactivation of these fibers drives AMPA-mediated cellular firing of parvalbumin-GABAergic interneurons. These parvalbumin-GABAergic-interneurons, in turn, inhibit nAcc medium spiny output neurons, as such, controlling inhibitory neurotransmission within nAcc. The mesoaccumbens-glutamatergic pathway is the first glutamatergic input to nAcc shown to mediate aversion, instead of reward, and the first pathway shown to establish excitatory synapses on nAcc parvalbumin-GABAergic interneurons. PMID:27019014

  2. Comprehensive association analysis of 27 genes from the GABAergic system in Japanese individuals affected with schizophrenia.

    PubMed

    Balan, Shabeesh; Yamada, Kazuo; Iwayama, Yoshimi; Hashimoto, Takanori; Toyota, Tomoko; Shimamoto, Chie; Maekawa, Motoko; Takagai, Shu; Wakuda, Tomoyasu; Kameno, Yosuke; Kurita, Daisuke; Yamada, Kohei; Kikuchi, Mitsuru; Hashimoto, Tasuku; Kanahara, Nobuhisa; Yoshikawa, Takeo

    2017-01-07

    Involvement of the gamma-aminobutyric acid (GABA)-ergic system in schizophrenia pathogenesis through disrupted neurodevelopment has been highlighted in numerous studies. However, the function of common genetic variants of this system in determining schizophrenia risk is unknown. We therefore tested the association of 375 tagged SNPs in genes derived from the GABAergic system, such as GABAA receptor subunit genes, and GABA related genes (glutamate decarboxylase genes, GABAergic-marker gene, genes involved in GABA receptor trafficking and scaffolding) in Japanese schizophrenia case-control samples (n=2926; 1415 cases and 1511 controls). We observed nominal association of SNPs in nine GABAA receptor subunit genes and the GPHN gene with schizophrenia, although none survived correction for study-wide multiple testing. Two SNPs located in the GABRA1 gene, rs4263535 (Pallele=0.002; uncorrected) and rs1157122 (Pallele=0.006; uncorrected) showed top hits, followed by rs723432 (Pallele=0.007; uncorrected) in the GPHN gene. All three were significantly associated with schizophrenia and survived gene-wide multiple testing. Haplotypes containing associated variants in GABRA1 but not GPHN were significantly associated with schizophrenia. To conclude, we provided substantiating genetic evidence for the involvement of the GABAergic system in schizophrenia susceptibility. These results warrant further investigations to replicate the association of GABRA1 and GPHN with schizophrenia and to discern the precise mechanisms of disease pathophysiology.

  3. Uptake and metabolism of fructose by rat neocortical cells in vivo and by isolated nerve terminals in vitro

    PubMed Central

    Hassel, Bjørnar; Elsais, Ahmed; Frøland, Anne Sofie; Taubøll, Erik; Gjerstad, Leif; Quan, Yi; Dingledine, Ray; Rise, Frode

    2015-01-01

    Fructose reacts spontaneously with proteins in the brain to form advanced glycation end products (AGE) that may elicit neuroinflammation and cause brain pathology, including Alzheimer’s disease. We investigated whether fructose is eliminated by oxidative metabolism in neocortex. Injection of [14C]fructose or its AGE-prone metabolite [14C]glyceraldehyde into rat neocortex in vivo led to formation of 14C-labeled alanine, glutamate, aspartate, GABA, and glutamine. In isolated neocortical nerve terminals, [14C]fructose labeled glutamate, GABA, and aspartate, indicating uptake of fructose into nerve terminals and oxidative fructose metabolism in these structures. Hexokinase 1, which channels fructose into glycolysis, was highly expressed, and enzyme activity was similar with fructose or glucose as substrates, whereas the fructose-specific ketohexokinase was weakly expressed. The fructose transporter Glut5 was expressed at only ~4% of the level of neuronal glucose transporter Glut3, suggesting transport across plasma membranes of brain cells as the limiting factor in removal of extracellular fructose. Fructose may be formed from glucose through the polyol pathway. The genes encoding enzymes of this pathway, aldose reductase and sorbitol dehydrogenase, were expressed in rat neocortex. We conclude that fructose is transported into neocortical cells, including nerve terminals, and that it is metabolized and thereby detoxified primarily through hexokinase activity. PMID:25708447

  4. Brevetoxin-induced phosphorylation of Pyk2 and Src in murine neocortical neurons involves distinct signaling pathways

    PubMed Central

    Cao, Zhengyu; George, Joju; Baden, Daniel G.; Murray, Thomas F.

    2009-01-01

    Brevetoxins (PbTx-1 to PbTx-10) are potent lipid soluble polyether neurotoxins produced by the marine dinoflagellate Karenia brevis. Brevetoxins bind to site 5 of the α-subunit of voltage-gated sodium channels (VGSCs) and augment Na+ influx. In neocortical neurons brevetoxins elevate intracellular Ca2+ and augment NMDA receptor signaling. In this study, we explored the effects of PbTx-2 on Pyk2 and Src activation in neocortical neurons. We found that both Pyk2 and Src were activated following PbTx-2 exposure. PbTx-2-induced Pyk2 Tyr402 phosphorylation was dependent on elevation of Ca2+ influx through NMDA receptors. Moreover, Pyk2 Tyr402 phosphorylation was also found to require PKC activation inasmuch as RO-31-8425 and GF 109203x both attenuated the response. In contrast, PbTx-2-induced Src Tyr416 phosphorylation involved a Gq-coupled receptor inasmuch as U73122, a specific PLC inhibitor, abolished the response. This Gq-coupled receptor appears to be mGluR 5. The PKCδ inhibitor rottlerin abolished PbTx-2-induced Src activation demonstrating that this isoform of PKC is involved in the activation of Src by PbTx-2. Considered together these data suggest that although activation of neuronal Pyk2 and Src result from PbTx-2 stimulation of VGSC, engagement of these two non-receptor tyrosine kinases involves distinct signaling pathways. PMID:17963734

  5. Decoding the Formation of New Semantics: MVPA Investigation of Rapid Neocortical Plasticity during Associative Encoding through Fast Mapping

    PubMed Central

    Atir-Sharon, Tali; Gilboa, Asaf; Hazan, Hananel; Koilis, Ester; Manevitz, Larry M.

    2015-01-01

    Neocortical structures typically only support slow acquisition of declarative memory; however, learning through fast mapping may facilitate rapid learning-induced cortical plasticity and hippocampal-independent integration of novel associations into existing semantic networks. During fast mapping the meaning of new words and concepts is inferred, and durable novel associations are incidentally formed, a process thought to support early childhood's exuberant learning. The anterior temporal lobe, a cortical semantic memory hub, may critically support such learning. We investigated encoding of semantic associations through fast mapping using fMRI and multivoxel pattern analysis. Subsequent memory performance following fast mapping was more efficiently predicted using anterior temporal lobe than hippocampal voxels, while standard explicit encoding was best predicted by hippocampal activity. Searchlight algorithms revealed additional activity patterns that predicted successful fast mapping semantic learning located in lateral occipitotemporal and parietotemporal neocortex and ventrolateral prefrontal cortex. By contrast, successful explicit encoding could be classified by activity in medial and dorsolateral prefrontal and parahippocampal cortices. We propose that fast mapping promotes incidental rapid integration of new associations into existing neocortical semantic networks by activating related, nonoverlapping conceptual knowledge. In healthy adults, this is better captured by unique anterior and lateral temporal lobe activity patterns, while hippocampal involvement is less predictive of this kind of learning. PMID:26257961

  6. Cannabinoid CB1 receptors are localized primarily on cholecystokinin-containing GABAergic interneurons in the rat hippocampal formation.

    PubMed

    Tsou, K; Mackie, K; Sañudo-Peña, M C; Walker, J M

    1999-01-01

    Localization of cannabinoid CB 1 receptors on GABAergic interneurons in the rat hippocampal formation was studied by double-labeling immunohistochemistry with confocal microscopy. Virtually all CB1-immunoreactive neurons (95%) are GABAergic. CB 1 fluorescence showed a punctate pattern. In contrast, the GABA fluorescence was distributed homogeneously, suggesting that while CB 1 receptors and GABA exist in the same cells they are not localized in the same subcellular compartments. Although virtually all CB1 neurons were GABAergic, many GABAergic neurons did not contain CB1 receptors. GABAergic interneurons in the hippocampal formation can be further divided into subpopulations with distinct connections and functions, using cell markers such as neuropeptides and calcium binding proteins. CB1 receptors were highly co-localized with cholecystokinin and partially co-localized with calretinin and calbindin, but not with parvalbumin. This suggests that cannabinoids may modulate GABAergic neurotransmission at the synapses on the soma and at synapses on the proximal dendrites of the principal neurons, as well as at synapses on other GABAergic interneurons.

  7. Pro-brain-derived neurotrophic factor inhibits GABAergic neurotransmission by activating endocytosis and repression of GABAA receptors.

    PubMed

    Riffault, Baptiste; Medina, Igor; Dumon, Camille; Thalman, Carine; Ferrand, Nadine; Friedel, Perrine; Gaiarsa, Jean-Luc; Porcher, Christophe

    2014-10-01

    GABA is the canonical inhibitory neurotransmitter in the CNS. This inhibitory action is largely mediated by GABA type A receptors (GABAARs). Among the many factors controlling GABAergic transmission, brain-derived neurotrophic factor (BDNF) appears to play a major role in regulating synaptic inhibition. Recent findings have demonstrated that BDNF can be released as a precursor (proBDNF). Although the role of mature BDNF on GABAergic synaptogenesis and maintenance has been well studied, an important question still unanswered is whether secreted proBDNF might affect GABAergic neurotransmission. Here, we have used 14 d in vitro primary culture of hippocampal neurons and ex vivo preparations from rats to study the function of proBDNF in regulation of GABAAR trafficking and activity. We demonstrate that proBDNF impairs GABAergic transmission by the activation of two distinct pathways: (1) a RhoA-Rock-PTEN pathway that decreases the phosphorylation levels of GABAAR, thus affecting receptor function and triggering endocytosis and degradation of internalized receptors, and (2) a JAK-STAT-ICER pathway leading to the repression of GABAARs synthesis. These effects lead to the diminution of GABAergic synapses and are correlated with a decrease in GABAergic synaptic currents. These results revealed new functions for proBDNF-p75 neurotrophin receptor signaling pathway in the control of the efficacy of GABAergic synaptic activity by regulating the trafficking and synthesis of GABAARs at inhibitory synapses.

  8. Non-associative Potentiation of Perisomatic Inhibition Alters the Temporal Coding of Neocortical Layer 5 Pyramidal Neurons

    PubMed Central

    Lourenço, Joana; Pacioni, Simone; Rebola, Nelson; van Woerden, Geeske M.; Marinelli, Silvia; DiGregorio, David; Bacci, Alberto

    2014-01-01

    In the neocortex, the coexistence of temporally locked excitation and inhibition governs complex network activity underlying cognitive functions, and is believed to be altered in several brain diseases. Here we show that this equilibrium can be unlocked by increased activity of layer 5 pyramidal neurons of the mouse neocortex. Somatic depolarization or short bursts of action potentials of layer 5 pyramidal neurons induced a selective long-term potentiation of GABAergic synapses (LTPi) without affecting glutamatergic inputs. Remarkably, LTPi was selective for perisomatic inhibition from parvalbumin basket cells, leaving dendritic inhibition intact. It relied on retrograde signaling of nitric oxide, which persistently altered presynaptic GABA release and diffused to inhibitory synapses impinging on adjacent pyramidal neurons. LTPi reduced the time window of synaptic summation and increased the temporal precision of spike generation. Thus, increases in single cortical pyramidal neuron activity can induce an interneuron-selective GABAergic plasticity effectively altering the computation of temporally coded information. PMID:25003184

  9. Prefrontal cortical GABAergic dysfunction contributes to age-related working memory impairment.

    PubMed

    Bañuelos, Cristina; Beas, B Sofia; McQuail, Joseph A; Gilbert, Ryan J; Frazier, Charles J; Setlow, Barry; Bizon, Jennifer L

    2014-03-05

    Working memory functions supported by the prefrontal cortex decline in normal aging. Disruption of corticolimbic GABAergic inhibitory circuits can impair working memory in young subjects; however, relatively little is known regarding how aging impacts prefrontal cortical GABAergic signaling and whether such changes contribute to cognitive deficits. The current study used a rat model to evaluate the effects of aging on expression of prefrontal GABAergic synaptic proteins in relation to working memory decline, and to test whether pharmacological manipulations of prefrontal GABAergic signaling can improve working memory abilities in aged subjects. Results indicate that in aged medial prefrontal cortex (mPFC), expression of the vesicular GABA transporter VGAT was unchanged; however, there was a significant increase in expression of the GABA synthesizing enzyme GAD67, and a significant decrease in the primary neuronal GABA transporter GAT-1 and in both subunits of the GABA(B) receptor (GABA(B)R). Expression of VGAT, GAD67, and GAT-1 was not associated with working memory ability. In contrast, among aged rats, GABA(B)R expression was significantly and negatively associated with working memory performance, such that lower GABA(B)R expression predicted better working memory. Subsequent experiments showed that systemic administration of a GABA(B)R antagonist, CGP55845, dose-dependently enhanced working memory in aged rats. This enhancing effect of systemic CGP55845 was reproduced by direct intra-mPFC administration. Together, these data suggest that age-related dysregulation of GABAergic signaling in prefrontal cortex may play a causal role in impaired working memory and that targeting GABA(B)Rs may provide therapeutic benefit for age-related impairments in executive functions.

  10. Neuregulin 1 promotes excitatory synapse development and function in GABAergic interneurons.

    PubMed

    Ting, Annie K; Chen, Yongjun; Wen, Lei; Yin, Dong-Min; Shen, Chengyong; Tao, Yanmei; Liu, Xihui; Xiong, Wen-Cheng; Mei, Lin

    2011-01-05

    Neuregulin 1 (NRG1) and its receptor ErbB4 are both susceptibility genes of schizophrenia. However, little is known about the underlying mechanisms of their malfunction. Although ErbB4 is enriched in GABAergic interneurons, the role of NRG1 in excitatory synapse formation in these neurons remains poorly understood. We showed that NRG1 increased both the number and size of PSD-95 puncta and the frequency and amplitude of miniature EPSCs (mEPSCs) in GABAergic interneurons, indicating that NRG1 stimulates the formation of new synapses and strengthens existing synapses. In contrast, NRG1 treatment had no effect on either the number or size of excitatory synapses in glutamatergic neurons, suggesting its synaptogenic effect is specific to GABAergic interneurons. Ecto-ErbB4 treatment diminished both the number and size of excitatory synapses, suggesting that endogenous NRG1 may be critical for basal synapse formation. NRG1 could stimulate the stability of PSD-95 in the manner that requires tyrosine kinase activity of ErbB4. Finally, deletion of ErbB4 in parvalbumin-positive interneurons led to reduced frequency and amplitude of mEPSCs, providing in vivo evidence that ErbB4 is important in excitatory synaptogenesis in interneurons. Together, our findings suggested a novel synaptogenic role of NRG1 in excitatory synapse development, possibly via stabilizing PSD-95, and this effect is specific to GABAergic interneurons. In light of the association of the genes of both NRG1 and ErbB4 with schizophrenia and dysfunction of GABAergic system in this disorder, these results provide insight into its potential pathological mechanism.

  11. Leptin Responsive and GABAergic Projections to the Rostral Preoptic Area in Mice.

    PubMed

    Zuure, W A; Quennell, J H; Anderson, G M

    2016-03-01

    The adipocyte-derived hormone leptin plays a critical role in the control of reproduction via signalling in hypothalamic neurones. The drivers of the hypothalamic-pituitary-gonadal axis, the gonadotrophin-releasing hormone (GnRH) neurones, do not have the receptors for leptin. Therefore, intermediate leptin responsive neurones must provide leptin-to-GnRH signalling. We investigated the populations of leptin responsive neurones that provide input to the rostral preoptic area (rPOA) where GnRH cell bodies reside. Fluorescent retrograde tracer beads (RetroBeads; Lumafluor Inc., Naples, FL, USA) were injected into the rPOA of transgenic leptin receptor enhanced green fluorescent protein (Lepr-eGFP) reporter mice. Uptake of the RetroBeads by Lepr-eGFP neurones was assessed throughout the hypothalamus. RetroBead uptake was most evident in the medial arcuate nucleus (ARC), the dorsomedial nucleus (DMN) and the ventral premammillary nucleus (PMV) of the hypothalamus. The uptake of RetroBeads specifically by Lepr-eGFP neurones was highest in the medial ARC (18% of tracer-labelled neurones Lepr-eGFP-positive). Because neurones that are both leptin responsive and GABAergic play a critical role in the regulation of fertility by leptin, we next focussed on the location of these populations. To address whether GABAergic neurones in leptin-responsive hypothalamic regions project to the rPOA, the experiment was repeated in GABA neurone reporter mice (Vgat-tdTomato). Between 10% and 45% of RetroBead-labelled neurones in the ARC were GABAergic, whereas uptake of tracer by GABAergic neurones in the DMN and PMV was very low (< 5%). These results show that both leptin responsive and GABAergic neurones from the ARC project to the region of the GnRH cell bodies. Our findings suggest that LEPR-expressing GABA neurones from the ARC may be mediators of leptin-to-GnRH signalling.

  12. Glutamate alteration of glutamic acid decarboxylase (GAD) in GABAergic neurons: the role of cysteine proteases.

    PubMed

    Monnerie, Hubert; Le Roux, Peter D

    2008-09-01

    Brain cell vulnerability to neurologic insults varies greatly, depending on their neuronal subpopulation. Among cells that survive a pathological insult such as ischemia or brain trauma, some may undergo morphological and/or biochemical changes that could compromise brain function. We previously reported that surviving cortical GABAergic neurons exposed to glutamate in vitro displayed an NMDA receptor (NMDAR)-mediated alteration in the levels of the GABA synthesizing enzyme glutamic acid decarboxylase (GAD65/67) [Monnerie, H., Le Roux, P., 2007. Reduced dendrite growth and altered glutamic acid decarboxylase (GAD) 65- and 67-kDa isoform protein expression from mouse cortical GABAergic neurons following excitotoxic injury in vitro. Exp. Neurol. 205, 367-382]. In this study, we examined the mechanisms by which glutamate excitotoxicity caused a change in cortical GABAergic neurons' GAD protein levels. Removing extracellular calcium prevented the NMDAR-mediated decrease in GAD protein levels, measured using Western blot techniques, whereas inhibiting calcium entry through voltage-gated calcium channels had no effect. Glutamate's effect on GAD protein isoforms was significantly attenuated by preincubation with the cysteine protease inhibitor N-Acetyl-L-Leucyl-L-Leucyl-L-norleucinal (ALLN). Using class-specific protease inhibitors, we observed that ALLN's effect resulted from the blockade of calpain and cathepsin protease activities. Cell-free proteolysis assay confirmed that both proteases were involved in glutamate-induced alteration in GAD protein levels. Together these results suggest that glutamate-induced excitotoxic stimulation of NMDAR in cultured cortical neurons leads to altered GAD protein levels from GABAergic neurons through intracellular calcium increase and protease activation including calpain and cathepsin. Biochemical alterations in surviving cortical GABAergic neurons in various disease states may contribute to the altered balance between excitation

  13. Multiple roles for mTOR signaling in both glutamatergic and GABAergic synaptic transmission

    PubMed Central

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

    2012-01-01

    Summary The mammalian target of rapamycin (mTOR) signaling pathway in neurons integrates a variety of extracellular signals to produce appropriate translational responses. mTOR signaling is hyperactive in neurological syndromes in both humans and mouse models that are characterized by epilepsy, autism and cognitive disturbances. In addition, rapamycin, a clinically important immunosuppressant, is a specific and potent inhibitor of mTOR signaling. While mTOR is known to regulate growth and synaptic plasticity of glutamatergic neurons, its effects on basic parameters of synaptic transmission are less well studied, and its role in regulating GABAergic transmission is unexplored. We therefore performed an electrophysiological and morphological comparison of glutamatergic and GABAergic neurons in which mTOR signaling was either increased by loss of the repressor Pten or decreased by treatment with rapamycin. We found that hyperactive mTOR signaling increased evoked synaptic responses in both glutamatergic and GABAergic neurons by approximately 50%, due to an increase in the number of synaptic vesicles available for release, the number of synapses formed and the miniature event size. Prolonged (72 hours) rapamycin treatment prevented these abnormalities and also decreased synaptic transmission in wild-type glutamatergic, but not GABAergic, neurons. Further analyses suggested that hyperactivation of the mTOR pathway also impairs presynaptic function, possibly by interfering with vesicle fusion. Despite this presynaptic impairment, the net effect of Pten loss is enhanced synaptic transmission in both GABAergic and glutamatergic neurons, which has numerous implications – depending on where in the brain mutations of an mTOR suppressor gene takes place during development. PMID:22895726

  14. A Transgenic Mouse Line Expressing the Red Fluorescent Protein tdTomato in GABAergic Neurons

    PubMed Central

    Besser, Stefanie; Sicker, Marit; Marx, Grit; Winkler, Ulrike; Eulenburg, Volker; Hülsmann, Swen; Hirrlinger, Johannes

    2015-01-01

    GABAergic inhibitory neurons are a large population of neurons in the central nervous system (CNS) of mammals and crucially contribute to the function of the circuitry of the brain. To identify specific cell types and investigate their functions labelling of cell populations by transgenic expression of fluorescent proteins is a powerful approach. While a number of mouse lines expressing the green fluorescent protein (GFP) in different subpopulations of GABAergic cells are available, GFP expressing mouse lines are not suitable for either crossbreeding to other mouse lines expressing GFP in other cell types or for Ca2+-imaging using the superior green Ca2+-indicator dyes. Therefore, we have generated a novel transgenic mouse line expressing the red fluorescent protein tdTomato in GABAergic neurons using a bacterial artificial chromosome based strategy and inserting the tdTomato open reading frame at the start codon within exon 1 of the GAD2 gene encoding glutamic acid decarboxylase 65 (GAD65). TdTomato expression was observed in all expected brain regions; however, the fluorescence intensity was highest in the olfactory bulb and the striatum. Robust expression was also observed in cortical and hippocampal neurons, Purkinje cells in the cerebellum, amacrine cells in the retina as well as in cells migrating along the rostral migratory stream. In cortex, hippocampus, olfactory bulb and brainstem, 80% to 90% of neurons expressing endogenous GAD65 also expressed the fluorescent protein. Moreover, almost all tdTomato-expressing cells coexpressed GAD65, indicating that indeed only GABAergic neurons are labelled by tdTomato expression. This mouse line with its unique spectral properties for labelling GABAergic neurons will therefore be a valuable new tool for research addressing this fascinating cell type. PMID:26076353

  15. Prefrontal Cortical GABAergic Dysfunction Contributes to Age-Related Working Memory Impairment

    PubMed Central

    Bañuelos, Cristina; Beas, B. Sofia; McQuail, Joseph A.; Gilbert, Ryan J.; Frazier, Charles J.; Setlow, Barry

    2014-01-01

    Working memory functions supported by the prefrontal cortex decline in normal aging. Disruption of corticolimbic GABAergic inhibitory circuits can impair working memory in young subjects; however, relatively little is known regarding how aging impacts prefrontal cortical GABAergic signaling and whether such changes contribute to cognitive deficits. The current study used a rat model to evaluate the effects of aging on expression of prefrontal GABAergic synaptic proteins in relation to working memory decline, and to test whether pharmacological manipulations of prefrontal GABAergic signaling can improve working memory abilities in aged subjects. Results indicate that in aged medial prefrontal cortex (mPFC), expression of the vesicular GABA transporter VGAT was unchanged; however, there was a significant increase in expression of the GABA synthesizing enzyme GAD67, and a significant decrease in the primary neuronal GABA transporter GAT-1 and in both subunits of the GABA(B) receptor (GABA(B)R). Expression of VGAT, GAD67, and GAT-1 was not associated with working memory ability. In contrast, among aged rats, GABA(B)R expression was significantly and negatively associated with working memory performance, such that lower GABA(B)R expression predicted better working memory. Subsequent experiments showed that systemic administration of a GABA(B)R antagonist, CGP55845, dose-dependently enhanced working memory in aged rats. This enhancing effect of systemic CGP55845 was reproduced by direct intra-mPFC administration. Together, these data suggest that age-related dysregulation of GABAergic signaling in prefrontal cortex may play a causal role in impaired working memory and that targeting GABA(B)Rs may provide therapeutic benefit for age-related impairments in executive functions. PMID:24599447

  16. Activation of presynaptic kainate receptors suppresses GABAergic synaptic transmission in the rat globus pallidus

    PubMed Central

    Jin, Xiao-Tao; Smith, Yoland

    2007-01-01

    The globus pallidus (GP) plays a central integrative role in the basal ganglia circuitry. It receives strong GABAergic inputs from the striatum and significant glutamatergic afferents from the subthalamic nucleus (STN). The change in firing rate and pattern of GP neurons is a cardinal feature of Parkinson’s disease pathophysiology. Kainate receptor GluR6/7 subunits immunoreactivity is expressed presynaptically in GABAergic striatopallidal terminals (Kane-Jackson and Smith 2003; Jin et al., 2006), which provides a substrate for regulation of GABAergic transmission in GP. To test this hypothesis, we recorded GABAA-mediated inhibitory postsynaptic currents (IPSCs) in the GP following electrical stimulation of the striatum. Following blockade of AMPA and NMDA receptors with selective antagonists, bath application of kainate (KA) (0.3–3 μM) reduced significantly the amplitude of evoked IPSCs. This inhibition was associated with a significant increase in paired-pulse facilitation ratio and a reduction of the frequency, but not amplitude, of miniature IPSCs (mIPSCs), suggesting a presynaptic site of KA action. The KA effects on striatopallidal GABAergic transmission were blocked by the G-protein inhibitor, N-ethylmaleimide (NEM), or protein kinase C (PKC) inhibitor calphostin C. Our results demonstrate that KAR activation inhibits GABAergic transmission through a presynaptic G protein-coupled, PKC-dependent metabotropic mechanism in the rat GP. These findings open up the possibility for the development of kainate-mediated pharmacotherapies aim at decreasing the excessive and abnormally regulated inhibition of GP neurons in Parkinson’s disease. PMID:17881134

  17. Hairy/Enhancer-of-Split MEGANE and Proneural MASH1 Factors Cooperate Synergistically in Midbrain GABAergic Neurogenesis

    PubMed Central

    Wende, Clara-Zoe; Zoubaa, Saida; Blak, Alexandra; Echevarria, Diego; Martinez, Salvador; Guillemot, François; Wurst, Wolfgang; Guimera, Jordi

    2015-01-01

    GABAergic neurons are the primary inhibitory cell type in the mature brain and their dysfunction is associated with important neurological conditions like schizophrenia and anxiety. We aimed to discover the underlying mechanisms for dorsal/ventral midbrain GABAergic neurogenesis. Previous work by us and others has provided crucial insights into the key function of Mgn and Mash1 genes in determining GABAergic neurotransmitter fate. Induction of dorsal midbrain GABAergic neurons does not take place at any time during development in either of the single mutant mice. However, GABAergic neurons in the ventral midbrain remained unchanged. Thus, the similarities in MB-GABAergic phenotype observed in the Mgn and Mash1 single mutants suggest the existence of other factors that take over the function of MGN and MASH1 in the ventral midbrain or the existence of different molecular mechanisms. We show that this process essentially depends on heterodimers and homodimers formed by MGN and MASH1 and deciphered the in vivo relevance of the interaction by phenotypic analysis of Mgn/Mash1 double knockout and compound mice. Furthermore, the combination of gain- and loss-of-function experiments in the developing midbrain showed co-operative roles for Mgn and Mash1 genes in determining GABAergic identity. Transcription factors belonging to the Enhancer-of-split-related and proneural families have long been believed to counterpart each other’s function. This work uncovers a synergistic cooperation between these two families, and provides a novel paradigm for how these two families cooperate for the acquisition of MB-GABAergic neuronal identity. Understanding their molecular mechanisms is essential for cell therapy strategies to amend GABAergic deficits. PMID:25993409

  18. GABAergic and glycinergic inhibitory synaptic transmission in the ventral cochlear nucleus studied in VGAT channelrhodopsin-2 mice.

    PubMed

    Xie, Ruili; Manis, Paul B

    2014-01-01

    Both glycine and GABA mediate inhibitory synaptic transmission in the ventral cochlear nucleus (VCN). In mice, the time course of glycinergic inhibition is slow in bushy cells and fast in multipolar (stellate) cells, and is proposed to contribute to the processing of temporal cues in both cell types. Much less is known about GABAergic synaptic transmission in this circuit. Electrical stimulation of the auditory nerve or the tuberculoventral pathway evokes little GABAergic synaptic current in brain slice preparations, and spontaneous GABAergic miniature synaptic currents occur infrequently. To investigate synaptic currents carried by GABA receptors in bushy and multipolar cells, we used transgenic mice in which channelrhodopsin-2 and EYFP is driven by the vesicular GABA transporter (VGAT-ChR2-EYFP) and is expressed in both GABAergic and glycinergic neurons. Light stimulation evoked action potentials in EYFP-expressing presynaptic cells, and evoked inhibitory postsynaptic potentials (IPSPs) in non-expressing bushy and planar multipolar cells. Less than 10% of the IPSP amplitude in bushy cells arose from GABAergic synapses, whereas 40% of the IPSP in multipolar neurons was GABAergic. In voltage clamp, glycinergic IPSCs were significantly slower in bushy neurons than in multipolar neurons, whereas there was little difference in the kinetics of the GABAergic IPSCs between two cell types. During prolonged stimulation, the ratio of steady state vs. peak IPSC amplitude was significantly lower for glycinergic IPSCs. Surprisingly, the reversal potentials of GABAergic IPSCs were negative to those of glycinergic IPSCs in both bushy and multipolar neurons. In the absence of receptor blockers, repetitive light stimulation was only able to effectively evoke IPSCs up to 20 Hz in both bushy and multipolar neurons. We conclude that local GABAergic release within the VCN can differentially influence bushy and multipolar cells.

  19. Extracellular Molecular Markers and Soma Size of Inhibitory Neurons: Evidence for Four Subtypes of GABAergic Cells in the Inferior Colliculus

    PubMed Central

    Beebe, Nichole L.; Young, Jesse W.; Mellott, Jeffrey G.

    2016-01-01

    Inhibition plays an important role in shaping responses to stimuli throughout the CNS, including in the inferior colliculus (IC), a major hub in both ascending and descending auditory pathways. Subdividing GABAergic cells has furthered the understanding of inhibition in many brain areas, most notably in the cerebral cortex. Here, we seek the same understanding of subcortical inhibitory cell types by combining staining for two types of extracellular markers—perineuronal nets (PNs) and perisomatic rings of terminals expressing vesicular glutamate transporter 2 (VGLUT2) —to subdivide IC GABAergic cells in adult guinea pigs. We found four distinct groups of GABAergic cells in the IC: (1) those with both a PN and a VGLUT2 ring; (2) those with only a PN; (3) those with only a VGLUT2 ring; and (4) those with neither marker. In addition, these four GABAergic subtypes differ in their soma size and distribution among IC subdivisions. Functionally, the presence or absence of VGLUT2 rings indicates differences in inputs, whereas the presence or absence of PNs indicates different potential for plasticity and temporal processing. We conclude that these markers distinguish four GABAergic subtypes that almost certainly serve different roles in the processing of auditory stimuli within the IC. SIGNIFICANCE STATEMENT GABAergic inhibition plays a critical role throughout the brain. Identification of subclasses of GABAergic cells (up to 15 in the cerebral cortex) has furthered the understanding of GABAergic roles in circuit modulation. Inhibition is also prominent in the inferior colliculus, a subcortical hub in auditory pathways. Here, we use two extracellular markers to identify four distinct groups of GABAergic cells. Perineuronal nets and perisomatic rings of glutamatergic boutons are present in many subcortical areas and often are associated with inhibitory cells, but they have rarely been used to identify inhibitory subtypes. Our results further the understanding of

  20. Distinct behavioral consequences of short-term and prolonged GABAergic depletion in prefrontal cortex and dorsal hippocampus

    PubMed Central

    Reichel, Judith M.; Nissel, Sabine; Rogel-Salazar, Gabriela; Mederer, Anna; Käfer, Karola; Bedenk, Benedikt T.; Martens, Henrik; Anders, Rebecca; Grosche, Jens; Michalski, Dominik; Härtig, Wolfgang; Wotjak, Carsten T.

    2015-01-01

    GABAergic interneurons are essential for a functional equilibrium between excitatory and inhibitory impulses throughout the CNS. Disruption of this equilibrium can lead to various neurological or neuropsychiatric disorders such as epilepsy or schizophrenia. Schizophrenia itself is clinically defined by negative (e.g., depression) and positive (e.g., hallucinations) symptoms as well as cognitive dysfunction. GABAergic interneurons are proposed to play a central role in the etiology and progression of schizophrenia; however, the specific mechanisms and the time-line of symptom development as well as the distinct involvement of cortical and hippocampal GABAergic interneurons in the etiology of schizophrenia-related symptoms are still not conclusively resolved. Previous work demonstrated that GABAergic interneurons can be selectively depleted in adult mice by means of saporin-conjugated anti-vesicular GABA transporter antibodies (SAVAs) in vitro and in vivo. Given their involvement in schizophrenia-related disease etiology, we ablated GABAergic interneurons in the medial prefrontal cortex (mPFC) and dorsal hippocampus (dHPC) in adult male C57BL/6N mice. Subsequently we assessed alterations in anxiety, sensory processing, hyperactivity and cognition after long-term (>14 days) and short-term (<14 days) GABAergic depletion. Long-term GABAergic depletion in the mPFC resulted in a decrease in sensorimotor-gating and impairments in cognitive flexibility. Notably, the same treatment at the level of the dHPC completely abolished spatial learning capabilities. Short-term GABAergic depletion in the dHPC revealed a transient hyperactive phenotype as well as marked impairments regarding the acquisition of a spatial memory. In contrast, recall of a spatial memory was not affected by the same intervention. These findings emphasize the importance of functional local GABAergic networks for the encoding but not the recall of hippocampus-dependent spatial memories. PMID:25628548

  1. Distinct behavioral consequences of short-term and prolonged GABAergic depletion in prefrontal cortex and dorsal hippocampus.

    PubMed

    Reichel, Judith M; Nissel, Sabine; Rogel-Salazar, Gabriela; Mederer, Anna; Käfer, Karola; Bedenk, Benedikt T; Martens, Henrik; Anders, Rebecca; Grosche, Jens; Michalski, Dominik; Härtig, Wolfgang; Wotjak, Carsten T

    2014-01-01

    GABAergic interneurons are essential for a functional equilibrium between excitatory and inhibitory impulses throughout the CNS. Disruption of this equilibrium can lead to various neurological or neuropsychiatric disorders such as epilepsy or schizophrenia. Schizophrenia itself is clinically defined by negative (e.g., depression) and positive (e.g., hallucinations) symptoms as well as cognitive dysfunction. GABAergic interneurons are proposed to play a central role in the etiology and progression of schizophrenia; however, the specific mechanisms and the time-line of symptom development as well as the distinct involvement of cortical and hippocampal GABAergic interneurons in the etiology of schizophrenia-related symptoms are still not conclusively resolved. Previous work demonstrated that GABAergic interneurons can be selectively depleted in adult mice by means of saporin-conjugated anti-vesicular GABA transporter antibodies (SAVAs) in vitro and in vivo. Given their involvement in schizophrenia-related disease etiology, we ablated GABAergic interneurons in the medial prefrontal cortex (mPFC) and dorsal hippocampus (dHPC) in adult male C57BL/6N mice. Subsequently we assessed alterations in anxiety, sensory processing, hyperactivity and cognition after long-term (>14 days) and short-term (<14 days) GABAergic depletion. Long-term GABAergic depletion in the mPFC resulted in a decrease in sensorimotor-gating and impairments in cognitive flexibility. Notably, the same treatment at the level of the dHPC completely abolished spatial learning capabilities. Short-term GABAergic depletion in the dHPC revealed a transient hyperactive phenotype as well as marked impairments regarding the acquisition of a spatial memory. In contrast, recall of a spatial memory was not affected by the same intervention. These findings emphasize the importance of functional local GABAergic networks for the encoding but not the recall of hippocampus-dependent spatial memories.

  2. GABAergic and glycinergic inhibitory synaptic transmission in the ventral cochlear nucleus studied in VGAT channelrhodopsin-2 mice

    PubMed Central

    Xie, Ruili; Manis, Paul B.

    2014-01-01

    Both glycine and GABA mediate inhibitory synaptic transmission in the ventral cochlear nucleus (VCN). In mice, the time course of glycinergic inhibition is slow in bushy cells and fast in multipolar (stellate) cells, and is proposed to contribute to the processing of temporal cues in both cell types. Much less is known about GABAergic synaptic transmission in this circuit. Electrical stimulation of the auditory nerve or the tuberculoventral pathway evokes little GABAergic synaptic current in brain slice preparations, and spontaneous GABAergic miniature synaptic currents occur infrequently. To investigate synaptic currents carried by GABA receptors in bushy and multipolar cells, we used transgenic mice in which channelrhodopsin-2 and EYFP is driven by the vesicular GABA transporter (VGAT-ChR2-EYFP) and is expressed in both GABAergic and glycinergic neurons. Light stimulation evoked action potentials in EYFP-expressing presynaptic cells, and evoked inhibitory postsynaptic potentials (IPSPs) in non-expressing bushy and planar multipolar cells. Less than 10% of the IPSP amplitude in bushy cells arose from GABAergic synapses, whereas 40% of the IPSP in multipolar neurons was GABAergic. In voltage clamp, glycinergic IPSCs were significantly slower in bushy neurons than in multipolar neurons, whereas there was little difference in the kinetics of the GABAergic IPSCs between two cell types. During prolonged stimulation, the ratio of steady state vs. peak IPSC amplitude was significantly lower for glycinergic IPSCs. Surprisingly, the reversal potentials of GABAergic IPSCs were negative to those of glycinergic IPSCs in both bushy and multipolar neurons. In the absence of receptor blockers, repetitive light stimulation was only able to effectively evoke IPSCs up to 20 Hz in both bushy and multipolar neurons. We conclude that local GABAergic release within the VCN can differentially influence bushy and multipolar cells. PMID:25104925

  3. Microcircuits of excitatory and inhibitory neurons in layer 2/3 of mouse barrel cortex.

    PubMed

    Avermann, Michael; Tomm, Christian; Mateo, Celine; Gerstner, Wulfram; Petersen, Carl C H

    2012-06-01

    Synaptic interactions between nearby excitatory and inhibitory neurons in the neocortex are thought to play fundamental roles in sensory processing. Here, we have combined optogenetic stimulation, whole cell recordings, and computational modeling to define key functional microcircuits within layer 2/3 of mouse primary somatosensory barrel cortex. In vitro optogenetic stimulation of excitatory layer 2/3 neurons expressing channelrhodopsin-2 evoked a rapid sequence of excitation followed by inhibition. Fast-spiking (FS) GABAergic neurons received large-amplitude, fast-rising depolarizing postsynaptic potentials, often driving action potentials. In contrast, the same optogenetic stimulus evoked small-amplitude, subthreshold postsynaptic potentials in excitatory and non-fast-spiking (NFS) GABAergic neurons. To understand the synaptic mechanisms underlying this network activity, we investigated unitary synaptic connectivity through multiple simultaneous whole cell recordings. FS GABAergic neurons received unitary excitatory postsynaptic potentials with higher probability, larger amplitudes, and faster kinetics compared with NFS GABAergic neurons and other excitatory neurons. Both FS and NFS GABAergic neurons evoked robust inhibition on postsynaptic layer 2/3 neurons. A simple computational model based on the experimentally determined electrophysiological properties of the different classes of layer 2/3 neurons and their unitary synaptic connectivity accounted for key aspects of the network activity evoked by optogenetic stimulation, including the strong recruitment of FS GABAergic neurons acting to suppress firing of excitatory neurons. We conclude that FS GABAergic neurons play an important role in neocortical microcircuit function through their strong local synaptic connectivity, which might contribute to driving sparse coding in excitatory layer 2/3 neurons of mouse barrel cortex in vivo.

  4. Brain-derived neurotrophic factor mediates the activity-dependent regulation of inhibition in neocortical cultures.

    PubMed

    Rutherford, L C; DeWan, A; Lauer, H M; Turrigiano, G G

    1997-06-15

    The excitability of cortical circuits is modulated by interneurons that release the inhibitory neurotransmitter GABA. In primate and rodent visual cortex, activity deprivation leads to a decrease in the expression of GABA. This suggests that activity is able to adjust the strength of cortical inhibition, but this has not been demonstrated directly. In addition, the nature of the signal linking activity to GABA expression has not been determined. Activity is known to regulate the expression of the neurotrophin brain-derived neurotrophic factor (BDNF), and BDNF has been shown to influence the phenotype of GABAergic interneurons. We use a culture system from postnatal rat visual cortex to test the hypothesis that activity is regulating the strength of cortical inhibition through the regulation of BDNF. Cultures were double-labeled against GABA and the neuronal marker MAP2, and the percentage of neurons that were GABA-positive was determined. Blocking spontaneous activity in these cultures reversibly decreased the number of GABA-positive neurons without affecting neuronal survival. Voltage-clamp analysis of inhibitory currents demonstrated that activity blockade also decreased GABA-mediated inhibition onto pyramidal neurons and raised pyramidal neuron firing rates. All of these effects were prevented by incubation with BDNF during activity blockade, but not by neurotrophin 3 or nerve growth factor. Additionally, blockade of neurotrophin signaling mimicked the effects of activity blockade on GABA expression. These data suggest that activity regulates cortical inhibition through a BDNF-dependent mechanism and that this neurotrophin plays an important role in the control of cortical excitability.

  5. Projections from fetal neocortical transplants placed in the frontal neocortex of newborn rats. A Phaseolus vulgaris-leucoagglutinin tracing study.

    PubMed

    Sørensen, J C; Castro, A J; Klausen, B; Zimmer, J

    1992-01-01

    Fetal rat neocortex grafted into lesion cavities made in the newborn rat neocortex can exchange multiple axonal connections with the host brain. Most previous studies demonstrating efferent transplant-to-host brain connections have used fluorescent retrograde tracers injected into the host brain (Castro et al. 1985, 1987; Floeter and Jones 1984; O'Leary and Stanfield 1989). Other studies have used anterograde axonal tracing with either tritium-labelled amino acids impregnating the transplant and its efferents (Floeter and Jones 1985) or horseradish peroxidase injected into the transplants (Chang et al. 1984, 1986). In the present study we used the anterograde axonal tracer Phaseolus vulgaris-leucoagglutinin (PHA-L) to examine in detail the course and termination of the efferent neocortical graft fibers. Twenty-six newborn rats had the right frontal cortex forepaw area removed by vacuum aspiration, while anesthetized by hypothermia. A piece of fetal frontal cortex 14-16 embryonic days old (E14-16) was immediately thereafter placed in the lesion, and the recipient rats allowed to survive for 5-7 months. At this time the rats were reoperated under sodium pentobarbital (Nembutal) anesthesia and the transplants iontophoretically injected with PHA-L. Two weeks later the animals were again anesthetized, perfused, and processed for PHA-L immunocytochemistry and routine histology. Analysis of acetylcholinesterase- (AChE) and Nissl-stained sections showed graft survival in 19 of the 26 animals used in this study. When these 19 brains were processed for PHA-L immunocytochemistry, 5 of them were found with certainty to have the PHA-L injection confined to the transplant. Based on these cases PHA-L-reactive fibers arising from labelled transplant neurons were traced into the ipsilateral host neocortex adjacent to the transplant and found to project through the subcortical white matter to the ipsilateral parietal neocortical area 1, and claustrum. Callosal fibers were traced to

  6. DEVELOPMENTAL HYPOTHYROIDISM REDUCES PARVALBUMIN EXPRESSION IN GABAERGIC NEURONS OF CORTEX AND HIPPOCAMPUS: IMMUNOHISTOCHEMICAL FINDINGS AND FUNCTIONAL CORRELATES.

    EPA Science Inventory

    GABAergic interneurons comprise the bulk of local inhibitory neuronal circuitry in cortex and hippocampus and a subpopulation of these interneurons contain the calcium binding protein, parvalbumin (PV). A previous report indicated that severe hypothyroidism reduced PV immunoreact...

  7. Medial septum-diagonal band of Broca (MSDB) GABAergic regulation of hippocampal acetylcholine efflux is dependent on cognitive demands.

    PubMed

    Roland, Jessica J; Stewart, Amanda L; Janke, Kellie L; Gielow, Matthew R; Kostek, John A; Savage, Lisa M; Servatius, Richard J; Pang, Kevin C H

    2014-01-08

    The septohippocampal pathway contains cholinergic, GABAergic, and glutamatergic projections and has an established role in learning, memory, and hippocampal theta rhythm. Both GABAergic and cholinergic neurons in the medial septum-diagonal band of Broca (MSDB) have been associated with spatial memory, but the relationship between the two neuronal populations is not fully understood. The present study investigated the effect of selective GABAergic MSDB lesions on hippocampal acetylcholine (ACh) efflux and spatial memory during tasks that varied in memory demand. Male Sprague Dawley rats were given GABAergic lesions of the MSDB using GAT1-saporin (GAT1-SAP) and examined on spontaneous exploration (Experiment 1) and non-matching to position without (NMTP; Experiment 2) and with a delay (DNMTP; Experiment 3), while concurrently using in vivo microdialysis to measure hippocampal ACh efflux. Intraseptal GAT1-SAP treatment did not alter baseline or behaviorally stimulated hippocampal ACh efflux or maze exploration (Experiment 1). Moreover, GAT1-SAP did not alter evoked hippocampal ACh efflux related to NMTP nor did it impair working memory in NMTP (Experiment 2). In contrast, both ACh efflux and performance in DNMTP were impaired by intraseptal GAT1-SAP. Thus, GABAergic MSDB neurons are important for spatial working memory and modulate hippocampal ACh efflux under conditions of high memory load. The relationship between the septohippocampal cholinergic and GABAergic systems and working memory will be discussed.

  8. An interneuron progenitor maintains neurogenic potential in vivo and differentiates into GABAergic interneurons after transplantation in the postnatal rat brain.

    PubMed

    Wang, Qi; Hong, Peiwei; Gao, Hui; Chen, Yuntian; Yang, Qi; Jiang, Mei; Li, Hedong

    2016-01-11

    Dysfunction of cortical GABAergic interneurons are involved in numerous neurological disorders including epilepsy, schizophrenia and autism; and replenishment of these cells by transplantation strategy has proven to be a feasible and effective method to help revert the symptoms in several animal models. To develop methodology of generating transplantable GABAergic interneurons for therapy, we previously reported the isolation of a v-myc-induced GABAergic interneuron progenitor clone GE6 from embryonic ganglionic eminence (GE). These cells can proliferate and form functional inhibitory synapses in culture. Here, we tested their differentiation behavior in vivo by transplanting them into the postnatal rat forebrain. We found that GE6 cells migrate extensively in the neonatal forebrain and differentiate into both neurons and glia, but preferentially into neurons when compared with a sister progenitor clone CTX8. The neurogenic potential of GE6 cells is also maintained after transplantation into a non-permissive environment such as adult cortex or when treated with inflammatory cytokine in culture. The GE6-derived neurons were able to mature in vivo as GABAergic interneurons expressing GABAergic, not glutamatergic, presynaptic puncta. Finally, we propose that v-myc-induced human interneuron progenitor clones could be an alternative cell source of transplantable GABAergic interneurons for treating related neurological diseases in future clinic.

  9. Human olfactory consciousness and cognition: its unusual features may not result from unusual functions but from limited neocortical processing resources

    PubMed Central

    Stevenson, Richard J.; Attuquayefio, Tuki

    2013-01-01

    Human and animal olfactory perception is shaped both by functional demands and by various environmental constraints seemingly peculiar to chemical stimuli. These demands and constraints may have generated a sensory system that is cognitively distinct from the major senses. In this article we identify these various functional demands and constraints, and examine whether they can be used to account for olfaction's unique cognitive features on a case-by-case basis. We then use this as grounds to argue that specific conscious processes do have functional value, a finding that naturally emerges when a comparative approach to consciousness across the senses is adopted. More generally, we conclude that certain peculiar features of olfactory cognition may owe more to limited neocortical processing resources, than they do to the challenges faced by perceiving chemical stimuli. PMID:24198808

  10. Homology of the mesopallium in the adult chicken identified by gene expression of the neocortical marker cholecystokinin.

    PubMed

    Atoji, Yasuro; Karim, Mohammad Rabiul

    2014-03-06

    Studies of gene expression and fiber connections have suggested that the primary visual (entopallium) and auditory (field L2) centers in the avian telencephalon are homologous to layer 4 of extrastriate and auditory neocortices of mammals, respectively. In addition, it has been proposed that the arcopallium contains neurons homologous to layers 5/6 and that the mesopallium may be homologous to superficial neocortical layers, but gene expression evidence for the latter is lacking in adult birds. In the present study using adult chickens we have examined the gene expression of cholecystokinin (CCK) mRNA, a selective marker for layers 2/3 of mammalian neocortex. CCK mRNA was expressed in neurons of the entire mesopallium, but not in any part of the nidopallium. Together with hodological evidence of connections between the mesopallium and the two primary sensory areas, our results are consistent with the suggestion that the mesopallium is comparable to certain superficial layers of mammalian neocortex.

  11. The impact of NMDA Receptor hypofunction on GABAergic interneurons in the pathophysiology of schizophrenia

    PubMed Central

    Cohen, Samuel M.; Tsien, Richard W.; Goff, Donald C.; Halassa, Michael M.

    2016-01-01

    While the dopamine hypothesis has dominated schizophrenia research for several decades, more recent studies have highlighted the role of fast synaptic transmitters and their receptors in schizophrenia etiology. Here we review evidence that schizophrenia is associated with a reduction in N-methyl-D-aspartate receptor (NMDAR) function. By highlighting post mortem, neuroimaging and electrophysiological studies, we provide evidence for preferential disruption of GABAergic circuits in the context of NMDAR hypo-activity states. The functional relationship between NMDARs and GABAergic neurons is realized at the molecular, cellular, microcircuit and systems levels. A synthesis of findings across these levels explains how NMDA-mediated inhibitory dysfunction may lead to aberrant interactions among brain regions, accounting for key clinical features of schizophrenia. This synthesis of schizophrenia unifies observations from diverse fields and may help chart pathways for developing novel diagnostics and therapeutics. PMID:25583246

  12. 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

  13. Role of Prelimbic GABAergic Circuits in Sensory and Emotional Aspects of Neuropathic Pain.

    PubMed

    Zhang, Zizhen; Gadotti, Vinicius M; Chen, Lina; Souza, Ivana A; Stemkowski, Patrick L; Zamponi, Gerald W

    2015-08-04

    Noxious stimuli are detected by peripheral nociceptors and then transmitted to higher CNS centers, where they are perceived as an unpleasant sensation. The mechanisms that govern the emotional component associated with pain are still incompletely understood. Here, we used optogenetic approaches both in vitro and in vivo to address this issue. We found that peripheral nerve injury inhibits pyramidal cell firing in the prelimbic area of the prefrontal cortex as a result of feed-forward inhibition mediated by parvalbumin-expressing GABAergic interneurons. In addition, activation of inhibitory archaerhodopsin or excitatory channelrhodopsin-2 in these neurons decreased and increased pain responses, respectively, in freely moving mice and accordingly modulated conditioned place preference scores and place escape/avoidance behavior. Our findings thus demonstrate an important role of the prelimbic area in sensory and emotional aspects of pain and identify GABAergic circuits in this region as a potential target for pain therapeutics.

  14. Forebrain GABAergic neuron precursors integrate into adult spinal cord and reduce injury-induced neuropathic pain

    PubMed Central

    Bráz, JM; Sharif-Naeini, R; Vogt, D; Kriegstein, A; Alvarez-Buylla, A; Rubenstein, JL; Basbaum, AI

    2012-01-01

    Neuropathic pain is a chronic debilitating disease characterized by mechanical allodynia and spontaneous pain. Because symptoms are often unresponsive to conventional methods of pain treatment, new therapeutic approaches are essential. Here, we describe a strategy that not only ameliorates symptoms of neuropathic pain, but is also potentially disease modifying. We show that transplantation of immature telencephalic GABAergic interneurons from the mouse medial ganglionic eminence (MGE) into the adult mouse spinal cord completely reverses the mechanical hypersensitivity produced by peripheral nerve injury. Underlying this improvement is a remarkable integration of the MGE transplants into the host spinal cord circuitry, in which the transplanted cells make functional connections with both primary afferent and spinal cord neurons. By contrast, MGE transplants were not effective against inflammatory pain. Our findings suggest that MGE-derived GABAergic interneurons overcome the spinal cord hyperexcitability that is a hallmark of nerve-injury induced neuropathic pain. PMID:22632725

  15. Optogenetic activation of septal GABAergic afferents entrains neuronal firing in the medial habenula

    PubMed Central

    Choi, Kyuhyun; Lee, Youngin; Lee, Changwoo; Hong, Seokheon; Lee, Soonje; Kang, Shin Jung; Shin, Ki Soon

    2016-01-01

    The medial habenula (MHb) plays an important role in nicotine-related behaviors such as nicotine aversion and withdrawal. The MHb receives GABAergic input from the medial septum/diagonal band of Broca (MS/DB), yet the synaptic mechanism that regulates MHb activity is unclear. GABA (γ -aminobutyric acid) is a major inhibitory neurotransmitter activating both GABAA receptors and GABAB receptors. Depending on intracellular chloride concentration, however, GABAA receptors also function in an excitatory manner. In the absence of various synaptic inputs, we found that MHb neurons displayed spontaneous tonic firing at a rate of about ~4.4 Hz. Optogenetic stimulation of MS/DB inputs to the MHb evoked GABAA receptor-mediated synaptic currents, which produced stimulus-locked neuronal firing. Subsequent delayed yet lasting activation of GABAB receptors attenuated the intrinsic tonic firing. Consequently, septal GABAergic input alone orchestrates both excitatory GABAA and inhibitory GABAB receptors, thereby entraining the firing of MHb neurons. PMID:27703268

  16. Tcf3 Represses Wnt–β-Catenin Signaling and Maintains Neural Stem Cell Population during Neocortical Development

    PubMed Central

    Itoh, Yasuhiro; Hirabayashi, Yusuke; Gotoh, Yukiko

    2014-01-01

    During mouse neocortical development, the Wnt–β-catenin signaling pathway plays essential roles in various phenomena including neuronal differentiation and proliferation of neural precursor cells (NPCs). Production of the appropriate number of neurons without depletion of the NPC population requires precise regulation of the balance between differentiation and maintenance of NPCs. However, the mechanism that suppresses Wnt signaling to prevent premature neuronal differentiation of NPCs is poorly understood. We now show that the HMG box transcription factor Tcf3 (also known as Tcf7l1) contributes to this mechanism. Tcf3 is highly expressed in undifferentiated NPCs in the mouse neocortex, and its expression is reduced in intermediate neuronal progenitors (INPs) committed to the neuronal fate. We found Tcf3 to be a repressor of Wnt signaling in neocortical NPCs in a reporter gene assay. Tcf3 bound to the promoter of the proneural bHLH gene Neurogenin1 (Neurog1) and repressed its expression. Consistent with this, Tcf3 repressed neuronal differentiation and increased the self-renewal activity of NPCs. We also found that Wnt signal stimulation reduces the level of Tcf3, and increases those of Tcf1 (also known as Tcf7) and Lef1, positive mediators of Wnt signaling, in NPCs. Together, these results suggest that Tcf3 antagonizes Wnt signaling in NPCs, thereby maintaining their undifferentiated state in the neocortex and that Wnt signaling promotes the transition from Tcf3-mediated repression to Tcf1/Lef1-mediated enhancement of Wnt signaling, constituting a positive feedback loop that facilitates neuronal differentiation. PMID:24832538

  17. Activity-dependent endogenous taurine release facilitates excitatory neurotransmission in the neocortical marginal zone of neonatal rats.

    PubMed

    Qian, Taizhe; Chen, Rongqing; Nakamura, Masato; Furukawa, Tomonori; Kumada, Tatsuro; Akita, Tenpei; Kilb, Werner; Luhmann, Heiko J; Nakahara, Daiichiro; Fukuda, Atsuo

    2014-01-01

    In the developing cerebral cortex, the marginal zone (MZ), consisting of early-generated neurons such as Cajal-Retzius cells, plays an important role in cell migration and lamination. There is accumulating evidence of widespread excitatory neurotransmission mediated by γ-aminobutyric acid (GABA) in the MZ. Cajal-Retzius cells express not only GABAA receptors but also α2/β subunits of glycine receptors, and exhibit glycine receptor-mediated depolarization due to high [Cl(-)]i. However, the physiological roles of glycine receptors and their endogenous agonists during neurotransmission in the MZ are yet to be elucidated. To address this question, we performed optical imaging from the MZ using the voltage-sensitive dye JPW1114 on tangential neocortical slices of neonatal rats. A single electrical stimulus evoked an action-potential-dependent optical signal that spread radially over the MZ. The amplitude of the signal was not affected by glutamate receptor blockers, but was suppressed by either GABAA or glycine receptor antagonists. Combined application of both antagonists nearly abolished the signal. Inhibition of Na(+), K(+)-2Cl(-) cotransporter by 20 µM bumetanide reduced the signal, indicating that this transporter contributes to excitation. Analysis of the interstitial fluid obtained by microdialysis from tangential neocortical slices with high-performance liquid chromatography revealed that GABA and taurine, but not glycine or glutamate, were released in the MZ in response to the electrical stimulation. The ambient release of taurine was reduced by the addition of a voltage-sensitive Na(+) channel blocker. Immunohistochemistry and immunoelectron microscopy indicated that taurine was stored both in Cajal-Retzius and non-Cajal-Retzius cells in the MZ, but was not localized in presynaptic structures. Our results suggest that activity-dependent non-synaptic release of endogenous taurine facilitates excitatory neurotransmission through activation of glycine

  18. Noradrenaline induces IPSCs in rat medial septal/diagonal band neurons: involvement of septohippocampal GABAergic neurons.

    PubMed Central

    Alreja, M; Liu, W

    1996-01-01

    1. The physiological and pharmacological actions of noradrenaline (NA) on neurons of the medial septum and diagonal band of Broca (MSDB) were examined using extracellular, intracellular and whole-cell patch-clamp recordings in an in vitro rat brain slice preparation. 2. In current- and voltage-clamp recordings with KCl- or potassium gluconate-containing electrodes, bath-applied NA increased the number of tetrodoxin- and bicuculline-sensitive synaptic events in > 80% of cholinergic- and GABA-type neurons tested. The NA-induced synaptic activity originated from GABAergic neurons located within the MSDB itself, as a similar effect occurred in brain slices in which the MSDB had been surgically isolated from neighbouring structures. 3. In antidromic studies, NA dose-dependently increased firing in a subpopulation of septohippocampal neurons with fast conducting fibres (mean conduction velocity, 1.78 +/- 0.10 m s-1; presumably GABAergic). The NA excitation was mimicked by the alpha 1-agonist phenylephrine (PE) and blocked by the alpha 1-antagonists prazosin and WB-4101, suggesting the presence of alpha 1-receptors on septohippocampal GABAergic neurons. 4. Similarly, in whole-cell recordings in both cholinergic- and non-cholinergic-type MSDB neurons, prazosin blocked the effects of NA and PE mimicked the effects of NA by inducing IPSCs with a similar amplitude distribution. 5. Consistent with the above findings, GABA-type neurons that responded directly to NA and PE with a prazosin-sensitive inward current were found within the MSDB. 6. In conclusion, NA, via alpha 1-adrenoceptors, excites MSDB septohippocampal GABAergic neurons and influences both septal and septohippocampal circuitry. Images Figure 1 PMID:8814616

  19. Developmental changes in the acute ethanol sensitivity of glutamatergic and GABAergic transmission in the BNST.

    PubMed

    Wills, T A; Kash, T L; Winder, D G

    2013-11-01

    Glutamatergic and GABAergic transmission undergo significant changes during adolescence. Receptors for both of these transmitters (NMDAR, and GABAA) are known to be key targets for the acute effects of ethanol in adults. The current study set out to investigate the acute effects of ethanol on both NMDAR-mediated excitatory transmission and GABAergic inhibitory transmission within the bed nucleus of the stria terminalis (BNST) across age. The BNST is an area of the brain implicated in the negative reinforcing properties associated with alcohol dependence, and the BNST plays a critical role in stress-induced relapse. Therefore, assessing the developmental regulation of ethanol sensitivity in this key brain region is important to understanding the progression of ethanol dependence. To do this, whole-cell recordings of isolated NMDAR-evoked excitatory postsynaptic currents (eEPSCs) or evoked GABAergic inhibitory postsynaptic currents (eIPSCs) were performed on BNST neurons in slices from 4- or 8-week-old male C57BL/6J mice. Ethanol (50 mm) produced greater inhibition of NMDAR-eEPSCs in adolescent mice than in adult mice. This enhanced sensitivity in adolescence was not a result of shifts in function of the GluN2B subunit of the NMDAR, measured by Ro25-6981 inhibition and decay kinetics measured across age. Adolescent mice also exhibited greater ethanol sensitivity of GABAergic transmission, as ethanol (50 mm) enhanced eIPSCs in the BNST of adolescent but not adult mice. Collectively, this work illustrates that a moderate dose of ethanol produces greater inhibition of transmission in the BNST (through greater excitatory inhibition and enhancement of inhibitory transmission) in adolescents compared to adults. Given the role of the BNST in alcohol dependence, these developmental changes in acute ethanol sensitivity could accelerate neuroadaptations that result from chronic ethanol use during the critical period of adolescence.

  20. Differential Control of Cocaine Self-Administration by GABAergic and Glutamatergic CB1 Cannabinoid Receptors.

    PubMed

    Martín-García, Elena; Bourgoin, Lucie; Cathala, Adeline; Kasanetz, Fernando; Mondesir, Miguel; Gutiérrez-Rodriguez, Ana; Reguero, Leire; Fiancette, Jean-François; Grandes, Pedro; Spampinato, Umberto; Maldonado, Rafael; Piazza, Pier Vincenzo; Marsicano, Giovanni; Deroche-Gamonet, Véronique

    2016-08-01

    The type 1 cannabinoid receptor (CB1) modulates numerous neurobehavioral processes and is therefore explored as a target for the treatment of several mental and neurological diseases. However, previous studies have investigated CB1 by targeting it globally, regardless of its two main neuronal localizations on glutamatergic and GABAergic neurons. In the context of cocaine addiction this lack of selectivity is critical since glutamatergic and GABAergic neuronal transmission is involved in different aspects of the disease. To determine whether CB1 exerts different control on cocaine seeking according to its two main neuronal localizations, we used mutant mice with deleted CB1 in cortical glutamatergic neurons (Glu-CB1) or in forebrain GABAergic neurons (GABA-CB1). In Glu-CB1, gene deletion concerns the dorsal telencephalon, including neocortex, paleocortex, archicortex, hippocampal formation and the cortical portions of the amygdala. In GABA-CB1, it concerns several cortical and non-cortical areas including the dorsal striatum, nucleus accumbens, thalamic, and hypothalamic nuclei. We tested complementary components of cocaine self-administration, separating the influence of primary and conditioned effects. Mechanisms underlying each phenotype were explored using in vivo microdialysis and ex vivo electrophysiology. We show that CB1 expression in forebrain GABAergic neurons controls mouse sensitivity to cocaine, while CB1 expression in cortical glutamatergic neurons controls associative learning processes. In accordance, in the nucleus accumbens, GABA-CB1 receptors control cocaine-induced dopamine release and Glu-CB1 receptors control AMPAR/NMDAR ratio; a marker of synaptic plasticity. Our findings demonstrate a critical distinction of the altered balance of Glu-CB1 and GABA-CB1 activity that could participate in the vulnerability to cocaine abuse and addiction. Moreover, these novel insights advance our understanding of CB1 neuropathophysiology.

  1. GABAergic signalling in a neurogenic niche of the turtle spinal cord

    PubMed Central

    Reali, Cecilia; Fernández, Anabel; Radmilovich, Milka; Trujillo-Cenóz, Omar; Russo, Raúl E

    2011-01-01

    Abstract The region that surrounds the central canal (CC) in the turtle spinal cord is a neurogenic niche immersed within already functional circuits, where radial glia expressing brain lipid binding protein (BLBP) behave as progenitors. The behaviour of both progenitors and neuroblasts within adult neurogenic niches must be regulated to maintain the functional stability of the host circuit. In the brain, GABA plays a major role in this kind of regulation but little is known about GABAergic signalling in neurogenic niches of the postnatal spinal cord. Here we explored the action of GABA around the CC of the turtle spinal cord by combining patch-clamp recordings of CC-contacting cells, immunohistochemistry for key components of GABAergic signalling and Ca2+ imaging. Two potential sources of GABA appeared around the CC: GABAergic terminals and CC-contacting neurones. GABA depolarized BLBP+ progenitors via GABA transporter-3 (GAT3) and/or GABAA receptors. In CC-contacting neurones, GABAA receptor activation generated responses ranging from excitation to inhibition. This functional heterogeneity appeared to originate from different ratios of activity of the Na+–K+–2Cl− co-transporter (NKCC1) and the K+–Cl− co-transporter (KCC2). In both progenitors and immature neurones, GABA induced an increase in intracellular Ca2+ that required extracellular Ca2+ and was blocked by the selective GABAA receptor antagonist gabazine. Our study shows that GABAergic signalling around the CC shares fundamental properties with those in the embryo and adult neurogenic niches, suggesting that GABA may be part of the mechanisms regulating the production and integration of neurones within operational spinal circuits in the turtle. PMID:21911613

  2. Loss of GABAergic cortical neurons underlies the neuropathology of Lafora disease

    PubMed Central

    2014-01-01

    Background Lafora disease is an autosomal recessive form of progressive myoclonic epilepsy caused by defects in the EPM2A and EPM2B genes. Primary symptoms of the pathology include seizures, ataxia, myoclonus, and progressive development of severe dementia. Lafora disease can be caused by defects in the EPM2A gene, which encodes the laforin protein phosphatase, or in the NHLRC1 gene (also called EPM2B) codifying the malin E3 ubiquitin ligase. Studies on cellular models showed that laforin and malin interact and operate as a functional complex apparently regulating cellular functions such as glycogen metabolism, cellular stress response, and the proteolytic processes. However, the pathogenesis and the molecular mechanism of the disease, which imply either laforin or malin are poorly understood. Thus, the aim of our study is to elucidate the molecular mechanism of the pathology by characterizing cerebral cortex neurodegeneration in the well accepted murine model of Lafora disease EPM2A-/- mouse. Results In this article, we want to asses the primary cause of the neurodegeneration in Lafora disease by studying GABAergic neurons in the cerebral cortex. We showed that the majority of Lafora bodies are specifically located in GABAergic neurons of the cerebral cortex of 3 months-old EPM2A-/- mice. Moreover, GABAergic neurons in the cerebral cortex of younger mice (1 month-old) are decreased in number and present altered neurotrophins and p75NTR signalling. Conclusions Here, we concluded that there is impairment in GABAergic neurons neurodevelopment in the cerebral cortex, which occurs prior to the formation of Lafora bodies in the cytoplasm. The dysregulation of cerebral cortex development may contribute to Lafora disease pathogenesis. PMID:24472629

  3. Prenatal betamethasone does not affect glutamatergic or GABAergic neurogenesis in preterm newborns.

    PubMed

    Vose, L R; Vinukonda, G; Diamond, D; Korumilli, R; Hu, F; Zia, M T K; Hevner, R; Ballabh, P

    2014-06-13

    Prenatal glucocorticoids (GCs) are routinely used for pregnant women in preterm labor to prevent respiratory distress syndrome and intraventricular hemorrhage in premature infants. However, the effect of antenatal GCs on neurogenesis in preterm neonates remains elusive. Herein, we hypothesized that prenatal GCs might suppress both glutamatergic and GABAergic neurogenesis in preterm rabbits and that this treatment would induce distinct changes in the expression of transcription factors regulating these developmental events. To test our hypotheses, we treated pregnant rabbits with betamethasone at E27 and E28, delivered the pups at E29 (term=32d), and assessed neurogenesis at birth and postnatal day 3. We quantified radial glia (Sox2(+)) and intermediate progenitor cells (Tbr2(+)) in the dorsal cortical subventricular zone to assess glutamatergic neuronal progenitors, and counted Nkx2.1(+) and Dlx2(+) cells in the ganglionic eminence to evaluate GABAergic neurogenesis. In addition, we assayed transcription factors regulating neurogenesis. We found that prenatal GCs did not affect the densities of radial glia and intermediate progenitors of glutamatergic or GABAergic neurons. The number of GABA(+) interneurons in the ganglionic eminence was similar between the prenatal GC-treated pups compared to untreated controls. Moreover, the mRNA expression of transcription factors, including Pax6, Ngn1/2, Emx1/2, Insm1, Dlx1, Nkx2.1, and Gsh2, were comparable between the two groups. However, there was a transient elevation in Mash1 protein in betamethasone-treated pups relative to controls at birth. These data suggest that prenatal GC treatment does not significantly impact the balance of glutamatergic and GABAergic neurogenesis in premature infants.

  4. GABAA receptors can initiate the formation of functional inhibitory GABAergic synapses

    PubMed Central

    Fuchs, Celine; Abitbol, Karine; Burden, Jemima J; Mercer, Audrey; Brown, Laura; Iball, Jonathan; Anne Stephenson, F; Thomson, Alex M; Jovanovic, Jasmina N

    2013-01-01

    The mechanisms that underlie the selection of an inhibitory GABAergic axon's postsynaptic targets and the formation of the first contacts are currently unknown. To determine whether expression of GABAA receptors (GABAARs) themselves – the essential functional postsynaptic components of GABAergic synapses – can be sufficient to initiate formation of synaptic contacts, a novel co-culture system was devised. In this system, the presynaptic GABAergic axons originated from embryonic rat basal ganglia medium spiny neurones, whereas their most prevalent postsynaptic targets, i.e. α1/β2/γ2-GABAARs, were expressed constitutively in a stably transfected human embryonic kidney 293 (HEK293) cell line. The first synapse-like contacts in these co-cultures were detected by colocalization of presynaptic and postsynaptic markers within 2 h. The number of contacts reached a plateau at 24 h. These contacts were stable, as assessed by live cell imaging; they were active, as determined by uptake of a fluorescently labelled synaptotagmin vesicle-luminal domain-specific antibody; and they supported spontaneous and action potential-driven postsynaptic GABAergic currents. Ultrastructural analysis confirmed the presence of characteristics typical of active synapses. Synapse formation was not observed with control or N-methyl-d-aspartate receptor-expressing HEK293 cells. A prominent increase in synapse formation and strength was observed when neuroligin-2 was co-expressed with GABAARs, suggesting a cooperative relationship between these proteins. Thus, in addition to fulfilling an essential functional role, postsynaptic GABAARs can promote the adhesion of inhibitory axons and the development of functional synapses. PMID:23909897

  5. Generation of GABAergic and dopaminergic interneurons from endogenous embryonic olfactory bulb precursor cells.

    PubMed

    Vergaño-Vera, Eva; Yusta-Boyo, María J; de Castro, Fernando; Bernad, Antonio; de Pablo, Flora; Vicario-Abejón, Carlos

    2006-11-01

    During the embryonic period, many olfactory bulb (OB) interneurons arise in the lateral ganglionic eminence (LGE) from precursor cells expressing Dlx2, Gsh2 and Er81 transcription factors. Whether GABAergic and dopaminergic interneurons are also generated within the embryonic OB has not been studied thoroughly. In contrast to abundant Dlx2 and Gsh2 expression in ganglionic eminences (GE), Dlx2 and Gsh2 proteins are not expressed in the E12.5-13.5 mouse OB, whereas the telencephalic pallial domain marker Pax6 is abundant. We found GABAergic and dopaminergic neurons originating from dividing precursor cells in E13.5 OB and in short-term dissociated cultures prepared from the rostral half of E13.5 OB. In OB cultures, 22% of neurons were GAD+, of which 53% were Dlx2+, whereas none expressed Gsh2. By contrast, 70% of GAD+ cells in GE cultures were Dlx2+ and 16% expressed Gsh2. In E13.5 OB slices transplanted with EGFP-labeled E13.5 OB precursor cells, 31.7% of EGFP+ cells differentiated to GABAergic neurons. OB and LGE precursors transplanted into early postnatal OB migrated and differentiated in distinct patterns. Transplanted OB precursors gave rise to interneurons with dendritic spines in close proximity to synaptophysin-positive boutons. Interneurons were also abundant in differentiating OB neural stem cell cultures; the neurons responded to the neurotrophin Bdnf and expressed presynaptic proteins. In vivo, the Bdnf receptor TrkB colocalized with synaptic proteins at the glomeruli. These findings suggest that, in addition to receiving interneurons from the LGE, the embryonic OB contains molecularly distinct local precursor cells that generate mature GABAergic and dopaminergic neurons.

  6. Parvalbumin-positive GABAergic interneurons are increased in the dorsal hippocampus of the dystrophic mdx mouse.

    PubMed

    Del Tongo, Claudia; Carretta, Donatella; Fulgenzi, Gianluca; Catini, Claudio; Minciacchi, Diego

    2009-12-01

    Duchenne muscular dystrophy (DMD) is characterized by variable alterations of the dystrophin gene and by muscle weakness and cognitive impairment. We postulated an association between cognitive impairment and architectural changes of the hippocampal GABAergic system. We investigated a major subpopulation of GABAergic neurons, the parvalbumin-immunopositive (PV-I) cells, in the dorsal hippocampus of the mdx mouse, an acknowledged model of DMD. PV-I neurons were quantified and their distribution was compared in CA1, CA2, CA3, and dentate gyrus in wild-type and mdx mice. The cell morphology and topography of PV-I neurons were maintained. Conversely, the number of PV-I neurons was significantly increased in the mdx mouse. The percent increase of PV-I neurons was from 45% for CA2, up to 125% for the dentate gyrus. In addition, the increased parvalbumin content in the mdx hippocampus was confirmed by Western blot. A change in the hippocampus processing abilities is the expected functional counterpart of the modification displayed by PV-I GABAergic neurons. Altered hippocampal functionality can be responsible for part of the cognitive impairment in DMD.

  7. Gap junctions linking the dendritic network of GABAergic interneurons in the hippocampus.

    PubMed

    Fukuda, T; Kosaka, T

    2000-02-15

    The network of GABAergic interneurons connected by chemical synapses is a candidate for the generator of synchronized oscillations in the hippocampus. We present evidence that parvalbumin (PV)-containing GABAergic neurons in the rat hippocampal CA1 region, known to form a network by mutual synaptic contacts, also form another network connected by dendrodendritic gap junctions. Distal dendrites of PV neurons run parallel to the alveus (hippocampal white matter) and establish multiple contacts with one another at the border between the stratum oriens and the alveus. In electron microscopic serial section analysis, gap junctions could be identified clearly at 24% of these contact sites. A dendrodendritic chemical synapse and a mixed synapse also were found between PV-immunoreactive dendrites. Three-dimensional reconstruction of the dendritic arborization revealed that both PV neurons of the well known vertical type (presumptive basket cells and axoaxonic cells) and those of another horizontal type constitute the dendritic network at the light microscopic level. The extent of dendritic fields of single PV neurons in the lateral direction was 538 +/- 201 micrometer (n = 5) in the vertical type and 838 +/- 159 micrometer (n = 6) in the horizontal type. Our previous and present observations indicate that PV-containing GABAergic neurons in the hippocampus form the dual networks connected by chemical and electrical synapses located at axosomatic and dendrodendritic contact sites, respectively. Gap junctions linking the dendritic network may mediate coherent synaptic inputs to distant interneurons and thereby facilitate the synchronization of oscillatory activities generated in the interneuron network.

  8. Evidence for the existence of non-GABAergic, cholinergic interneurons in the rodent hippocampus.

    PubMed

    Frotscher, M; Vida, I; Bender, R

    2000-01-01

    Previous studies have revealed a small number of hippocampal interneurons immunoreactive for choline acetyltransferase, the acetylcholine-synthesizing enzyme. It remained an open question, however, whether these neurons represented a subgroup of inhibitory GABAergic neurons co-localizing acetylcholine. In this study, we have combined immunocytochemistry for choline acetyltransferase and in situ hybridization for glutamate decarboxylase messenger RNA, the GABA-synthesizing enzyme. None of the choline acetyltransferase-immunoreactive neurons in the various layers of the hippocampus proper and fascia dentata were found to co-localize glutamate decarboxylase messenger RNA. The lack of an in situ hybridization signal in these neurons is unlikely to result from the combination of the two labeling techniques. When combining in situ hybridization for glutamate decarboxylase messenger RNA with immunostaining for parvalbumin, a calcium-binding protein expressed by many GABAergic hippocampal interneurons, numerous double-labeled cells were observed. These data provide neurochemical evidence for the existence of non-GABAergic, supposedly cholinergic non-principal cells in the hippocampus.

  9. TrkB receptor signaling is required for establishment of GABAergic synapses in the cerebellum

    PubMed Central

    Rico, Beatriz; Xu, Baoji; Reichardt, Louis F.

    2009-01-01

    Neurotrophins are essential to the normal development and maintenance of the nervous system. Neurotrophin signaling is mediated by Trk family tyrosine kinases such as TrkA, TrkB and TrkC, as well as by the pan-neurotrophin receptor p75NTR. Here we have deleted the trkB gene in cerebellar precursors by Wnt1-driven Cre–mediated recombination to study the function of the TrkB in the cerebellum. Despite the absence of TrkB, the mature cerebellum of mutant mice appears similar to that of wild type, with all types of cell present in normal numbers and positions. Granule and Purkinje cell dendrites appear normal and the former have typical numbers of excitatory synapses. By contrast, inhibitory interneurons are strongly affected: although present in normal numbers, they express reduced amounts of GABAergic markers and develop reduced numbers of GABAergic boutons and synaptic specializations. Thus, TrkB is essential to the development of GABAergic neurons and regulates synapse formation in addition to its role in the development of axon terminals. PMID:11836532

  10. LAMP5 Fine-Tunes GABAergic Synaptic Transmission in Defined Circuits of the Mouse Brain

    PubMed Central

    Tiveron, Marie-Catherine; Beurrier, Corinne; Céni, Claire; Andriambao, Naly; Combes, Alexis; Koehl, Muriel; Maurice, Nicolas; Gatti, Evelina; Abrous, Dhoher Nora; Kerkerian-Le Goff, Lydia; Pierre, Philippe; Cremer, Harold

    2016-01-01

    LAMP5 is member of the LAMP family of membrane proteins. In contrast to the canonical members of this protein family, LAMP1 and LAMP2, which show widespread expression in many tissues, LAMP 5 is brain specific in mice. In C. elegans, the LAMP5 ortholog UNC-46 has been suggested to act a trafficking chaperone, essential for the correct targeting of the nematode vesicular GABA-transporter UNC-47. We show here that in the mouse brain LAMP5 is expressed in subpopulations of GABAergic forebrain neurons in the striato-nigral system and the olfactory bulb. The protein was present at synaptic terminals, overlapping with the mammalian vesicular GABA-transporter VGAT. In LAMP5-deficient mice localization of the transporter was unaffected arguing against a conserved role in VGAT trafficking. Electrophysiological analyses in mutants showed alterations in short term synaptic plasticity suggesting that LAMP5 is involved in controlling the dynamics of evoked GABAergic transmission. At the behavioral level, LAMP5 mutant mice showed decreased anxiety and deficits in olfactory discrimination. Altogether, this work implicates LAMP5 function in GABAergic neurotransmission in defined neuronal subpopulations. PMID:27272053

  11. Layer-specific potentiation of network GABAergic inhibition in the CA1 area of the hippocampus

    PubMed Central

    Colavita, Michelangelo; Terral, Geoffrey; Lemercier, Clement E.; Drago, Filippo; Marsicano, Giovanni; Massa, Federico

    2016-01-01

    One of the most important functions of GABAergic inhibition in cortical regions is the tight control of spatiotemporal activity of principal neuronal ensembles. However, electrophysiological recordings do not provide sufficient spatial information to determine the spatiotemporal properties of inhibitory plasticity. Using Voltage Sensitive Dye Imaging (VSDI) in mouse hippocampal slices, we demonstrate that GABAA-mediated field inhibitory postsynaptic potentials undergo layer-specific potentiation upon activation of metabotropic glutamate receptors (mGlu). VSDI recordings allowed detection of pharmacologically isolated GABAA-dependent hyperpolarization signals. Bath-application of the selective group-I mGlu receptor agonist, (S)-3,5-Dihydroxyphenylglycine (DHPG), induces an enhancement of the GABAergic VSDI-recorded signal, which is more or less pronounced in different hippocampal layers. This potentiation is mediated by mGlu5 and downstream activation of IP3 receptors. Our results depict network GABAergic activity in the hippocampal CA1 region and its sub-layers, showing also a novel form of inhibitory synaptic plasticity tightly coupled to glutamatergic activity. PMID:27345695

  12. Abnormal GABAergic function and face processing in schizophrenia: A pharmacologic-fMRI study.

    PubMed

    Tso, Ivy F; Fang, Yu; Phan, K Luan; Welsh, Robert C; Taylor, Stephan F

    2015-10-01

    The involvement of the gamma-aminobutyric acid (GABA) system in schizophrenia is suggested by postmortem studies and the common use of GABA receptor-potentiating agents in treatment. In a recent study, we used a benzodiazepine challenge to demonstrate abnormal GABAergic function during processing of negative visual stimuli in schizophrenia. This study extended this investigation by mapping GABAergic mechanisms associated with face processing and social appraisal in schizophrenia using a benzodiazepine challenge. Fourteen stable, medicated schizophrenia/schizoaffective patients (SZ) and 13 healthy controls (HC) underwent functional MRI using the blood oxygenation level-dependent (BOLD) technique while they performed the Socio-emotional Preference Task (SePT) on emotional face stimuli ("Do you like this face?"). Participants received single-blinded intravenous saline and lorazepam (LRZ) in two separate sessions separated by 1-3weeks. Both SZ and HC recruited medial prefrontal cortex/anterior cingulate during the SePT, relative to gender identification. A significant drug by group interaction was observed in the medial occipital cortex, such that SZ showed increased BOLD signal to LRZ challenge, while HC showed an expected decrease of signal; the interaction did not vary by task. The altered BOLD response to LRZ challenge in SZ was significantly correlated with increased negative affect across multiple measures. The altered response to LRZ challenge suggests that abnormal face processing and negative affect in SZ are associated with altered GABAergic function in the visual cortex, underscoring the role of impaired visual processing in socio-emotional deficits in schizophrenia.

  13. Medial septal GABAergic projection neurons promote object exploration behavior and type 2 theta rhythm

    PubMed Central

    Gangadharan, Gireesh; Shin, Jonghan; Kim, Seong-Wook; Kim, Angela; Paydar, Afshin; Kim, Duk-Soo; Miyazaki, Taisuke; Watanabe, Masahiko; Yanagawa, Yuchio; Kim, Jinhyun; Kim, Yeon-Soo; Kim, Daesoo; Shin, Hee-Sup

    2016-01-01

    Exploratory drive is one of the most fundamental emotions, of all organisms, that are evoked by novelty stimulation. Exploratory behavior plays a fundamental role in motivation, learning, and well-being of organisms. Diverse exploratory behaviors have been described, although their heterogeneity is not certain because of the lack of solid experimental evidence for their distinction. Here we present results demonstrating that different neural mechanisms underlie different exploratory behaviors. Localized Cav3.1 knockdown in the medial septum (MS) selectively enhanced object exploration, whereas the null mutant (KO) mice showed enhanced-object exploration as well as open-field exploration. In MS knockdown mice, only type 2 hippocampal theta rhythm was enhanced, whereas both type 1 and type 2 theta rhythm were enhanced in KO mice. This selective effect was accompanied by markedly increased excitability of septo-hippocampal GABAergic projection neurons in the MS lacking T-type Ca2+ channels. Furthermore, optogenetic activation of the septo-hippocampal GABAergic pathway in WT mice also selectively enhanced object exploration behavior and type 2 theta rhythm, whereas inhibition of the same pathway decreased the behavior and the rhythm. These findings define object exploration distinguished from open-field exploration and reveal a critical role of T-type Ca2+ channels in the medial septal GABAergic projection neurons in this behavior. PMID:27208094

  14. Activity- and age-dependent GABAergic synaptic plasticity in the developing rat hippocampus.

    PubMed

    Gubellini, P; Ben-Ari, Y; Gaïarsa, J L

    2001-12-01

    Activity-dependent plasticity of GABAergic synaptic transmission was investigated in rat hippocampal slices obtained between postnatal day (P) 0-15 using the whole-cell patch-clamp recording technique. Spontaneous GABA(A) receptor-mediated postsynaptic currents (sGABA(A)-PSCs) were isolated in the presence of ionotropic glutamate receptor antagonists. A conditioning protocol relevant to the physiological condition, consisting of repetitive depolarizing pulses (DPs) at 0.1 Hz, was able to induce long-lasting changes in both frequency and amplitude of sGABA(A)-PSCs between P0 and P8. Starting from P12, DPs were unable to induce any form of synaptic plasticity. The effects of DPs were tightly keyed to the frequency at which they were delivered. When delivered at a lower (0.05 Hz) or higher (1 Hz) frequency, DPs failed to induce any long-lasting change in the frequency or amplitude of sGABA(A)-PSCs. In two cases, DPs were able to activate sGABA(A)-PSCs in previously synaptically silent cells at P0-1. These results show that long-term changes in GABAergic synaptic activity can be induced during a restricted period of development by a conditioning protocol relevant to the physiological condition. It is suggested that such activity-induced modifications may represent a physiological mechanism for the functional maturation of GABAergic synaptic transmission.

  15. GABAergic and glycinergic inhibition modulate monaural auditory response properties in the avian superior olivary nucleus

    PubMed Central

    Coleman, W. L.; Fischl, M. J.; Weimann, S. R.

    2011-01-01

    The superior olivary nucleus (SON) is the primary source of inhibition in the avian auditory brainstem. While much is known about the role of inhibition at the SON's target nuclei, little is known about how the SON itself processes auditory information or how inhibition modulates these properties. Additionally, the synaptic physiology of inhibitory inputs within the SON has not been described. We investigated these questions using in vivo and in vitro electrophysiological techniques in combination with immunohistochemistry in the chicken, an organism for which the auditory brainstem has otherwise been well characterized. We provide a thorough characterization of monaural response properties in the SON and the influence of inhibitory input in shaping these features. We found that the SON contains a heterogeneous mixture of response patterns to acoustic stimulation and that in most neurons these responses are modulated by both GABAergic and glycinergic inhibitory inputs. Interestingly, many SON neurons tuned to low frequencies have robust phase-locking capability and the precision of this phase locking is enhanced by inhibitory inputs. On the synaptic level, we found that evoked and spontaneous inhibitory postsynaptic currents (IPSCs) within the SON are also mediated by both GABAergic and glycinergic inhibition in all neurons tested. Analysis of spontaneous IPSCs suggests that most SON cells receive a mixture of both purely GABAergic terminals, as well as terminals from which GABA and glycine are coreleased. Evidence for glycinergic signaling within the SON is a novel result that has important implications for understanding inhibitory function in the auditory brainstem. PMID:21368002

  16. Neurogliaform and Ivy Cells: A Major Family of nNOS Expressing GABAergic Neurons

    PubMed Central

    Armstrong, Caren; Krook-Magnuson, Esther; Soltesz, Ivan

    2012-01-01

    Neurogliaform and Ivy cells are members of an abundant family of neuronal nitric oxide synthase (nNOS) expressing GABAergic interneurons found in diverse brain regions. These cells have a defining dense local axonal plexus, and display unique synaptic properties including a biphasic postsynaptic response with both a slow GABAA component and a GABAB component following even a single action potential. The type of transmission displayed by these cells has been termed “volume transmission,” distinct from both tonic and classical synaptic transmission. Electrical connections are also notable in that, unlike other GABAergic cell types, neurogliaform family cells will form gap junctions not only with other neurogliaform cells, but also with non-neurogliaform family GABAergic cells. In this review, we focus on neurogliaform and Ivy cells throughout the hippocampal formation, where recent studies highlight their role in feedforward inhibition, uncover their ability to display a phenomenon called persistent firing, and reveal their modulation by opioids. The unique properties of this family of cells, their abundance, rich connectivity, and modulation by clinically relevant drugs make them an attractive target for future studies in vivo during different behavioral and pharmacological conditions. PMID:22623913

  17. Maintenance of GABAergic activity by neuregulin 1-ErbB4 in amygdala for fear memory.

    PubMed

    Lu, Yisheng; Sun, Xiang-Dong; Hou, Feng-Qing; Bi, Lin-Lin; Yin, Dong-Min; Liu, Fang; Chen, Yong-Jun; Bean, Jonathan C; Jiao, Hui-Feng; Liu, Xihui; Li, Bao-Ming; Xiong, Wen-Cheng; Gao, Tian-Ming; Mei, Lin

    2014-11-19

    Inhibitory neurotransmission in amygdala is important for fear learning and memory. However, mechanisms that control the inhibitory activity in amygdala are not well understood. We provide evidence that neuregulin 1 (NRG1) and its receptor ErbB4 tyrosine kinase are critical for maintaining GABAergic activity in amygdala. Neutralizing endogenous NRG1, inhibition, or genetic ablation of ErbB4, which was expressed in a majority of palvalbumin (PV)+ neurons in amygdala, reduced GABAergic transmission and inhibited tone-cued fear conditioning. Specific ablation of ErbB4 in PV+ neurons reduced eIPSC/eEPSC ratios and impaired fear conditioning. Notably, expression of ErbB4 in amygdala was sufficient to diminish synaptic dysfunction and fear conditioning deficits in PV-ErbB4-/- mice. These observations indicated that NRG1 signaling maintains high GABAergic activity in amygdala and, thus, regulates fear memory. Considering that both NRG1 and ErbB4 are susceptibility genes of schizophrenia, our study sheds light on potential pathophysiological mechanisms of this disorder.

  18. Neural cell adhesion molecule-mediated Fyn activation promotes GABAergic synapse maturation in postnatal mouse cortex.

    PubMed

    Chattopadhyaya, Bidisha; Baho, Elie; Huang, Z Josh; Schachner, Melitta; Di Cristo, Graziella

    2013-04-03

    GABAergic basket interneurons form perisomatic synapses, which are essential for regulating neural networks, and their alterations are linked to various cognitive dysfunction. Maturation of basket synapses in postnatal cortex is activity dependent. In particular, activity-dependent downregulation of polysialiac acid carried by the neural cell adhesion molecule (NCAM) regulates the timing of their maturation. Whether and how NCAM per se affects GABAergic synapse development is unknown. Using single-cell genetics to knock out NCAM in individual basket interneurons in mouse cortical slice cultures, at specific developmental time periods, we found that NCAM loss during perisomatic synapse formation impairs the process of basket cell axonal branching and bouton formation. However, loss of NCAM once the synapses are already formed did not show any effect. We further show that NCAM120 and NCAM140, but not the NCAM180 isoform, rescue the phenotype. Finally, we demonstrate that a dominant-negative form of Fyn kinase mimics, whereas a constitutively active form of Fyn kinase rescues, the effects of NCAM knockdown. Altogether, our data suggest that NCAM120/NCAM140-mediated Fyn activation promotes GABAergic synapse maturation in postnatal cortex.

  19. General anesthesia as a possible GABAergic modulator affects visual processing in children

    PubMed Central

    Van den Boomen, C.; de Graaff, J. C.; de Jong, T. P. V. M.; Kalkman, C. J.; Kemner, C.

    2013-01-01

    Gamma-Aminobutyric Acid (GABA) inhibitory interneurons play an important role in visual processing, as is revealed by studies administering drugs in human and monkey adults. Investigating this process in children requires different methodologies, due to ethical considerations. The current study aimed to investigate whether a new method, being general anesthesia using Sevoflurane, can be used to trace the effects of GABAergic modulation on visual brain functioning in children. To this aim, visual processing was investigated in children aged 4–12 years who were scheduled for minor urologic procedures under general anesthesia in day-care treatment. In a visual segmentation task, the difference in Event-Related Potential (ERP) response to homogeneous and textured stimuli was investigated. In addition, psychophysical performance on visual acuity and contrast sensitivity were measured. Results were compared between before and shortly after anesthesia. In two additional studies, effects at 1 day after anesthesia and possible effects of task-repetition were investigated. ERP results showed longer latency and lower amplitude of the Texture Negativity (TN) component shortly after compared to before anesthesia. No effects of anesthesia on psychophysical measurements were found. No effects at 1 day after anesthesia or of repetition were revealed either. These results show that GABAergic modulation through general anesthesia affects ERP reflections of visual segmentation in a similar way in children as benzodiazepine does in adults, but that effects are not permanent. This demonstrates that ERP measurement after anesthesia is a successful method to study effects of GABAergic modulation in children. PMID:23630461

  20. GABAergic involvement in motor effects of an adenosine A(2A) receptor agonist in mice.

    PubMed

    Khisti, R T; Chopde, C T; Abraham, E

    2000-04-03

    Adenosine A(2A) agonists are known to induce catalepsy and inhibit dopamine mediated motor hyperactivity. An antagonistic interaction between adenosine A(2A) and dopamine D(2) receptors is known to regulate GABA-mediated neurotransmission in striatopallidal neurons. Stimulation of adenosine A(2A) and dopamine D(2) receptors has been shown to increase and inhibit GABA release respectively in pallidal GABAergic neurons. However, the role of GABAergic neurotransmission in the motor effects of adenosine A(2A) receptors is not yet known. Therefore in the present study the effect of GABAergic agents on adenosine A(2A) receptor agonist (NECA- or CGS 21680) induced catalepsy and inhibition of amphetamine elicited motor hyperactivity was examined. Pretreatment with GABA, the GABA(A) agonist muscimol or the GABA(B) agonist baclofen potentiated whereas the GABA(A) antagonist bicuculline attenuated NECA- or CGS 21680-induced catalepsy. However, the GABA(B) antagonists phaclophen and delta-aminovaleric acid had no effect. Administration of NECA or CGS 21680 not only reduced spontaneous locomotor activity but also antagonized amphetamine elicited motor hyperactivity. These effects of NECA and CGS 21680 were potentiated by GABA or muscimol and antagonized by bicuculline. These findings provide behavioral evidence for the role of GABA in the motor effects of adenosine A(2A) receptor agonists. Activation of adenosine A(2A) receptors increases GABA release which could reduce dopaminergic tone and induce catalepsy or inhibit amphetamine mediated motor hyperactivity.

  1. Repeated binge-like ethanol drinking alters ethanol drinking patterns and depresses striatal GABAergic transmission.

    PubMed

    Wilcox, Mark V; Cuzon Carlson, Verginia C; Sherazee, Nyssa; Sprow, Gretchen M; Bock, Roland; Thiele, Todd E; Lovinger, David M; Alvarez, Veronica A

    2014-02-01

    Repeated cycles of binge alcohol drinking and abstinence are key components in the development of dependence. However, the precise behavioral mechanisms underlying binge-like drinking and its consequences on striatal synaptic physiology remain unclear. In the present study, ethanol and water drinking patterns were recorded with high temporal resolution over 6 weeks of binge-like ethanol drinking using the 'drinking in the dark' (DID) protocol. The bottle exchange occurring at the beginning of each session prompted a transient increase in the drinking rate that might facilitate the acquisition of ethanol binge-like drinking. Ethanol drinking mice also displayed a 'front-loading' behavior, in which the highest rate of drinking was recorded during the first 15 min. This rate increased over weeks and paralleled the mild escalation of blood ethanol concentrations. GABAergic and glutamatergic transmission in the dorsal striatum were examined following DID. Spontaneous glutamatergic transmission and the density of dendritic spines were unchanged after ethanol drinking. However, the frequency of GABAA receptor-mediated inhibitory postsynaptic currents was depressed in medium spiny neurons of ethanol drinking mice. A history of ethanol drinking also increased ethanol preference and altered the acute ethanol effects on GABAergic transmission differentially in dorsolateral and dorsomedial striatum. Together, the study shows that the bottle exchange during DID promotes fast, voluntary ethanol drinking and that this intermittent pattern of ethanol drinking causes a depression of GABAergic transmission in the dorsal striatum.

  2. Association of dopaminergic/GABAergic genes with attention deficit hyperactivity disorder in children.

    PubMed

    Wang, Guang-Xin; Ma, Yan-Hui; Wang, Shi-Fu; Ren, Guang-Fang; Guo, Hui

    2012-11-01

    Attention deficit hyperactivity disorder (ADHD) is the most commonly diagnosed neurobehavioral disorder in children and adolescents; however, its etiology is unknown. In this study, we investigated the association of five polymorphisms in dopaminergic/GABAergic genes with ADHD using polymerase chain reaction-restriction fragment length polymorphism in a group of 54 children with ADHD and 67 healthy controls. The distribution of AA genotype and A allele frequencies of rs5320 in the dopamine beta-hydroxylase gene in ADHD children differed significantly from that in healthy controls; however, no associations were found between four other polymorphisms in dopaminergic/GABAergic genes and ADHD. We also identified the best model consisting of four loci. We conclude that the rs5320 polymorphism may be considered as a genetic risk factor of ADHD, but the other four polymorphisms were not confirmed to be related directly to ADHD. The multilocus of dopaminergic/GABAergic genes acted in combination to affect susceptibility to ADHD in the children studied.

  3. APP modulates KCC2 expression and function in hippocampal GABAergic inhibition.

    PubMed

    Chen, Ming; Wang, Jinzhao; Jiang, Jinxiang; Zheng, Xingzhi; Justice, Nicholas J; Wang, Kun; Ran, Xiangqian; Li, Yi; Huo, Qingwei; Zhang, Jiajia; Li, Hongmei; Lu, Nannan; Wang, Ying; Zheng, Hui; Long, Cheng; Yang, Li

    2017-01-05

    Amyloid precursor protein (APP) is enriched at the synapse, but its synaptic function is still poorly understood. We previously showed that GABAergic short-term plasticity is impaired in App knock-out (App(-/-)) animals, but the precise mechanism by which APP regulates GABAergic synaptic transmission has remained elusive. Using electrophysiological, biochemical, moleculobiological, and pharmacological analysis, here we show that APP can physically interact with KCC2, a neuron-specific K(+)-Cl(-) cotransporter that is essential for Cl(-) homeostasis and fast GABAergic inhibition. APP deficiency results in significant reductions in both total and membrane KCC2 levels, leading to a depolarizing shift in the GABA reversal potential (EGABA). Simultaneous measurement of presynaptic action potentials and inhibitory postsynaptic currents (IPSCs) in hippocampal neurons reveals impaired unitary IPSC amplitudes attributable to a reduction in α1 subunit levels of GABAAR. Importantly, restoration of normal KCC2 expression and function in App(-/-) mice rescues EGABA, GABAAR α1 levels and GABAAR mediated phasic inhibition. We show that APP functions to limit tyrosine-phosphorylation and ubiquitination and thus subsequent degradation of KCC2, providing a mechanism by which APP influences KCC2 abundance. Together, these experiments elucidate a novel molecular pathway in which APP regulates, via protein-protein interaction with KCC2, GABAAR mediated inhibition in the hippocampus.

  4. Histone Deacetylase Inhibition Rescues Maternal Deprivation-Induced GABAergic Metaplasticity through Restoration of AKAP Signaling.

    PubMed

    Authement, Michael E; Kodangattil, Jayaraj N; Gouty, Shawn; Rusnak, Milan; Symes, Aviva J; Cox, Brian M; Nugent, Fereshteh S

    2015-06-03

    Adverse early-life experiences such as child neglect and abuse increase the risk of developing addiction and stress-related disorders through alterations in motivational systems including the mesolimbic dopamine (DA) pathway. Here we investigated whether a severe early-life stress (i.e., maternal deprivation, MD) promotes DA dysregulation through an epigenetic impairment of synaptic plasticity within ventral tegmental area (VTA) DA neurons. Using a single 24-hr episode of MD and whole-cell patch clamp recording in rat midbrain slices, we show that MD selectively induces long-term depression (LTD) and shifts spike timing-dependent plasticity (STDP) toward LTD at GABAergic synapses onto VTA DA neurons through epigenetic modifications of postsynaptic scaffolding A-kinase anchoring protein 79/150 (AKAP79/150) signaling. Histone deacetylase (HDAC) inhibition rescues GABAergic metaplasticity and normalizes AKAP signaling in MD animals. MD-induced reversible HDAC-mediated GABAergic dysfunction within the VTA may be a mechanistic link for increased propensity to mental health disorders following MD.

  5. A new role for GABAergic transmission in the control of male rat sexual behavior expression.

    PubMed

    Rodríguez-Manzo, Gabriela; Canseco-Alba, Ana

    2017-03-01

    GABAergic transmission in the ventral tegmental area (VTA) exerts a tonic inhibitory influence on mesolimbic dopaminergic neurons' activity. Blockade of VTA GABAA receptors increases dopamine release in the nucleus accumbens (NAcc). Increases in NAcc dopamine levels typically accompany sexual behavior display. Copulation to satiety is characterized by the instatement of a long lasting (72h) sexual behavior inhibition and the mesolimbic system appears to be involved in this phenomenon. GABAergic transmission in the VTA might play a role in the maintenance of this long lasting sexual inhibitory state. To test this hypothesis, in the present work we investigated the effect of GABAA receptor blockade in sexually exhausted males 24h after copulation to satiety, once the sexual inhibitory state is established, and compared it with its effect in sexually experienced rats. Results showed that low doses of systemically administered bicuculline induced sexual behavior expression in sexually exhausted rats, but lacked an effect on copulation of sexually experienced animals. Intra-VTA bilateral infusion of bicuculline did not modify sexual behavior of sexually experienced rats, but induced sexual behavior expression in all the sexually exhausted males. Hence, GABA plays a role in the control of sexual behavior expression at the VTA. The role played by GABAergic transmission in male sexual behavior expression of animals with distinct sexual behavior conditions is discussed.

  6. GABAergic and glycinergic inhibition modulate monaural auditory response properties in the avian superior olivary nucleus.

    PubMed

    Coleman, W L; Fischl, M J; Weimann, S R; Burger, R M

    2011-05-01

    The superior olivary nucleus (SON) is the primary source of inhibition in the avian auditory brainstem. While much is known about the role of inhibition at the SON's target nuclei, little is known about how the SON itself processes auditory information or how inhibition modulates these properties. Additionally, the synaptic physiology of inhibitory inputs within the SON has not been described. We investigated these questions using in vivo and in vitro electrophysiological techniques in combination with immunohistochemistry in the chicken, an organism for which the auditory brainstem has otherwise been well characterized. We provide a thorough characterization of monaural response properties in the SON and the influence of inhibitory input in shaping these features. We found that the SON contains a heterogeneous mixture of response patterns to acoustic stimulation and that in most neurons these responses are modulated by both GABAergic and glycinergic inhibitory inputs. Interestingly, many SON neurons tuned to low frequencies have robust phase-locking capability and the precision of this phase locking is enhanced by inhibitory inputs. On the synaptic level, we found that evoked and spontaneous inhibitory postsynaptic currents (IPSCs) within the SON are also mediated by both GABAergic and glycinergic inhibition in all neurons tested. Analysis of spontaneous IPSCs suggests that most SON cells receive a mixture of both purely GABAergic terminals, as well as terminals from which GABA and glycine are coreleased. Evidence for glycinergic signaling within the SON is a novel result that has important implications for understanding inhibitory function in the auditory brainstem.

  7. GABAergic effect on resting-state functional connectivity: Dynamics under pharmacological antagonism.

    PubMed

    Nasrallah, Fatima A; Singh, Kavita Kaur D/O Ranjit; Yeow, Ling Yun; Chuang, Kai-Hsiang

    2017-01-21

    Resting state functional connectivity MRI measures synchronous activity among brain regions although the mechanisms governing the temporally coherent BOLD signals remain unclear. Recent studies suggest that γ-amino butyric acid (GABA) levels are correlated with functional connectivity. To understand whether changes in GABA transmission alter functional connectivity, we modulated the GABAergic activity by a GABAA receptor antagonist, bicuculline. Resting and evoked electrophysiology and BOLD signals were measured in isoflurane-anesthetized rats under infusion of low-dose bicuculline or vehicle individually. Both somatosensory BOLD activations and evoked potentials induced by forepaw stimulation were increased significantly under bicuculline compared to vehicle, indicating increased excitability. Gradually elevated resting BOLD correlation within and between the somatosensory and visual cortices, as well as between somatosensory and caudate putamen but not within subcortical areas were found with the infusion of bicuculline. Increased cerebral blood flow was observed throughout the cortical and subcortical areas where the receptor density is high, but it didn't correlate with BOLD connectivity except in the primary somatosensory cortex. Furthermore, resting EEG coherence in the alpha and beta bands exhibited consistent change with the BOLD correlation. The increased cortico-cortical and cortico-striatal connectivity without dependence on the receptor distribution indicate that the functional connectivity may be mediated by long-range projection via the cortical and striatal GABAergic inter-neurons. Our results indicate an important role of the GABAergic system on neural and hemodynamic oscillations, which further supports the neuronal basis of functional connectivity MRI and its correlation with neurotransmission.

  8. APP modulates KCC2 expression and function in hippocampal GABAergic inhibition

    PubMed Central

    Chen, Ming; Wang, Jinzhao; Jiang, Jinxiang; Zheng, Xingzhi; Justice, Nicholas J; Wang, Kun; Ran, Xiangqian; Li, Yi; Huo, Qingwei; Zhang, Jiajia; Li, Hongmei; Lu, Nannan; Wang, Ying; Zheng, Hui; Long, Cheng; Yang, Li

    2017-01-01

    Amyloid precursor protein (APP) is enriched at the synapse, but its synaptic function is still poorly understood. We previously showed that GABAergic short-term plasticity is impaired in App knock-out (App-/-) animals, but the precise mechanism by which APP regulates GABAergic synaptic transmission has remained elusive. Using electrophysiological, biochemical, moleculobiological, and pharmacological analysis, here we show that APP can physically interact with KCC2, a neuron-specific K+-Cl- cotransporter that is essential for Cl- homeostasis and fast GABAergic inhibition. APP deficiency results in significant reductions in both total and membrane KCC2 levels, leading to a depolarizing shift in the GABA reversal potential (EGABA). Simultaneous measurement of presynaptic action potentials and inhibitory postsynaptic currents (IPSCs) in hippocampal neurons reveals impaired unitary IPSC amplitudes attributable to a reduction in α1 subunit levels of GABAAR. Importantly, restoration of normal KCC2 expression and function in App-/- mice rescues EGABA, GABAAR α1 levels and GABAAR mediated phasic inhibition. We show that APP functions to limit tyrosine-phosphorylation and ubiquitination and thus subsequent degradation of KCC2, providing a mechanism by which APP influences KCC2 abundance. Together, these experiments elucidate a novel molecular pathway in which APP regulates, via protein-protein interaction with KCC2, GABAAR mediated inhibition in the hippocampus. DOI: http://dx.doi.org/10.7554/eLife.20142.001 PMID:28054918

  9. Phenotype-dependent Ca(2+) dynamics in single boutons of various anatomically identified GABAergic interneurons in the rat hippocampus.

    PubMed

    Lőrincz, Tibor; Kisfali, Máté; Lendvai, Balázs; Sylvester Vizi, Elek

    2016-02-01

    Interneurons (INs) of the hippocampus exert versatile inhibition on pyramidal cells by silencing the network at different oscillation frequencies. Although IN discharge can phase-lock to various rhythms in the hippocampus, under high-frequency axon firing, the boutons may not be able to follow the fast activity. Here, we studied Ca(2+) responses to action potentials (APs) in single boutons using combined two-photon microscopy and patch clamp electrophysiology in three types of INs: non-fast-spiking (NFS) neurons showing cannabinoid 1 receptor labelling and dendrite targeting, fast-spiking partially parvalbumin-positive cells synapsing with dendrites (DFS), and parvalbumin-positive cells with perisomatic innervation (PFS). The increase in [Ca(2+) ]i from AP trains was substantially higher in NFS boutons than in DFS or PFS boutons. The decay of bouton Ca(2+) responses was markedly faster in DFS and PFS cells compared with NFS neurons. The bouton-to-bouton variability of AP-evoked Ca(2+) transients in the same axon was surprisingly low in each cell type. Importantly, local responses were saturated after shorter trains of APs in NFS cells than in PFS cells. This feature of fast-spiking neurons might allow them to follow higher-frequency gamma oscillations for a longer time than NFS cells. The function of NFS boutons may better support asynchronous GABA release. In conclusion, we demonstrate several neuron-specific Ca(2+) transients in boutons of NFS, PFS and DFS neurons, which may serve differential functions in hippocampal networks.

  10. Multiple anxiogenic drugs recruit a parvalbumin-containing subpopulation of GABAergic interneurons in the basolateral amygdala.

    PubMed

    Hale, Matthew W; Johnson, Philip L; Westerman, Alex M; Abrams, Jolane K; Shekhar, Anantha; Lowry, Christopher A

    2010-10-01

    The basolateral amygdala is a nodal structure within a distributed and interconnected network that regulates anxiety states and anxiety-related behavior. Administration of multiple anxiogenic drugs increases cellular responses (i.e., increases c-Fos expression) in a subregion of the basolateral amygdala, but the neurochemical phenotypes of these cells are not known. The basolateral amygdala contains glutamatergic projection neurons and several populations of γ-aminobutyric acid-synthesizing (GABAergic) interneurons, including a population of parvalbumin (PV)-expressing GABAergic interneurons that co-express the excitatory 5-HT(2A) receptor. The role for these PV-expressing GABAergic interneurons in anxiety-states is unclear. In this experiment we examined the effects of multiple anxiogenic drugs including the 5-HT(2C/2A) receptor agonist m-chlorophenyl piperazine (mCPP), the adenosine receptor antagonist caffeine, the α(2)-adrenoreceptor antagonist yohimbine and the partial inverse agonist at the benzodiazepine allosteric site on the GABA(A) receptor, N-methyl-beta-carboline-3-carboxamide (FG-7142), on c-Fos expression in PV-immunoreactive (PV-ir) interneurons in subdivisions of the basolateral amygdala. All drugs with the exception of mCPP increased c-Fos expression in PV-ir neurons in the basolateral amygdaloid nucleus, anterior part (BLA). The numbers of c-Fos-immunoreactive (c-Fos-ir)/PV-ir GABAergic interneurons in the BLA were positively correlated with the numbers of c-Fos-ir serotonergic neurons in the mid-rostrocaudal dorsal raphe nucleus (DR) and with a measure of anxiety-related behavior. All four drugs increased c-Fos expression in non-PV-ir cells in most of the subdivisions of the basolateral amygdala that were sampled, compared with vehicle-injected controls. Together, these data suggest that the PV/5-HT(2A) receptor expressing GABAergic interneurons in the basolateral amygdala are part of a DR-basolateral amygdala neuronal circuit modulating

  11. Reduced brain levels of DHEAS in hepatic coma patients: significance for increased GABAergic tone in hepatic encephalopathy.

    PubMed

    Ahboucha, Samir; Talani, Giuseppe; Fanutza, Tomas; Sanna, Enrico; Biggio, Giovanni; Gamrani, Halima; Butterworth, Roger F

    2012-07-01

    Increased neurosteroids with allosteric modulatory activity on GABA(A) receptors such as 3α-5α tertrahydroprogesterone; allopregnanolone (ALLO), are candidates to explain the phenomenon of "increased GABAergic tone" in hepatic encephalopathy (HE). However, it is not known how changes of other GABA(A) receptor modulators such as dehydroepiandrosterone sulfate (DHEAS) contribute to altered GABAergic tone in HE. Concentrations of DHEAS were measured by radioimmunoassay in frontal cortex samples obtained at autopsy from 11 cirrhotic patients who died in hepatic coma and from an equal number of controls matched for age, gender, and autopsy delay intervals free from hepatic or neurological diseases. To assess whether reduced brain DHEAS contributes to increased GABAergic tone, in vitro patch clamp recordings in rat prefrontal cortex neurons were performed. A significant reduction of DHEAS (5.81±0.88 ng/g tissue) compared to control values (9.70±0.79 ng/g, p<0.01) was found. Brain levels of DHEAS in patients with liver disease who died without HE (11.43±1.74 ng/g tissue), and in a patient who died in uremic coma (12.56 ng/g tissue) were within the control range. Increasing ALLO enhances GABAergic tonic currents concentration-dependently, but increasing DHEAS reduces these currents. High concentrations of DHEAS (50 μM) reduce GABAergic tonic currents in the presence of ALLO, whereas reduced concentrations of DHEAS (1 μM) further stimulate these currents. These findings demonstrate that decreased concentrations of DHEAS together with increased brain concentrations of ALLO increase GABAergic tonic currents synergistically; suggesting that reduced brain DHEAS could further increase GABAergic tone in human HE.

  12. Presynaptic Inhibitory Terminals Are Functionally Abnormal in a Rat Model of Posttraumatic Epilepsy

    PubMed Central

    Faria, Leonardo C.

    2010-01-01

    Partially isolated “undercut” neocortex with intact pial circulation is a well-established model of posttraumatic epileptogenesis. Results of previous experiments showed a decreased frequency of miniature inhibitory postsynaptic currents (mIPSCs) in layer V pyramidal (Pyr) neurons of undercuts. We further examined possible functional abnormalities in GABAergic inhibition in rat epileptogenic neocortical slices in vitro by recording whole cell monosynaptic IPSCs in layer V Pyr cells and fast-spiking (FS) GABAergic interneurons using a paired pulse paradigm. Compared with controls, IPSCs in Pyr neurons of injured slices showed increased threshold and decreased peak amplitude at threshold, decreased input/output slopes, increased failure rates, and a shift from paired pulse depression toward paired pulse facilitation (increased paired pulse ratio or PPR). Increasing [Ca2+]o from 2 to 4 mM partially reversed these abnormalities in Pyr cells of the epileptogenic tissue. IPSCs onto FS cells also had an increased PPR and failures. Blockade of GABAB receptors did not affect the paired results. These findings suggest that there are functional alterations in GABAergic presynaptic terminals onto both Pyr and FS cells in this model of posttraumatic epileptogenesis. PMID:20484536

  13. Abnormal UP/DOWN Membrane Potential Dynamics Coupled with the Neocortical Slow Oscillation in Dentate Granule Cells during the Latent Phase of Temporal Lobe Epilepsy123

    PubMed Central

    Ouedraogo, David W.; Lenck-Santini, Pierre-Pascal; Marti, Geoffrey; Robbe, David; Crépel, Valérie

    2016-01-01

    The dentate gyrus, a major entry point to the hippocampus, gates (or filters) incoming information from the cortex. During sleep or anesthesia, the slow-wave oscillation (SWO) orchestrates hippocampus–neocortex communication, which is important for memory formation. The dentate gate is altered in temporal lobe epilepsy (TLE) early during epileptogenesis, which favors the propagation of pathological activities. Yet, whether the gating of physiological SWO by dentate granule cells (DGCs) is altered in TLE has remained unexplored. We combined intracellular recordings of membrane potential (Vm) of DGCs and local field potential recordings of the SWO in parietal cortex in anesthetized rats early during epileptogenesis [post-status epilepticus (SE) rats]. As expected, in control rats, the Vm of DGCs weakly and rarely oscillated in the SWO frequency range. In contrast, in post-SE rats, the Vm of DGCs displayed strong and long-lasting SWO. In these cells, clear UP and DOWN states, in phase with the neocortical SWO, led to a bimodal Vm distribution. In post-SE rats, the firing of DGCs was increased and more temporally modulated by the neocortical SWO. We conclude that UP/DOWN state dynamics dominate the Vm of DGCs and firing early during epileptogenesis. This abnormally strong neocortical influence on the dynamics of DGCs may profoundly modify the hippocampus–neocortex dialogue during sleep and associated cognitive functions. PMID:27257629

  14. Selective loss and axonal sprouting of GABAergic interneurons in the sclerotic hippocampus induced by LiCl-pilocarpine.

    PubMed

    Long, Lili; Xiao, Bo; Feng, Li; Yi, Fang; Li, Guoliang; Li, Shuyu; Mutasem, M Abuhamed; Chen, Si; Bi, Fangfang; Li, Yi

    2011-02-01

    In this study, we performed immunohistochemistry for somatostatin (SS), neuropeptide Y (NPY), and parvalbumin (PV) in LiCl-pilocarpine-treated rats to observe quantitative changes and axonal sprouting of GABAergic interneurons in the hippocampus, especially in the sclerotic hippocampus. Fluoro-Jade B (FJB) was performed to detect the specific degeneration of GABAergic interneurons. Compared with age-matched control rats, there were fewer SS/NPY/PV-immunoreactive (IR) interneurons in the hilus of the sclerotic hippocampus in pilocarpine-treated rats; hilar dentritic inhibitory interneurons were most vulnerable. FJB stain revealed degeneration was evident at 2 months after status epilepticus. Some SS-IR and NPY-IR interneurons were also stained for FJB, but there was no evidence of degeneration of PV-IR interneurons. Axonal sprouting of GABAergic interneurons was present in the hippocampus of epileptic rats, and a dramatic increase of SS-IR fibers was observed throughout all layers of CA1 region in the sclerotic hippocampus. These results confirm selective loss and degeneration of a specific subset of GABAergic interneurons in specific subfields of the hippocampus. Axonal sprouting of inhibitory GABAergic interneurons, especially numerous increase of SS-IR neutrophils within CA1 region of the sclerotic hippocampus, may constitute the aberrant inhibitory circum and play a significant role in the generation and compensation of temporal lobe epilepsy.

  15. Akting up in the GABA hypothesis of schizophrenia: Akt1 deficiency modulates GABAergic functions and hippocampus-dependent functions

    PubMed Central

    Chang, Chia-Yuan; Chen, Yi-Wen; Wang, Tsu-Wei; Lai, Wen-Sung

    2016-01-01

    Accumulating evidence implies that both AKT1 and GABAA receptor (GABAAR) subunit genes are involved in schizophrenia pathogenesis. Activated Akt promotes GABAergic neuron differentiation and increases GABAAR expression on the plasma membrane. To elucidate the role of Akt1 in modulating GABAergic functions and schizophrenia-related cognitive deficits, a set of 6 in vitro and in vivo experiments was conducted. First, an Akt1/2 inhibitor was applied to evaluate its effect on GABAergic neuron-like cell formation from P19 cells. Inhibiting Akt resulted in a reduction in parvalbumin-positive neuron-like cells. In Akt1−/− and wild-type mice, seizures induced using pentylenetetrazol (a GABAAR antagonist) were measured, and GABAAR expression and GABAergic interneuron abundance in the brain were examined. Female Akt1−/− mice, but not male Akt1−/− mice, exhibited less pentylenetetrazol-induced convulsive activity than their corresponding wild-type controls. Reduced parvalbumin-positive interneuron abundance and GABAAR subunit expression, especially in the hippocampus, were also observed in female Akt1−/− mice compared to female wild-type mice. Neuromorphometric analyses revealed significantly reduced neurite complexity in hippocampal pyramidal neurons. Additionally, female Akt1−/− mice displayed increased hippocampal oscillation power and impaired spatial memory compared to female wild-type mice. Our findings suggest that Akt1 deficiency modulates GABAergic interneurons and GABAAR expression, contributing to hippocampus-dependent cognitive functional impairment. PMID:27615800

  16. Modulation of GABAergic transmission in development and neurodevelopmental disorders: investigating physiology and pathology to gain therapeutic perspectives

    PubMed Central

    Deidda, Gabriele; Bozarth, Ignacio F.; Cancedda, Laura

    2014-01-01

    During mammalian ontogenesis, the neurotransmitter GABA is a fundamental regulator of neuronal networks. In neuronal development, GABAergic signaling regulates neural proliferation, migration, differentiation, and neuronal-network wiring. In the adult, GABA orchestrates the activity of different neuronal cell-types largely interconnected, by powerfully modulating synaptic activity. GABA exerts these functions by binding to chloride-permeable ionotropic GABAA receptors and metabotropic GABAB receptors. According to its functional importance during development, GABA is implicated in a number of neurodevelopmental disorders such as autism, Fragile X, Rett syndrome, Down syndrome, schizophrenia, Tourette's syndrome and neurofibromatosis. The strength and polarity of GABAergic transmission is continuously modulated during physiological, but also pathological conditions. For GABAergic transmission through GABAA receptors, strength regulation is achieved by different mechanisms such as modulation of GABAA receptors themselves, variation of intracellular chloride concentration, and alteration in GABA metabolism. In the never-ending effort to find possible treatments for GABA-related neurological diseases, of great importance would be modulating GABAergic transmission in a safe and possibly physiological way, without the dangers of either silencing network activity or causing epileptic seizures. In this review, we will discuss the different ways to modulate GABAergic transmission normally at work both during physiological and pathological conditions. Our aim is to highlight new research perspectives for therapeutic treatments that reinstate natural and physiological brain functions in neuro-pathological conditions. PMID:24904277

  17. Dopamine synapse is a neuroligin-2–mediated contact between dopaminergic presynaptic and GABAergic postsynaptic structures

    PubMed Central

    Uchigashima, Motokazu; Ohtsuka, Toshihisa; Kobayashi, Kazuto; Watanabe, Masahiko

    2016-01-01

    Midbrain dopamine neurons project densely to the striatum and form so-called dopamine synapses on medium spiny neurons (MSNs), principal neurons in the striatum. Because dopamine receptors are widely expressed away from dopamine synapses, it remains unclear how dopamine synapses are involved in dopaminergic transmission. Here we demonstrate that dopamine synapses are contacts formed between dopaminergic presynaptic and GABAergic postsynaptic structures. The presynaptic structure expressed tyrosine hydroxylase, vesicular monoamine transporter-2, and plasmalemmal dopamine transporter, which are essential for dopamine synthesis, vesicular filling, and recycling, but was below the detection threshold for molecules involving GABA synthesis and vesicular filling or for GABA itself. In contrast, the postsynaptic structure of dopamine synapses expressed GABAergic molecules, including postsynaptic adhesion molecule neuroligin-2, postsynaptic scaffolding molecule gephyrin, and GABAA receptor α1, without any specific clustering of dopamine receptors. Of these, neuroligin-2 promoted presynaptic differentiation in axons of midbrain dopamine neurons and striatal GABAergic neurons in culture. After neuroligin-2 knockdown in the striatum, a significant decrease of dopamine synapses coupled with a reciprocal increase of GABAergic synapses was observed on MSN dendrites. This finding suggests that neuroligin-2 controls striatal synapse formation by giving competitive advantage to heterologous dopamine synapses over conventional GABAergic synapses. Considering that MSN dendrites are preferential targets of dopamine synapses and express high levels of dopamine receptors, dopamine synapse formation may serve to increase the specificity and potency of dopaminergic modulation of striatal outputs by anchoring dopamine release sites to dopamine-sensing targets. PMID:27035941

  18. The GAD65 knock out mouse - a model for GABAergic processes in fear- and stress-induced psychopathology.

    PubMed

    Müller, Iris; Çalışkan, Gürsel; Stork, Oliver

    2015-01-01

    The γ-amino butyric acid (GABA) synthetic enzyme glutamic acid decarboxylase (GAD)65 is critically involved in the activity-dependent regulation of GABAergic inhibition in the central nervous system. It is also required for the maturation of the GABAergic system during adolescence, a phase that is critical for the development of several neuropsychiatric diseases. Mice bearing a null mutation of the GAD65 gene develop hyperexcitability of the amygdala and hippocampus, and a phenotype of increased anxiety and pathological fear memory reminiscent of posttraumatic stress disorder. Although genetic association of GAD65 in human has not yet been reported, these findings are in line with observations of reduced GABAergic function in these brain regions of anxiety disorder patients. The particular value of GAD65(-/-) mice thus lies in modeling the effects of reduced GABAergic function in the mature nervous system. The expression of GAD65 and a second GAD isozyme, GAD67, are differentially regulated in response to stress in limbic brain areas suggesting that by controlling GABAergic inhibition these enzymes determine the vulnerability for the development of pathological anxiety and other stress-induced phenotypes. In fact, we could recently show that GAD65 haplodeficiency, which results in delayed postnatal increase of GABA levels, provides resilience to juvenile-stress-induced anxiety to GAD65(+/-) mice thus foiling the increased fear and anxiety in homozygous GAD65(-/-) mice.

  19. GABAergic neurons of the medial septum play a nodal role in facilitation of nociception-induced affect

    PubMed Central

    Ang, Seok Ting; Lee, Andy Thiam Huat; Foo, Fang Chee; Ng, Lynn; Low, Chian-Ming; Khanna, Sanjay

    2015-01-01

    The present study explored the functional details of the influence of medial septal region (MSDB) on spectrum of nociceptive behaviours by manipulating intraseptal GABAergic mechanisms. Results showed that formalin-induced acute nociception was not affected by intraseptal microinjection of bicuculline, a GABAA receptor antagonist, or on selective lesion of septal GABAergic neurons. Indeed, the acute nociceptive responses were dissociated from the regulation of sensorimotor behaviour and generation of theta-rhythm by the GABAergic mechanisms in MSDB. The GABAergic lesion attenuated formalin-induced unconditioned cellular response in the anterior cingulate cortex (ACC) and blocked formalin-induced conditioned place avoidance (F-CPA), and as well as the contextual fear induced on conditioning with brief footshock. The effects of lesion on nociceptive-conditioned cellular responses were, however, variable. Interestingly, the lesion attenuated the conditioned representation of experimental context in dorsal hippocampus field CA1 in the F-CPA task. Collectively, the preceding suggests that the MSDB is a nodal centre wherein the GABAergic neurons mediate nociceptive affect-motivation by regulating cellular mechanisms in ACC that confer an aversive value to the noxious stimulus. Further, in conjunction with a modulatory influence on hippocampal contextual processing, MSDB may integrate affect with context as part of associative learning in the F-CPA task. PMID:26487082

  20. Activation of mu-opioid receptors in the ventrolateral orbital cortex inhibits the GABAergic miniature inhibitory postsynaptic currents in rats.

    PubMed

    Qu, Chao-Ling; Huo, Fu-Quan; Huang, Fen-Sheng; Tang, Jing-Shi

    2015-04-10

    Previous studies have indicated that mu-opioid receptors in the ventrolateral orbital cortex (VLO) are involved in antinociception in tail flick tests and GABAergic neurons or terminals express mu-opioid receptors in the VLO. The current study examined the effect of selective mu-opioid receptor agonist DAMGO on the GABAergic miniature inhibitory postsynaptic currents (mIPSCs) in the VLO in rats using the whole-cell patch clamp. The results demonstrated that 5 μM DAMGO application into the rat VLO slices significantly reduced the GABAergic mIPSCs frequency, without any effect on its amplitude, and this effect of DAMGO was reversed by pretreatment with selective mu-opioid receptor antagonist 1 μM CTOP. Importantly, application of CTOP alone into the VLO slices did not produce any effect on the frequency and amplitude of GABAergic mIPSCs. These results indicate a presynaptic effect of mu-opioid receptor activation on the GABAergic neurons in the VLO. The current data suggests that a presynaptic inhibition of the GABA release may contribute to the mu-opioid receptor mediated effects in the VLO and provides novel electrophysiological evidence for the underlying mechanisms of mu-opioid receptors in the VLO.

  1. GABAergic neurons of the medial septum play a nodal role in facilitation of nociception-induced affect.

    PubMed

    Ang, Seok Ting; Lee, Andy Thiam Huat; Foo, Fang Chee; Ng, Lynn; Low, Chian-Ming; Khanna, Sanjay

    2015-10-21

    The present study explored the functional details of the influence of medial septal region (MSDB) on spectrum of nociceptive behaviours by manipulating intraseptal GABAergic mechanisms. Results showed that formalin-induced acute nociception was not affected by intraseptal microinjection of bicuculline, a GABAA receptor antagonist, or on selective lesion of septal GABAergic neurons. Indeed, the acute nociceptive responses were dissociated from the regulation of sensorimotor behaviour and generation of theta-rhythm by the GABAergic mechanisms in MSDB. The GABAergic lesion attenuated formalin-induced unconditioned cellular response in the anterior cingulate cortex (ACC) and blocked formalin-induced conditioned place avoidance (F-CPA), and as well as the contextual fear induced on conditioning with brief footshock. The effects of lesion on nociceptive-conditioned cellular responses were, however, variable. Interestingly, the lesion attenuated the conditioned representation of experimental context in dorsal hippocampus field CA1 in the F-CPA task. Collectively, the preceding suggests that the MSDB is a nodal centre wherein the GABAergic neurons mediate nociceptive affect-motivation by regulating cellular mechanisms in ACC that confer an aversive value to the noxious stimulus. Further, in conjunction with a modulatory influence on hippocampal contextual processing, MSDB may integrate affect with context as part of associative learning in the F-CPA task.

  2. Dopamine D4 receptors regulate AMPA receptor trafficking and glutamatergic transmission in GABAergic interneurons of prefrontal cortex.

    PubMed

    Yuen, Eunice Y; Yan, Zhen

    2009-01-14

    GABAergic interneurons in prefrontal cortex (PFC) play a critical role in cortical circuits by providing feedforward and feedback inhibition and synchronizing neuronal activity. Impairments in GABAergic inhibition to PFC pyramidal neurons have been implicated in the abnormal neural synchrony and working memory disturbances in schizophrenia. The dopamine D(4) receptor, which is strongly linked to neuropsychiatric disorders, such as attention deficit-hyperactivity disorder (ADHD) and schizophrenia, is highly expressed in PFC GABAergic interneurons, while the physiological role of D(4) in these interneurons is largely unknown. In this study, we found that D(4) activation caused a persistent suppression of AMPAR-mediated synaptic transmission in PFC interneurons. This effect of D(4) receptors on AMPAR-EPSC was via a mechanism dependent on actin/myosin V motor-based transport of AMPA receptors, which was regulated by cofilin, a major actin depolymerizing factor. Moreover, we demonstrated that the major cofilin-specific phosphatase Slingshot, which was activated by calcineurin downstream of D(4) signaling, was required for the D(4) regulation of glutamatergic transmission. Thus, D(4) receptors, by using the unique calcineurin/Slingshot/cofilin signaling mechanism, regulate actin dynamics and AMPAR trafficking in PFC GABAergic interneurons. It provides a potential mechanism for D(4) receptors to control the excitatory synaptic strength in local-circuit neurons and GABAergic inhibition in the PFC network, which may underlie the role of D(4) receptors in normal cognitive processes and mental disorders.

  3. Ascl1 as a novel player in the Ptf1a transcriptional network for GABAergic cell specification in the retina.

    PubMed

    Mazurier, Nicolas; Parain, Karine; Parlier, Damien; Pretto, Silvia; Hamdache, Johanna; Vernier, Philippe; Locker, Morgane; Bellefroid, Eric; Perron, Muriel

    2014-01-01

    In contrast with the wealth of data involving bHLH and homeodomain transcription factors in retinal cell type determination, the molecular bases underlying neurotransmitter subtype specification is far less understood. Using both gain and loss of function analyses in Xenopus, we investigated the putative implication of the bHLH factor Ascl1 in this process. We found that in addition to its previously characterized proneural function, Ascl1 also contributes to the specification of the GABAergic phenotype. We showed that it is necessary for retinal GABAergic cell genesis and sufficient in overexpression experiments to bias a subset of retinal precursor cells towards a GABAergic fate. We also analysed the relationships between Ascl1 and a set of other bHLH factors using an in vivo ectopic neurogenic assay. We demonstrated that Ascl1 has unique features as a GABAergic inducer and is epistatic over factors endowed with glutamatergic potentialities such as Neurog2, NeuroD1 or Atoh7. This functional specificity is conferred by the basic DNA binding domain of Ascl1 and involves a specific genetic network, distinct from that underlying its previously demonstrated effects on catecholaminergic differentiation. Our data show that GABAergic inducing activity of Ascl1 requires the direct transcriptional regulation of Ptf1a, providing therefore a new piece of the network governing neurotransmitter subtype specification during retinogenesis.

  4. GABAergic influence on temporomandibular joint-responsive spinomedullary neurons depends on estrogen status.

    PubMed

    Tashiro, A; Bereiter, D A; Thompson, R; Nishida, Y

    2014-02-14

    Sensory input from the temporomandibular joint (TMJ) to neurons in superficial laminae at the spinomedullary (Vc/C1-2) region is strongly influenced by estrogen status. This study determined if GABAergic mechanisms play a role in estrogen modulation of TMJ nociceptive processing in ovariectomized female rats treated with high- (HE) or low-dose (LE) estradiol (E2) for 2days. Superficial laminae neurons were activated by ATP (1mM) injections into the joint space. The selective GABAA receptor antagonist, bicuculline methiodide (BMI, 5 or 50μM, 30μl), applied at the site of recording greatly enhanced the magnitude and duration of ATP-evoked responses in LE rats, but not in units from HE rats. The convergent cutaneous receptive field (RF) area of TMJ neurons was enlarged after BMI in LE but not HE rats, while resting discharge rates were increased after BMI independent of estrogen status. By contrast, the selective GABAA receptor agonist, muscimol (50μM, 30μl), significantly reduced the magnitude and duration of ATP-evoked activity, resting discharge rate, and cutaneous RF area of TMJ neurons in LE and HE rats, whereas lower doses (5μM) affected only units from LE rats. Protein levels of GABAA receptor β3 isoform at the Vc/C1-2 region were similar for HE and LE rats. These results suggest that GABAergic mechanisms contribute significantly to background discharge rates and TMJ-evoked input to superficial laminae neurons at the Vc/C1-2 region. Estrogen status may gate the magnitude of GABAergic influence on TMJ neurons at the earliest stages of nociceptive processing at the spinomedullary region.

  5. Post-tetanic potentiation of GABAergic IPSCs in cultured rat hippocampal neurones

    PubMed Central

    Jensen, Kimmo; Jensen, Morten Skovgaard; Lambert, John D C

    1999-01-01

    Dual whole-cell patch-clamp recording was used to investigate post-tetanic potentiation (PTP) of GABAergic IPSCs evoked between pairs of cultured rat hippocampal neurones. Tetanization of the presynaptic neurone at frequencies (f) ranging from 5 to 100 Hz resulted in PTP of the IPSCs. Maximum PTP had a magnitude of 51.6 % just after the stimulus train, and lasted up to 1 min. PTP was shown to be dependent on the number of stimuli in the train, but independent of f at frequencies ≥ 5 Hz. Blocking postsynaptic GABAA receptors with bicuculline during the tetanus did not affect the expression of PTP, showing that it is a presynaptic phenomenon. PTP was strongly affected by changing [Ca2+]oduring the tetanus: PTP was reduced by lowering [Ca2+]o, and increased by high [Ca2+]o. PTP was still present after presynaptic injection of BAPTA or EGTA, or following perfusion of the membrane-permeable ester EGTA-tetraacetoxymethyl ester (EGTA AM, 50 μM). On the other hand, EGTA AM blocked spontaneous, asynchronous IPSCs (asIPSCs), which were often associated with tetanic stimulation. Tetanic stimulation in the presence of 4-aminopyridine (4-AP), which promotes presynaptic Ca2+ influx, evoked sustained PTP of IPSCs in half of the neurones tested. The results indicate that PTP at inhibitory GABAergic synapses is related to the magnitude of presynaptic Ca2+ influx during the tetanic stimulation, leading to an enhanced probability of vesicle release in the post-tetanic period. The increase in [Ca2+]i occurs despite the presence of high-affinity exogenous and endogenous intracellular Ca2+ buffers. That PTP of IPSCs depends on the number, and not the frequency, of spikes in the GABAergic neurone is in accordance with a slow clearing of intracellular Ca2+ from the presynaptic terminals. PMID:10432340

  6. Genetic Deletion of the Clathrin Adaptor GGA3 Reduces Anxiety and Alters GABAergic Transmission

    PubMed Central

    Albrecht, David; Lomoio, Selene; Haydon, Philip G.; Moss, Stephen J.; Tesco, Giuseppina

    2016-01-01

    Golgi-localized γ-ear-containing ARF binding protein 3 (GGA3) is a monomeric clathrin adaptor that has been shown to regulate the trafficking of the Beta-site APP-cleaving enzyme (BACE1), which is required for production of the Alzheimer’s disease (AD)-associated amyloid βpeptide. Our previous studies have shown that BACE1 is degraded via the lysosomal pathway and that depletion of GGA3 results in increased BACE1 levels and activity owing to impaired lysosomal trafficking and degradation. We further demonstrated the role of GGA3 in the regulation of BACE1 in vivo by showing that BACE1 levels are increased in the brain of GGA3 null mice. We report here that GGA3 deletion results in novelty-induced hyperactivity and decreased anxiety-like behaviors. Given the pivotal role of GABAergic transmission in the regulation of anxiety-like behaviors, we performed electrophysiological recordings in hippocampal slices and found increased phasic and decreased tonic inhibition in the dentate gyrus granule cells (DGGC). Moreover, we found that the number of inhibitory synapses is increased in the dentate gyrus of GGA3 null mice in further support of the electrophysiological data. Thus, the increased GABAergic transmission is a leading candidate mechanism underlying the reduced anxiety-like behaviors observed in GGA3 null mice. All together these findings suggest that GGA3 plays a key role in GABAergic transmission. Since BACE1 levels are elevated in the brain of GGA3 null mice, it is possible that at least some of these phenotypes are a consequence of increased processing of BACE1 substrates. PMID:27192432

  7. Presynaptic glycine receptors on GABAergic terminals facilitate discharge of dopaminergic neurons in ventral tegmental area.

    PubMed

    Ye, Jiang-Hong; Wang, Fushun; Krnjevic, Kresimir; Wang, Weizhen; Xiong, Zhi-Gang; Zhang, Jingli

    2004-10-13

    GABA-mediated postsynaptic currents (IPSCs) were recorded from dopaminergic (DA) neurons of the ventral tegmental area (VTA) of rats, in acute brain slices, and from enzymatically or mechanically dissociated neurons. In young rats (3-10 d of age), where GABA is excitatory, glycine (1-3 microm) and taurine (10-30 microm) increased the amplitude of evoked IPSCs (eIPSCs) and the frequency of spontaneous IPSCs (sIPSCs) but had minimal postsynaptic effects. Strychnine (1 microm) blocked the action of glycine; when applied alone, it reduced the amplitude of eIPSCs and the frequency of sIPSCs, indicating a tonic facilitation of GABAergic excitation by some endogenous glycine agonist(s). In medium containing no Ca2+, or with Cd2+ or tetrodotoxin added, the amplitude and especially the frequency of sIPSCs greatly diminished. In many cells, glycine had no effect on remaining miniature IPSCs, suggesting a preterminal site of glycine receptors (GlyRs). Fura-2 fluorescent imaging showed a glycine-induced increase of [Ca2+] in nerve terminals (on DA neurons), which was suppressed by strychnine or 3 microm omega-conotoxin MVIIA. Therefore, the presynaptic GlyR-mediated facilitation of GABAergic transmission seems to be mediated by N- and/or P/Q-type Ca2+ channels. In older rats (22-30 d of age), where GABA causes inhibition, the effect of strychnine on GABAergic IPSCs was reversed to facilitation, indicating a tonic glycinergic inhibition of GABA release. Furthermore, glycine (1-3 microm) reduced the amplitude of eIPSCs and the frequency of sIPSCs. Hence, the overall effect of the presynaptic action of glycine is to enhance the firing of DA cells, both in very young and older rats.

  8. Functional Synaptic Integration of Forebrain GABAergic Precursors into the Adult Spinal Cord

    PubMed Central

    Etlin, Alex; Bráz, Joao M.; Kuhn, Julia A.; Wang, Xidao; Hamel, Katherine A.; Llewellyn-Smith, Ida J.

    2016-01-01

    Spinal cord transplants of embryonic cortical GABAergic progenitor cells derived from the medial ganglionic eminence (MGE) can reverse mechanical hypersensitivity in the mouse models of peripheral nerve injury- and paclitaxel-induced neuropathic pain. Here, we used electrophysiology, immunohistochemistry, and electron microscopy to examine the extent to which MGE cells integrate into host circuitry and recapitulate endogenous inhibitory circuits. Whether the transplants were performed before or after nerve injury, the MGE cells developed into mature neurons and exhibited firing patterns characteristic of subpopulations of cortical and spinal cord inhibitory interneurons. Conversely, the transplanted cells preserved cortical morphological and neurochemical properties. We also observed a robust anatomical and functional synaptic integration of the transplanted cells into host circuitry in both injured and uninjured animals. The MGE cells were activated by primary afferents, including TRPV1-expressing nociceptors, and formed GABAergic, bicuculline-sensitive, synapses onto host neurons. Unexpectedly, MGE cells transplanted before injury prevented the development of mechanical hypersensitivity. Together, our findings provide direct confirmation of an extensive, functional synaptic integration of MGE cells into host spinal cord circuits. This integration underlies normalization of the dorsal horn inhibitory tone after injury and may be responsible for the prophylactic effect of preinjury transplants. SIGNIFICANCE STATEMENT Spinal cord transplants of embryonic cortical GABAergic interneuron progenitors from the medial ganglionic eminence (MGE), can overcome the mechanical hypersensitivity produced in different neuropathic pain models in adult mice. Here, we examined the properties of transplanted MGE cells and the extent to which they integrate into spinal cord circuitry. Using electrophysiology, immunohistochemistry, and electron microscopy, we demonstrate that MGE cells

  9. POSTSYNAPTIC TARGETS OF GABAERGIC BASAL FOREBRAIN PROJECTIONS TO THE BASOLATERAL AMYGDALA

    PubMed Central

    McDonald, A. J.; Muller, J. F.; Mascagni, F.

    2011-01-01

    Recent studies indicate that the basolateral amygdala, like the neocortex and hippocampus, receives GABAergic inputs from the basal forebrain in addition to the well-established cholinergic inputs. Since the neuronal targets of these inputs have yet to be determined, it is difficult to predict the functional significance of this innervation. The present study addressed this question in the rat by employing anterograde tract tracing combined with immunohistochemistry at the light and electron microscopic levels of analysis. Amygdalopetal axons from the basal forebrain mainly targeted the basolateral nucleus (BL) of the amygdala. The morphology of these axons was heterogeneous and included GABAergic axons that contained vesicular GABA transporter protein (VGAT). These axons, designated type 1, exhibited distinctive large axonal varicosities that were typically clustered along the length of the axon. Type 1 axons formed multiple contacts with the cell bodies and dendrites of parvalbumin-containing (PV+) interneurons, but relatively few contacts with calretinin-containing and somatostatin-containing interneurons. At the ultrastructural level of analysis, the large terminals of type 1 axons exhibited numerous mitochondria and were densely packed with synaptic vesicles. Individual terminals formed broad symmetrical synapses with BL PV+ interneurons, and often formed additional symmetrical synapses with BL pyramidal cells. Some solitary type 1 terminals formed symmetrical synapses solely with BL pyramidal cells. These results suggest that GABAergic neurons of the basal forebrain provide indirect disinhibition, as well as direct inhibition, of BL pyramidal neurons. The possible involvement of these circuits in rhythmic oscillations related to emotional learning, attention, and arousal is discussed. PMID:21435381

  10. Endocannabinoids and prostaglandins both contribute to GnRH neuron-GABAergic afferent local feedback circuits

    PubMed Central

    Glanowska, Katarzyna M.

    2011-01-01

    Gonadotropin-releasing hormone (GnRH) neurons form the final common pathway for central control of fertility. Regulation of GnRH neurons by long-loop gonadal steroid feedback through steroid receptor-expressing afferents such as GABAergic neurons is well studied. Recently, local central feedback circuits regulating GnRH neurons were identified. GnRH neuronal depolarization induces short-term inhibition of their GABAergic afferents via a mechanism dependent on metabotropic glutamate receptor (mGluR) activation. GnRH neurons are enveloped in astrocytes, which express mGluRs. GnRH neurons also produce endocannabinoids, which can be induced by mGluR activation. We hypothesized the local GnRH-GABA circuit utilizes glia-derived and/or cannabinoid mechanisms and is altered by steroid milieu. Whole cell voltage-clamp was used to record GABAergic postsynaptic currents (PSCs) from GnRH neurons before and after action potential-like depolarizations were mimicked. In GnRH neurons from ovariectomized (OVX) mice, this depolarization reduced PSC frequency. This suppression was blocked by inhibition of prostaglandin synthesis with indomethacin, by a prostaglandin receptor antagonist, or by a specific glial metabolic poison, together suggesting the postulate that prostaglandins, potentially glia-derived, play a role in this circuit. This circuit was also inhibited by a CB1 receptor antagonist or by blockade of endocannabinoid synthesis in GnRH neurons, suggesting an endocannabinoid element, as well. In females, local circuit inhibition persisted in androgen-treated mice but not in estradiol-treated mice or young ovary-intact mice. In contrast, local circuit inhibition was present in gonad-intact males. These data suggest GnRH neurons interact with their afferent neurons using multiple mechanisms and that these local circuits can be modified by both sex and steroid feedback. PMID:21917995

  11. Permutation Lempel-Ziv complexity measure of electroencephalogram in GABAergic anaesthetics.

    PubMed

    Bai, Yang; Liang, Zhenhu; Li, Xiaoli; Voss, Logan J; Sleigh, Jamie W

    2015-12-01

    Monitoring the brain state in anaesthesia is crucial for clinical doctors. In this study, we propose a novel nonlinear method, the permutation Lempel-Ziv complexity (PLZC) index, which describes the complexity in the electroencephalographic (EEG) signal to quantify the effect of GABAergic anaesthetics on brain activities.We applied the PLZC to two EEG data sets that were recorded under sevoflurane and propofol anaesthesia. The results are compared with traditional mean value-based Lempel-Ziv complexity (LZC), permutation entropy (PE), composite PE index (CPEI), response entropy (RE), state entropy (SE) and bispectral index (BIS) or SynchFastSlow (SFS, derived from BIS). Pharmacokinetic/pharmacodynamic (PK/PD) modelling and prediction probability (Pk) were used to assess the performance of the proposed method for tracking GABAergic anaesthetic concentrations.We found that PLZC correlates closely with the anaesthetic drug effect. When applied in sevoflurane anaesthesia, the coefficient of determination R2 between the PLZC values and the sevoflurane effect site concentrations was (0.90 ± 0.07), mean  ±  standard deviation), and the prediction probability Pk was (0.85 ± 0.04). These values were higher than those for the other indices. While in propofol anaesthesia, the value of R2 between PLZC and the effect site concentrations was (0.89 +/- 0.07), and the Pk was (0.86 +/- 0.28), which were close to those for CPEI but better than those for the others.PLZC based on electroencephalogram signals can be used as a new index to characterize the depth of anaesthesia. This index outperformed LZC, PE, CPEI, RE, SE, and BIS or SFS in tracking drug concentration changes during GABAergic anaesthetics.PLZC is a potentially superior method for applications in intra-operative monitoring.

  12. Substance P excites GABAergic neurons in the mouse central amygdala through neurokinin 1 receptor activation

    PubMed Central

    Sosulina, L.; Strippel, C.; Romo-Parra, H.; Walter, A. L.; Kanyshkova, T.; Sartori, S. B.; Lange, M. D.; Singewald, N.

    2015-01-01

    Substance P (SP) is implicated in stress regulation and affective and anxiety-related behavior. Particularly high expression has been found in the main output region of the amygdala complex, the central amygdala (CE). Here we investigated the cellular mechanisms of SP in CE in vitro, taking advantage of glutamic acid decarboxylase-green fluorescent protein (GAD67-GFP) knockin mice that yield a reliable labeling of GABAergic neurons, which comprise 95% of the neuronal population in the lateral section of CE (CEl). In GFP-positive neurons within CEl, SP caused a membrane depolarization and increase in input resistance, associated with an increase in action potential firing frequency. Under voltage-clamp conditions, the SP-specific membrane current reversed at −101.5 ± 2.8 mV and displayed inwardly rectifying properties indicative of a membrane K+ conductance. Moreover, SP responses were blocked by the neurokinin type 1 receptor (NK1R) antagonist L-822429 and mimicked by the NK1R agonist [Sar9,Met(O2)11]-SP. Immunofluorescence staining confirmed localization of NK1R in GFP-positive neurons in CEl, predominantly in PKCδ-negative neurons (80%) and in few PKCδ-positive neurons (17%). Differences in SP responses were not observed between the major types of CEl neurons (late firing, regular spiking, low-threshold bursting). In addition, SP increased the frequency and amplitude of GABAergic synaptic events in CEl neurons depending on upstream spike activity. These data indicate a NK1R-mediated increase in excitability and GABAergic activity in CEl neurons, which seems to mostly involve the PKCδ-negative subpopulation. This influence can be assumed to increase reciprocal interactions between CElon and CEloff pathways, thereby boosting the medial CE (CEm) output pathway and contributing to the anxiogenic-like action of SP in the amygdala. PMID:26334021

  13. GABAergic Neurons Immunoreactive for Calcium Binding Proteins are Reduced in the Prefrontal Cortex in Major Depression

    PubMed Central

    Rajkowska, Grazyna; O'Dwyer, Gillian; Teleki, Zsofia; Stockmeier, Craig A; Miguel-Hidalgo, Jose Javier

    2009-01-01

    Post-mortem morphometric studies report reductions in the average density and size of cortical neurons in the dorsolateral prefrontal cortex (dlPFC) and orbitofrontal cortex (ORB) in major depressive disorder (MDD). The contribution of specific neuronal phenotypes to this general pathology in depression is still unclear. Post-mortem sections from the dlPFC and ORB regions of 14 subjects with MDD and 11 controls were immunostained to visualize calbindin-immunoreactive (CB-IR) and parvalbumin-immunoreactive (PV-IR) presumptive GABAergic neurons. A three-dimensional cell counting probe was used to assess the cell packing density and size of CB-IR neurons in layers II + IIIa and PV-IR neurons in layers III–VI. The density of CB-IR neurons was significantly reduced by 50% in depression in the dlPFC and there was a trend toward reduction in the ORB. The size of CB-IR somata was significantly decreased (18%) in depression in the dlPFC with a trend toward reduction in the ORB. In contrast, there was no difference in the density of PV-IR neurons between the depressed and control groups in the dlPFC. The size of PV-IR neuronal soma was unchanged in depressed compared to control subjects in either dlPFC or ORB. In depression, subpopulations of GABAergic neurons may be affected differently in dlPFC and ORB. A significant reduction in the density and size of GABAergic interneurons immunoreactive for calcium binding proteins was found predominantly in the dlPFC region. These cellular changes are consistent with recent neuroimaging studies revealing a reduction in the cortical levels of GABA in depression. PMID:17063153

  14. Prefrontal cognitive deficits in mice with altered cerebral cortical GABAergic interneurons

    PubMed Central

    Bissonette, Gregory B.; Bae, Mihyun H.; Suresh, Tejas; Jaffe, David E.; Powell, Elizabeth M.

    2013-01-01

    Alterations of inhibitory GABAergic neurons are implicated in multiple psychiatric and neurological disorders, including schizophrenia, autism and epilepsy. In particular, interneuron deficits in prefrontal areas, along with presumed decreased inhibition, have been reported in several human patients. The majority of forebrain GABAergic interneurons arise from a single subcortical source before migrating to their final regional destination. Factors that govern the interneuron populations have been identified, demonstrating that a single gene mutation may globally affect forebrain structures or a single area. In particular, mice lacking the urokinase plasminogen activator receptor (Plaur) gene have decreased GABAergic interneurons in frontal and parietal, but not caudal, cortical regions. Plaur assists in the activation of hepatocyte growth factor/scatter factor (HGF/SF), and several of the interneuron deficits are correlated with decreased levels of HGF/SF. In some cortical regions, the interneuron deficit can be remediated by endogenous overexpression of HGF/SF. In this study, we demonstrate decreased parvalbumin-expressing interneurons in the medial frontal cortex, but not in the hippocampus or basal lateral amygdala in the Plaur null mouse. The Plaur null mouse demonstrates impaired medial frontal cortical function in extinction of cued fear conditioning and the inability to form attentional sets. Endogenous HGF/SF overexpression increased the number of PV-expressing cells in medial frontal cortical areas to levels greater than found in wildtype mice, but did not remediate the behavioral deficits. These data suggest that proper medial frontal cortical function is dependent upon optimum levels of inhibition and that a deficit or excess of interneuron numbers impairs normal cognition. PMID:24211452

  15. Toxoplasma gondii Infections Alter GABAergic Synapses and Signaling in the Central Nervous System

    PubMed Central

    Brooks, Justin M.; Carrillo, Gabriela L.; Su, Jianmin; Lindsay, David S.; Blader, Ira J.

    2015-01-01

    ABSTRACT During infections with the protozoan parasite Toxoplasma gondii, gamma-aminobutyric acid (GABA) is utilized as a carbon source for parasite metabolism and also to facilitate parasite dissemination by stimulating dendritic-cell motility. The best-recognized function for GABA, however, is its role in the nervous system as an inhibitory neurotransmitter that regulates the flow and timing of excitatory neurotransmission. When this pathway is altered, seizures develop. Human toxoplasmosis patients suffer from seizures, suggesting that Toxoplasma interferes with GABA signaling in the brain. Here, we show that while excitatory glutamatergic presynaptic proteins appeared normal, infection with type II ME49 Toxoplasma tissue cysts led to global changes in the distribution of glutamic acid decarboxylase 67 (GAD67), a key enzyme that catalyzes GABA synthesis in the brain. Alterations in GAD67 staining were not due to decreased expression but rather to a change from GAD67 clustering at presynaptic termini to a more diffuse localization throughout the neuropil. Consistent with a loss of GAD67 from the synaptic terminals, Toxoplasma-infected mice develop spontaneous seizures and are more susceptible to drugs that induce seizures by antagonizing GABA receptors. Interestingly, GABAergic protein mislocalization and the response to seizure-inducing drugs were observed in mice infected with type II ME49 but not type III CEP strain parasites, indicating a role for a polymorphic parasite factor(s) in regulating GABAergic synapses. Taken together, these data support a model in which seizures and other neurological complications seen in Toxoplasma-infected individuals are due, at least in part, to changes in GABAergic signaling. PMID:26507232

  16. The presence of pacemaker HCN channels identifies theta rhythmic GABAergic neurons in the medial septum.

    PubMed

    Varga, Viktor; Hangya, Balázs; Kránitz, Kinga; Ludányi, Anikó; Zemankovics, Rita; Katona, István; Shigemoto, Ryuichi; Freund, Tamás F; Borhegyi, Zsolt

    2008-08-15

    The medial septum (MS) is an indispensable component of the subcortical network which synchronizes the hippocampus at theta frequency during specific stages of information processing. GABAergic neurons exhibiting highly regular firing coupled to the hippocampal theta rhythm are thought to form the core of the MS rhythm-generating network. In recent studies the hyperpolarization-activated, cyclic nucleotide-gated non-selective cation (HCN) channel was shown to participate in theta synchronization of the medial septum. Here, we tested the hypothesis that HCN channel expression correlates with theta modulated firing behaviour of MS neurons by a combined anatomical and electrophysiological approach. HCN-expressing neurons represented a subpopulation of GABAergic cells in the MS partly overlapping with parvalbumin (PV)-containing neurons. Rhythmic firing in the theta frequency range was characteristic of all HCN-expressing neurons. In contrast, only a minority of HCN-negative cells displayed theta related activity. All HCN cells had tight phase coupling to hippocampal theta waves. As a group, PV-expressing HCN neurons had a marked bimodal phase distribution, whereas PV-immunonegative HCN neurons did not show group-level phase preference despite significant individual phase coupling. Microiontophoretic blockade of HCN channels resulted in the reduction of discharge frequency, but theta rhythmic firing was perturbed only in a few cases. Our data imply that HCN-expressing GABAergic neurons provide rhythmic drive in all phases of the hippocampal theta activity. In most MS theta cells rhythm genesis is apparently determined by interactions at the level of the network rather than by the pacemaking property of HCN channels alone.

  17. Deficient tonic GABAergic conductance and synaptic balance in the fragile X syndrome amygdala

    PubMed Central

    Martin, Brandon S.; Corbin, Joshua G.

    2014-01-01

    Fragile X syndrome (FXS) is the leading cause of inherited intellectual disability. Comorbidities of FXS such as autism are increasingly linked to imbalances in excitation and inhibition (E/I) as well as dysfunction in GABAergic transmission in a number of brain regions including the amygdala. However, the link between E/I imbalance and GABAergic transmission deficits in the FXS amygdala is poorly understood. Here we reveal that normal tonic GABAA receptor-mediated neurotransmission in principal neurons (PNs) of the basolateral amygdala (BLA) is comprised of both δ- and α5-subunit-containing GABAA receptors. Furthermore, tonic GABAergic capacity is reduced in these neurons in the Fmr1 knockout (KO) mouse model of FXS (1.5-fold total, 3-fold δ-subunit, and 2-fold α5-subunit mediated) as indicated by application of gabazine (50 μM), 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP, 1 μM), and α5ia (1.5 μM) in whole cell patch-clamp recordings. Moreover, α5-containing tonic GABAA receptors appear to preferentially modulate nonsomatic compartments of BLA PNs. Examination of evoked feedforward synaptic transmission in these cells surprisingly revealed no differences in overall synaptic conductance or E/I balance between wild-type (WT) and Fmr1 KO mice. Instead, we observed altered feedforward kinetics in Fmr1 KO PNs that supports a subtle yet significant decrease in E/I balance at the peak of excitatory conductance. Blockade of α5-subunit-containing GABAA receptors replicated this condition in WT PNs. Therefore, our data suggest that tonic GABAA receptor-mediated neurotransmission can modulate synaptic E/I balance and timing established by feedforward inhibition and thus may represent a therapeutic target to enhance amygdala function in FXS. PMID:24848467

  18. Selective plasticity of hippocampal GABAergic interneuron populations following kindling of different brain regions.

    PubMed

    Botterill, J J; Nogovitsyn, N; Caruncho, H J; Kalynchuk, L E

    2017-02-01

    The vulnerability and plasticity of hippocampal GABAergic interneurons is a topic of broad interest and debate in the field of epilepsy. In this experiment, we used the electrical kindling model of epilepsy to determine whether seizures that originate in different brain regions have differential effects on hippocampal interneuron subpopulations. Long-Evans rats received 99 electrical stimulations of the hippocampus, amygdala, or caudate nucleus, followed by sacrifice and immunohistochemical or western blot analyses. We analyzed markers of dendritic (somatostatin), perisomatic (parvalbumin), and interneuron-selective (calretinin) inhibition, as well as an overall indicator (GAD67) of interneuron distribution across all major hippocampal subfields. Our results indicate that kindling produces selective effects on the number and morphology of different functional classes of GABAergic interneurons. In particular, limbic kindling appears to enhance dendritic inhibition, indicated by a greater number of somatostatin-immunoreactive (-ir) cells in the CA1 pyramidal layer and robust morphological sprouting in the dentate gyrus. We also found a reduction in the number of interneuron-selective calretinin-ir cells in the dentate gyrus of hippocampal-kindled rats, which suggests a possible reduction of synchronized dendritic inhibition. In contrast, perisomatic inhibition indicated by parvalbumin immunoreactivity appears to be largely resilient to the effects of kindling. Finally, we found a significant induction in the number of GAD67-cells in caudate-kindled rats in the dentate gyrus and CA3 hippocampal subfields. Taken together, our results demonstrate that kindling has subfield-selective effects on the different functional classes of hippocampal GABAergic interneurons. J. Comp. Neurol. 525:389-406, 2017. © 2016 Wiley Periodicals, Inc.

  19. Receptor Subtype-Dependent Galanin Actions on GABAergic Neurotransmission and Ethanol Responses in the Central Amygdala

    PubMed Central

    Bajo, Michal; Madamba, Samuel G.; Lu, Xiaoying; Sharkey, Lisa M.; Bartfai, Tamas; Siggins, George Robert

    2011-01-01

    The neuropeptide galanin and its three receptor subtypes (GalR1–3) are expressed in the central amygdala (CeA), a brain region involved in stress- and anxiety-related behaviors, as well as alcohol dependence. Galanin also has been suggested to play a role in alcohol intake and alcohol dependence. We examined the effects of galanin in CeA slices from wild type (WT) and knockout (KO) mice deficient of GalR2 and both GalR1 and GalR2 receptors. Galanin had dual effects on GABAergic transmission, decreasing the amplitudes of pharmacologically-isolated GABAergic inhibitory postsynaptic potentials (IPSPs) in over half of CeA neurons but augmenting IPSPs in the others. The increase in IPSP size was absent after superfusion of the GalR3 antagonist SNAP 37889, whereas the IPSP depression was absent in CeA neurons of GalR1 × GalR2 double KO and GalR2 KO mice. Paired-pulse facilitation studies showed weak or infrequent effects of galanin on GABA release. Thus, galanin may act postsynaptically through GalR3 to augment GABAergic transmission in some CeA neurons, whereas GalR2 receptors likely are involved in the depression of IPSPs. Co-superfusion of ethanol, which augments IPSPs presynaptically, together with galanin caused summated effects of ethanol and galanin in those CeA neurons showing galanin-augmented IPSPs, suggesting the two agents act via different mechanisms in this population. However, in neurons showing IPSP-diminishing galanin effects, galanin blunted the ethanol effects, suggesting a preemptive effect of galanin. These findings may increase understanding of the complex cellular mechanisms that underlie the anxiety-related behavioral effects of galanin and ethanol in CeA. PMID:21955024

  20. Glucose sensing by GABAergic neurons in the mouse nucleus tractus solitarii

    PubMed Central

    Boychuk, Carie R.; Gyarmati, Peter; Xu, Hong

    2015-01-01

    Changes in blood glucose concentration alter autonomic function in a manner consistent with altered neural activity in brain regions controlling digestive processes, including neurons in the brain stem nucleus tractus solitarii (NTS), which process viscerosensory information. With whole cell or on-cell patch-clamp recordings, responses to elevating glucose concentration from 2.5 to 15 mM were assessed in identified GABAergic NTS neurons in slices from transgenic mice that express EGFP in a subset of GABA neurons. Single-cell real-time RT-PCR was also performed to detect glutamic acid decarboxylase (GAD67) in recorded neurons. In most identified GABA neurons (73%), elevating glucose concentration from 2.5 to 15 mM resulted in either increased (40%) or decreased (33%) neuronal excitability, reflected by altered membrane potential and/or action potential firing. Effects on membrane potential were maintained when action potentials or fast synaptic inputs were blocked, suggesting direct glucose sensing by GABA neurons. Glucose-inhibited GABA neurons were found predominantly in the lateral NTS, whereas glucose-excited cells were mainly in the medial NTS, suggesting regional segregation of responses. Responses were prevented in the presence of glucosamine, a glucokinase (GCK) inhibitor. Depolarizing responses were prevented when KATP channel activity was blocked with tolbutamide. Whereas effects on synaptic input to identified GABAergic neurons were variable in GABA neurons, elevating glucose increased glutamate release subsequent to stimulation of tractus solitarius in unlabeled, unidentified neurons. These results indicate that GABAergic NTS neurons act as GCK-dependent glucose sensors in the vagal complex, providing a means of modulating central autonomic signals when glucose is elevated. PMID:26084907