Showing papers on "GABAergic published in 2018"

Transcriptomic and morphophysiological evidence for a specialized human cortical GABAergic cell type

Abstract: We describe convergent evidence from transcriptomics, morphology, and physiology for a specialized GABAergic neuron subtype in human cortex. Using unbiased single-nucleus RNA sequencing, we identify ten GABAergic interneuron subtypes with combinatorial gene signatures in human cortical layer 1 and characterize a group of human interneurons with anatomical features never described in rodents, having large ‘rosehip’-like axonal boutons and compact arborization. These rosehip cells show an immunohistochemical profile (GAD1+CCK+, CNR1–SST–CALB2–PVALB–) matching a single transcriptomically defined cell type whose specific molecular marker signature is not seen in mouse cortex. Rosehip cells in layer 1 make homotypic gap junctions, predominantly target apical dendritic shafts of layer 3 pyramidal neurons, and inhibit backpropagating pyramidal action potentials in microdomains of the dendritic tuft. These cells are therefore positioned for potent local control of distal dendritic computation in cortical pyramidal neurons.

Early emergence of cortical interneuron diversity in the mouse embryo

Abstract: GABAergic interneurons (GABA, γ-aminobutyric acid) regulate neural-circuit activity in the mammalian cerebral cortex. These cortical interneurons are structurally and functionally diverse. Here, we use single-cell transcriptomics to study the origins of this diversity in the mouse. We identify distinct types of progenitor cells and newborn neurons in the ganglionic eminences, the embryonic proliferative regions that give rise to cortical interneurons. These embryonic precursors show temporally and spatially restricted transcriptional patterns that lead to different classes of interneurons in the adult cerebral cortex. Our findings suggest that shortly after the interneurons become postmitotic, their diversity is already patent in their diverse transcriptional programs, which subsequently guide further differentiation in the developing cortex.

Inhibition in the amygdala anxiety circuitry

Abstract: Inhibitory neurotransmission plays a key role in anxiety disorders, as evidenced by the anxiolytic effect of the benzodiazepine class of γ-aminobutyric acid (GABA) receptor agonists and the recent discovery of anxiety-associated variants in the molecular components of inhibitory synapses. Accordingly, substantial interest has focused on understanding how inhibitory neurons and synapses contribute to the circuitry underlying adaptive and pathological anxiety behaviors. A key element of the anxiety circuitry is the amygdala, which integrates information from cortical and thalamic sensory inputs to generate fear and anxiety-related behavioral outputs. Information processing within the amygdala is heavily dependent on inhibitory control, although the specific mechanisms by which amygdala GABAergic neurons and synapses regulate anxiety-related behaviors are only beginning to be uncovered. Here, we summarize the current state of knowledge and highlight open questions regarding the role of inhibition in the amygdala anxiety circuitry. We discuss the inhibitory neuron subtypes that contribute to the processing of anxiety information in the basolateral and central amygdala, as well as the molecular determinants, such as GABA receptors and synapse organizer proteins, that shape inhibitory synaptic transmission within the anxiety circuitry. Finally, we conclude with an overview of current and future approaches for converting this knowledge into successful treatment strategies for anxiety disorders.

Heterogeneity and Diversity of Striatal GABAergic Interneurons: Update 2018.

Abstract: Our original review, "Heterogeneity and Diversity of Striatal GABAergic Interneurons," to which this is an invited update, was published in December, 2010 in Frontiers is Neuroanatomy. In that article, we reviewed several decades' worth of anatomical and electrophysiological data on striatal parvalbumin (PV)-, neuropeptide Y (NPY)- and calretinin(CR)-expressing GABAergic interneurons from many laboratories including our own. In addition, we reported on a recently discovered novel tyrosine hydroxylase (TH) expressing GABAergic interneuron class first revealed in transgenic TH EGFP reporter mouse line. In this review, we report on further advances in the understanding of the functional properties of previously reported striatal GABAergic interneurons and their synaptic connections. With the application of new transgenic fluorescent reporter and Cre-driver/reporter lines, plus optogenetic, chemogenetic and viral transduction methods, several additional subtypes of novel striatal GABAergic interneurons have been discovered, as well as the synaptic networks in which they are embedded. These findings make it clear that previous hypotheses in which striatal GABAergic interneurons modulate and/or control the firing of spiny neurons principally by simple feedforward and/or feedback inhibition are at best incomplete. A more accurate picture is one in which there are highly selective and specific afferent inputs, synaptic connections between different interneuron subtypes and spiny neurons and among different GABAergic interneurons that result in the formation of functional networks and ensembles of spiny neurons.

Opponent control of behavioral reinforcement by inhibitory and excitatory projections from the ventral pallidum

Abstract: The ventral pallidum (VP) lies at the interface between sensory, motor, and cognitive processing-with a particular role in mounting behavioral responses to rewards. Though the VP is predominantly GABAergic, glutamate neurons were recently identified, though their relative abundances and respective roles are unknown. Here, we show that VP glutamate neurons are concentrated in the rostral ventromedial VP and project to qualitatively similar targets as do VP GABA neurons. At the functional level, we used optogenetics to show that activity in VP GABA neurons can drive positive reinforcement, particularly through projections to the ventral tegmental area (VTA). On the other hand, activation of VP glutamate neurons leads to behavioral avoidance, particularly through projections to the lateral habenula. These findings highlight cell-type and projection-target specific roles for VP neurons in behavioral reinforcement, dysregulation of which could contribute to the emergence of negative symptoms associated with drug addiction and other neuropsychiatric disease.

GABAergic signaling linked to autophagy enhances host protection against intracellular bacterial infections.

Abstract: Gamma-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the brain; however, the roles of GABA in antimicrobial host defenses are largely unknown. Here we demonstrate that GABAergic activation enhances antimicrobial responses against intracellular bacterial infection. Intracellular bacterial infection decreases GABA levels in vitro in macrophages and in vivo in sera. Treatment of macrophages with GABA or GABAergic drugs promotes autophagy activation, enhances phagosomal maturation and antimicrobial responses against mycobacterial infection. In macrophages, the GABAergic defense is mediated via macrophage type A GABA receptor (GABAAR), intracellular calcium release, and the GABA type A receptor-associated protein-like 1 (GABARAPL1; an Atg8 homolog). Finally, GABAergic inhibition increases bacterial loads in mice and zebrafish in vivo, suggesting that the GABAergic defense plays an essential function in metazoan host defenses. Our study identified a previously unappreciated role for GABAergic signaling in linking antibacterial autophagy to enhance host innate defense against intracellular bacterial infection.

The GABAergic system as a therapeutic target for Alzheimer's disease

Abstract: Glutamatergic and cholinergic dysfunction are well-attested features of Alzheimer's disease (AD), progressing with other pathological indices of the disorder and exacerbating neuronal and network dysfunction. However, relatively little attention has been paid to the inhibitory component of the excitatory/inhibitory (E/I) network, particularly dysfunction in the gamma-aminobutyric acid (GABA) signaling system. There is growing evidence in support of GABAergic remodeling in the AD brain, potentially beginning in early stages of disease pathogenesis, and this could thus be a valid molecular target for drug development and pharmacological therapies. Several GABAergic drugs have been tested for efficacy in attenuating or reversing various features and symptoms of AD, and this could represent a novel path by which we might address the growing need for more effective and benign therapies.

Co-transmission of acetylcholine and GABA regulates hippocampal states.

Abstract: The basal forebrain cholinergic system is widely assumed to control cortical functions via non-synaptic transmission of a single neurotransmitter. Yet, we find that mouse hippocampal cholinergic terminals invariably establish GABAergic synapses, and their cholinergic vesicles dock at those synapses only. We demonstrate that these synapses do not co-release but co-transmit GABA and acetylcholine via different vesicles, whose release is triggered by distinct calcium channels. This co-transmission evokes composite postsynaptic potentials, which are mutually cross-regulated by presynaptic autoreceptors. Although postsynaptic cholinergic receptor distribution cannot be investigated, their response latencies suggest a focal, intra- and/or peri-synaptic localisation, while GABAA receptors are detected intra-synaptically. The GABAergic component alone effectively suppresses hippocampal sharp wave-ripples and epileptiform activity. Therefore, the differentially regulated GABAergic and cholinergic co-transmission suggests a hitherto unrecognised level of control over cortical states. This novel model of hippocampal cholinergic neurotransmission may lead to alternative pharmacotherapies after cholinergic deinnervation seen in neurodegenerative disorders.

Genetic and Molecular Regulation of Extrasynaptic GABA-A Receptors in the Brain: Therapeutic Insights for Epilepsy.

Abstract: GABA-A receptors play a pivotal role in many brain diseases. Epilepsy is caused by acquired conditions and genetic defects in GABA receptor channels regulating neuronal excitability in the brain. The latter is referred to as GABA channelopathies. In the last two decades, major advances have been made in the genetics of epilepsy. The presence of specific GABAergic genetic abnormalities leading to some of the classic epileptic syndromes has been identified. Advances in molecular cloning and recombinant systems have helped characterize mutations in GABA-A receptor subunit genes in clinical neurology. GABA-A receptors are the prime targets for neurosteroids (NSs). However, GABA-A receptors are not static but undergo rapid changes in their number or composition in response to the neuroendocrine milieu. This review describes the recent advances in the genetic and neuroendocrine control of extrasynaptic and synaptic GABA-A receptors in epilepsy and its impact on neurologic conditions. It highlights the current knowledge of GABA genetics in epilepsy, with an emphasis on the neuroendocrine regulation of extrasynaptic GABA-A receptors in network excitability and seizure susceptibility. Recent advances in molecular regulation of extrasynaptic GABA-A receptor–mediated tonic inhibition are providing unique new therapeutic approaches for epilepsy, status epilepticus, and certain brain disorders. The discovery of an extrasynaptic molecular mechanism represents a milestone for developing novel therapies such as NS replacement therapy for catamenial epilepsy.

Dendrite-targeting interneurons control synaptic NMDA-receptor activation via nonlinear α5-GABA A receptors

Abstract: Dendrite-targeting GABAergic interneurons powerfully control postsynaptic integration, synaptic plasticity, and learning. However, the mechanisms underlying the efficient GABAergic control of dendritic electrogenesis are not well understood. Using subtype-selective blockers for GABAA receptors, we show that dendrite-targeting somatostatin interneurons and NO-synthase-positive neurogliaform cells preferentially activate α5-subunit- containing GABAA receptors (α5-GABAARs), generating slow inhibitory postsynaptic currents (IPSCs) in hippocampal CA1 pyramidal cells. By contrast, only negligible contribution of these receptors could be found in perisomatic IPSCs, generated by fast-spiking parvalbumin interneurons. Remarkably, α5-GABAAR-mediated IPSCs were strongly outward-rectifying generating 4-fold larger conductances above –50 mV than at rest. Experiments and modeling show that synaptic activation of these receptors can very effectively control voltage-dependent NMDA-receptor activation as well as Schaffer-collateral evoked burst firing in pyramidal cells. Taken together, nonlinear-rectifying α5-GABAARs with slow kinetics match functional NMDA-receptor properties and thereby mediate powerful control of dendritic postsynaptic integration and action potential firing by dendrite-targeting interneurons. Somatostatin+ (SOM+ ) GABAergic interneurons are known to fine-tune synaptic plasticity as they inhibit dendritic spikes and burst firing. Here, the authors show that both SOM+ and NOS+ interneurons preferentially recruit nonlinear outward-rectifying GABA(A)R with alpha5 subunit, and that this inhibition with slow gating kinetics matches voltage and time-dependent activation of synaptic NMDARs, thereby controlling the generation of dendritic NMDA spikes.

Septo-hippocampal interaction.

Abstract: The septo–hippocampal pathway adjusts CA1 network excitability to different behavioral states and is crucially involved in theta rhythmogenesis. In the medial septum, cholinergic, glutamatergic and GABAergic neurons form a highly interconnected local network. Neurons of these three classes project to glutamatergic pyramidal neurons and different subsets of GABAergic neurons in the hippocampal CA1 region. From there, GABAergic neurons project back to the medial septum and form a feedback loop between the two remote brain areas. In vivo, the firing of GABAergic medial septal neurons is theta modulated, while theta modulation is not observed in cholinergic neurons. One prominent feature of glutamatergic neurons is the correlation of their firing rates to the animals running speed. The cellular diversity, the high local interconnectivity and different activity patterns of medial septal neurons during different behaviors complicate the functional dissection of this network. New technical advances help to define specific functions of individual cell classes. In this review, we seek to highlight recent findings and elucidate functional implications of the septo-hippocampal connectivity on the microcircuit scale.

Long-Term Stress Disrupts the Structural and Functional Integrity of GABAergic Neuronal Networks in the Medial Prefrontal Cortex of Rats.

Abstract: Clinical and experimental data suggest that fronto-cortical GABAergic deficits contribute to the pathophysiology of major depressive disorder (MDD). To further test this hypothesis, we used a well characterized rat model for depression and examined the effect of stress on GABAergic neuron numbers and GABA-mediated synaptic transmission in the medial prefrontal cortex (mPFC) of rats. Adult male Wistar rats were subjected to 9-weeks of chronic mild stress (CMS) and based on their hedonic-anhedonic behavior they were behaviorally phenotyped as being stress-susceptible (anhedonic) or stress-resilient. Post mortem quantitative histopathology was used to examine the effect of stress on parvalbumin (PV)-, calretinin- (CR), calbindin- (CB), cholecystokinin- (CCK), somatostatin-(SST) and neuropeptide Y-positive (NPY+) GABAergic neuron numbers in all cortical subareas of the mPFC (anterior cingulate (Cg1), prelimbic (PrL) and infralimbic (IL) cortexes). In vitro, whole-cell patch-clamp recordings from layer II-III pyramidal neurons of the ventral mPFC was used to examine GABAergic neurotransmission. The cognitive performance of the animals was assessed in a hippocampal-prefrontal-cortical circuit dependent learning task. Stress exposure reduced the number of CCK-, CR- and PV-positive GABAergic neurons in the mPFC, most prominently in the IL cortex. Interestingly, in the stress-resilient animals, we found higher number of neuropeptide Y-positive neurons in the entire mPFC. The electrophysiological analysis revealed reduced frequencies of spontaneous and miniature IPSCs in the anhedonic rats and decreased release probability of perisomatic-targeting GABAergic synapses and alterations in GABAB receptor mediated signaling. In turn, pyramidal neurons showed higher excitability. Anhedonic rats were also significantly impaired in the object-place paired-associate learning task. These data demonstrate that long-term stress results in functional and structural deficits of prefrontal GABAergic networks. Our findings support the concept that fronto-limbic GABAergic dysfunctions may contribute to emotional and cognitive symptoms of MDD.

Liraglutide Modulates Appetite and Body Weight Through Glucagon-Like Peptide 1 Receptor–Expressing Glutamatergic Neurons

Abstract: Glucagon-like peptide 1 receptor (GLP-1R) agonists are U.S. Food and Drug Administration–approved weight loss drugs. Despite their widespread use, the sites of action through which GLP-1R agonists (GLP1RAs) affect appetite and body weight are still not fully understood. We determined whether GLP-1Rs in either GABAergic or glutamatergic neurons are necessary for the short- and long-term effects of the GLP1RA liraglutide on food intake, visceral illness, body weight, and neural network activation. We found that mice lacking GLP-1Rs in vGAT-expressing GABAergic neurons responded identically to controls in all parameters measured, whereas deletion of GLP-1Rs in vGlut2-expressing glutamatergic neurons eliminated liraglutide-induced weight loss and visceral illness and severely attenuated its effects on feeding. Concomitantly, deletion of GLP-1Rs from glutamatergic neurons completely abolished the neural network activation observed after liraglutide administration. We conclude that liraglutide activates a dispersed but discrete neural network to mediate its physiological effects and that these effects require GLP-1R expression on glutamatergic but not GABAergic neurons.

Modeling Down Syndrome with Patient iPSCs Reveals Cellular and Migration Deficits of GABAergic Neurons.

Abstract: Summary The brain of Down syndrome (DS) patients exhibits fewer interneurons in the cerebral cortex, but its underlying mechanism remains unknown. By morphometric analysis of cortical interneurons generated from DS and euploid induced pluripotent stem cells (iPSCs), we found that DS GABA neurons are smaller and with fewer neuronal processes. The proportion of calretinin over calbindin GABA neurons is reduced, and the neuronal migration capacity is decreased. Such phenotypes were replicated following transplantation of the DS GABAergic progenitors into the mouse medial septum. Gene expression profiling revealed altered cell migratory pathways, and correction of the PAK1 pathway mitigated the cell migration deficit in vitro . These results suggest that impaired migration of DS GABAergic neurons may contribute to the reduced number of interneurons in the cerebral cortex and hippocampus in DS patients.

Brain GABA Levels Are Associated with Inhibitory Control Deficits in Older Adults.

Abstract: Healthy aging is accompanied by motor inhibition deficits that involve a slower process of stopping a prepotent motor response (i.e., reactive inhibition) rather than a diminished ability to anticipate stopping (i.e., proactive inhibition). Some studies suggest that efficient motor inhibition is related to GABAergic function. Since age-related alterations in the GABA system have also been reported, motor inhibition impairments might be linked to GABAergic alterations in the cortico-subcortical network that mediates motor inhibition. Thirty young human adults (mean age, 23.2 years; age range, 18-34 years; 14 men) and 29 older human adults (mean age, 67.5 years; age range, 60-74 years; 13 men) performed a stop-signal task with varying levels of stop-signal probability. GABA+ levels were measured with magnetic resonance spectroscopy (MRS) in right inferior frontal cortex, pre-supplementary motor area (pre-SMA), left sensorimotor cortex, bilateral striatum, and occipital cortex. We found that reactive inhibition was worse in older adults compared with young adults, as indicated by longer stop-signal reaction times (SSRTs). No group differences in proactive inhibition were observed as both groups slowed down their response to a similar degree with increasing stop-signal probability. The MRS results showed that tissue-corrected GABA+ levels were on average lower in older as compared with young adults. Moreover, older adults with lower GABA+ levels in the pre-SMA were slower at stopping (i.e., had longer SSRTs). These findings suggest a role for the GABA system in reactive inhibition deficits.SIGNIFICANCE STATEMENT Inhibitory control has been shown to diminish as a consequence of aging. We investigated whether the ability to stop a prepotent motor response and the ability to prepare to stop were related to GABA levels in different regions of the network that was previously identified to mediate inhibitory control. Overall, we found lower GABA levels in older adults compared with young adults. Importantly, those older adults who were slower at stopping had less GABA in the pre-supplementary motor area, a key node of the inhibitory control network. We propose that deficits in the stop process in part depend on the integrity of the GABA system.

GABAergic inhibitory neurons as therapeutic targets for cognitive impairment in schizophrenia

Abstract: Schizophrenia is considered primarily as a cognitive disorder. However, functional outcomes in schizophrenia are limited by the lack of effective pharmacological and psychosocial interventions for cognitive impairment. GABA (gamma-aminobutyric acid) interneurons are the main inhibitory neurons in the central nervous system (CNS), and they play a critical role in a variety of pathophysiological processes including modulation of cortical and hippocampal neural circuitry and activity, cognitive function-related neural oscillations (eg, gamma oscillations) and information integration and processing. Dysfunctional GABA interneuron activity can disrupt the excitatory/inhibitory (E/I) balance in the cortex, which could represent a core pathophysiological mechanism underlying cognitive dysfunction in schizophrenia. Recent research suggests that selective modulation of the GABAergic system is a promising intervention for the treatment of schizophrenia-associated cognitive defects. In this review, we summarized evidence from postmortem and animal studies for abnormal GABAergic neurotransmission in schizophrenia, and how altered GABA interneurons could disrupt neuronal oscillations. Next, we systemically reviewed a variety of up-to-date subtype-selective agonists, antagonists, positive and negative allosteric modulators (including dual allosteric modulators) for α5/α3/α2 GABAA and GABAB receptors, and summarized their pro-cognitive effects in animal behavioral tests and clinical trials. Finally, we also discuss various representative histone deacetylases (HDAC) inhibitors that target GABA system through epigenetic modulations, GABA prodrug and presynaptic GABA transporter inhibitors. This review provides important information on current potential GABA-associated therapies and future insights for development of more effective treatments.

A GABAergic cell type in the lateral habenula links hypothalamic homeostatic and midbrain motivation circuits with sex steroid signaling.

Abstract: The lateral habenula (LHb) has a key role in integrating a variety of neural circuits associated with reward and aversive behaviors. There is limited information about how the different cell types and neuronal circuits within the LHb coordinate physiological and motivational states. Here, we report a cell type in the medial division of the LHb (LHbM) in male rats that is distinguished by: (1) a molecular signature for GABAergic neurotransmission (Slc32a1/VGAT) and estrogen receptor (Esr1/ERα) expression, at both mRNA and protein levels, as well as the mRNA for vesicular glutamate transporter Slc17a6/VGLUT2, which we term the GABAergic estrogen-receptive neuron (GERN); (2) its axonal projection patterns, identified by in vivo juxtacellular labeling, to both local LHb and to midbrain modulatory systems; and (3) its somatic expression of receptors for vasopressin, serotonin and dopamine, and mRNA for orexin receptor 2. This cell type is anatomically located to receive afferents from midbrain reward (dopamine and serotonin) and hypothalamic water and energy homeostasis (vasopressin and orexin) circuits. These afferents shared the expression of estrogen synthase (aromatase) and VGLUT2, both in their somata and axon terminals. We demonstrate dynamic changes in LHbM VGAT+ cell density, dependent upon gonadal functional status, that closely correlate with motivational behavior in response to predator and forced swim stressors. The findings suggest that the homeostasis and reward-related glutamatergic convergent projecting pathways to LHbMC employ a localized neurosteroid signaling mechanism via axonal expression of aromatase, to act as a switch for GERN excitation/inhibition output prevalence, influencing depressive or motivated behavior.

Beyond Dopamine: GABA, Glutamate, and the Axial Symptoms of Parkinson Disease.

Abstract: Introduction: The axial symptoms of Parkinson disease (PD) include difficulties with balance, posture, speech, swallowing, and locomotion with freezing of gait, as well as axial rigidity. These axial symptoms impact negatively on quality of life for many patients, yet remain poorly understood. Dopaminergic treatments typically have little effect on the axial symptoms of PD, suggesting that disruptions in other neurotransmitter systems beyond the dopamine system may underlie these symptoms. The purpose of the present study was to examine the relationship between the axial symptoms of PD and GABA and glutamate levels quantified with magnetic resonance spectroscopy. Methods: The participant group included 20 patients with PD and 17 healthy control participants. Water-scaled GABA and Glx (glutamate + glutamine) concentrations were derived from GABA-edited MEGA-PRESS spectra acquired from the left basal ganglia and prefrontal cortex, and additional water-scaled Glx concentrations were acquired from standard PRESS spectra acquired from the pons. Spectra were analyzed with LCModel. The axial symptoms of PD were evaluated from subscales of the Unified Parkinson's Disease rating scale (MDS-UPDRS). Results: PD patients demonstrated significantly higher GABA levels in the basal ganglia, which correlated with the degree of gait disturbance. Basal ganglia Glx levels and prefrontal GABA and Glx levels did not differ significantly between patient and control groups, but within the PD group prefrontal Glx levels correlated negatively with difficulties turning in bed. Results from an exploratory subgroup analysis indicate that the associations between GABA, Glx, and axial symptoms scores are typically more prominent in akinetic-rigid patients than in tremor-dominant patients. Conclusion: Alterations in GABAergic and glutamatergic neurotransmission may contribute to some of the axial symptoms of PD.

Control of motor coordination by astrocytic tonic GABA release through modulation of excitation/inhibition balance in cerebellum

Abstract: Tonic inhibition in the brain is mediated through an activation of extrasynaptic GABAA receptors by the tonically released GABA, resulting in a persistent GABAergic inhibitory action. It is one of the key regulators for neuronal excitability, exerting a powerful action on excitation/inhibition balance. We have previously reported that astrocytic GABA, synthesized by monoamine oxidase B (MAOB), mediates tonic inhibition via GABA-permeable bestrophin 1 (Best1) channel in the cerebellum. However, the role of astrocytic GABA in regulating neuronal excitability, synaptic transmission, and cerebellar brain function has remained elusive. Here, we report that a reduction of tonic GABA release by genetic removal or pharmacological inhibition of Best1 or MAOB caused an enhanced neuronal excitability in cerebellar granule cells (GCs), synaptic transmission at the parallel fiber-Purkinje cell (PF-PC) synapses, and motor performance on the rotarod test, whereas an augmentation of tonic GABA release by astrocyte-specific overexpression of MAOB resulted in a reduced neuronal excitability, synaptic transmission, and motor performance. The bidirectional modulation of astrocytic GABA by genetic alteration of Best1 or MAOB was confirmed by immunostaining and in vivo microdialysis. These findings indicate that astrocytes are the key player in motor coordination through tonic GABA release by modulating neuronal excitability and could be a good therapeutic target for various movement and psychiatric disorders, which show a disturbed excitation/inhibition balance.

GABAergic inhibition in dual-transmission cholinergic and GABAergic striatal interneurons is abolished in Parkinson disease

Abstract: We report that half striatal cholinergic interneurons are dual transmitter cholinergic and GABAergic interneurons (CGINs) expressing ChAT, GAD65, Lhx7, and Lhx6 mRNAs, labeled with GAD and VGAT, generating monosynaptic dual cholinergic/GABAergic currents and an inhibitory pause response. Dopamine deprivation increases CGINs ongoing activity and abolishes GABAergic inhibition including the cortico-striatal pause because of high [Cl-]i levels. Dopamine deprivation also dramatically increases CGINs dendritic arbors and monosynaptic interconnections probability, suggesting the formation of a dense CGINs network. The NKCC1 chloride importer antagonist bumetanide, which reduces [Cl-]i levels, restores GABAergic inhibition, the cortico-striatal pause-rebound response, and attenuates motor effects of dopamine deprivation. Therefore, most of the striatal cholinergic excitatory drive is balanced by a concomitant powerful GABAergic inhibition that is impaired by dopamine deprivation. The attenuation by bumetanide of cardinal features of Parkinson's disease paves the way to a novel therapeutic strategy based on a restoration of low [Cl-]i levels and GABAergic inhibition.

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

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

Neural mechanisms underlying GABAergic regulation of adult hippocampal neurogenesis.

Abstract: Within the dentate gyrus of the adult hippocampus is the subgranular zone, which contains a neurogenic niche for radial-glia like cells, the most primitive neural stem cells in the adult brain The quiescence of neural stem cells is maintained by tonic gamma-aminobutyric acid (GABA) released from local interneurons Once these cells differentiate into neural progenitor cells, GABA continues to regulate their development into mature granule cells, the principal cell type of the dentate gyrus Here, we review the role of GABA circuits, signaling, and receptors in regulating development of adult-born cells, as well as the molecular players that modulate GABA signaling Furthermore, we review recent findings linking dysregulation of adult hippocampal neurogenesis to the altered GABAergic circuitry and signaling under various pathological conditions

Stress in Regulation of GABA Amygdala System and Relevance to Neuropsychiatric Diseases

Abstract: The amygdala is an almond-shaped nucleus located deep and medially within the temporal lobe and is thought to play a crucial role in the regulation of emotional processes. GABAergic neurotransmission inhibits the amygdala and prevents us from generating inappropriate emotional and behavioral responses. Stress may cause the reduction of the GABAergic interneuronal network and the development of neuropsychological diseases. In this review, we summarize the recent evidence investigating the possible mechanisms underlying GABAergic control of the amygdala and its interaction with acute and chronic stress. Taken together, this study may contribute to future progress in finding new approaches to reverse the attenuation of GABAergic neurotransmission induced by stress in the amygdala.

Glutamate Cotransmission in Cholinergic, GABAergic and Monoamine Systems: Contrasts and Commonalities.

Abstract: Multiple discoveries made since the identification of vesicular glutamate transporters (VGLUTs) two decades ago revealed that many neuronal populations in the brain use glutamate in addition to their "primary" neurotransmitter. Such a mode of cotransmission has been detected in dopamine (DA), acetylcholine (ACh), serotonin (5-HT), norepinephrine (NE) and surprisingly even in GABA neurons. Interestingly, work performed by multiple groups during the past decade suggests that the use of glutamate as a cotransmitter takes different forms in these different populations of neurons. In the present review, we will provide an overview of glutamate cotransmission in these different classes of neurons, highlighting puzzling differences in: (1) the proportion of such neurons expressing a VGLUT in different brain regions and at different stages of development; (2) the sub-cellular localization of the VGLUT; (3) the localization of the VGLUT in relation to the neurons' other vesicular transporter; and (4) the functional role of glutamate cotransmission.

Relationship between absolute and relative ratios of glutamate, glutamine and GABA and severity of autism spectrum disorder

Abstract: Autism spectrum disorder (ASD) is a neurodevelopmental pathology characterized by an impairment in social interaction, communication difficulties, and repetitive behaviors Glutamate signaling abnormalities are thought to be considered as major etiological mechanisms leading to ASD The search for amino-acidic catabolytes related to glutamate in patients with different levels of ASD might help current research to clarify the mechanisms underlying glutamate signaling and its disorders, particularly in relation to ASD In the present study, plasma levels of the amino acids and their derivatives glutamate, glutamine, and γ-aminobutyric acid (GABA), associated with their relative ratios, were evaluated using an enzyme-linked immunosorbent assay (ELISA) technique in 40 male children with ASD and in 38 age- and gender-matched neurotypical health controls The Social Responsiveness Scale (SRS) was used to evaluate social cognition, and the Childhood Autism Rating Scale (CARS) was used to assess subjects' behaviors Children with ASD exhibited a significant elevation of plasma GABA and glutamate/glutamine ratio, as well as significantly lower levels of plasma glutamine and glutamate/GABA ratios compared to controls No significant correlation was found between glutamate levels and the severity of autism, measured by CARS and SRS In receiver operating characteristic (ROC) curve analysis, the area under the curve for GABA compared to other parameters was close to one, indicating its potential use as a biomarker Glutamine appeared as the best predictive prognostic markers in the present study The results of the present study indicate a disturbed balance between GABAergic and glutamatergic neurotransmission in ASD The study also indicates that an increased plasma level of GABA can be potentially used as an early diagnostic biomarker for ASD

Mechanism of BDNF Modulation in GABAergic Synaptic Transmission in Healthy and Disease Brains

Abstract: In the mature healthy mammalian neuronal networks, γ-aminobutyric acid (GABA) mediates synaptic inhibition by acting on GABAA and GABAB receptors (GABAAR, GABABR) In immature networks and during numerous pathological conditions the strength of GABAergic synaptic inhibition is much less pronounced In these neurons the activation of GABAAR produces paradoxical depolarizing action that favors neuronal network excitation The depolarizing action of GABAAR is a consequence of deregulated chloride ion homeostasis In addition to depolarizing action of GABAAR, the GABABR mediated inhibition is also less efficient One of the key molecules regulating the GABAergic synaptic transmission is the brain derived neurotrophic factor (BDNF) BDNF and its precursor proBDNF, can be released in an activity-dependent manner Mature BDNF operates via its cognate receptors tropomyosin related kinase B (TrkB) whereas proBDNF binds the p75 neurotrophin receptor (p75NTR) In this review article, we discuss recent finding illuminating how mBDNF-TrkB and proBDNF-p75NTR signaling pathways regulate GABA related neurotransmission under physiological conditions and during epilepsy

A Developmental Study of Abnormal Behaviors and Altered GABAergic Signaling in the VPA-Treated Rat Model of Autism.

Abstract: Although studies have investigated the role of gamma-aminobutyric acid (GABA)ergic signaling in rodent neural development and behaviors relevant to autism, behavioral ontogeny, as underlain by the changes in GABAergic system, is poorly characterized in different brain regions. Here, we employed a valproic acid (VPA) rat model of autism to investigate the autism-like behaviors and GABAergic glutamic acid decarboxylase 67 (GAD67) expression underlying these altered behaviors in multiple brain areas at different developmental stages from birth to adulthood. We found that VPA-treated rats exhibited behavioral abnormalities relevant to autism, including delayed nervous reflex development, altered motor coordination, delayed sensory development, autistic-like and anxiety behaviors and impaired spatial learning and memory. We also found that VPA rats had the decreased expression of GAD67 in the hippocampus (HC) and cerebellum from childhood to adulthood, while decreased GAD67 expression of the temporal cortex (TC) was only observed in adulthood. Conversely, GAD67 expression was increased in the prefrontal cortex (PFC) from adolescence to adulthood. The dysregulated GAD67 expression could alter the excitatory-inhibitory balance in the cerebral cortex, HC and cerebellum. Our findings indicate an impaired GABAergic system could be a major etiological factor occurring in the cerebral cortex, HC and cerebellum of human cases of autism, which suggests enhancement of GABA signaling would be a promising therapeutic target for its treatment.