Gamma-aminobutyric Acid Signaling Research Articles

An evolutionarily conserved switch in response to GABA affects development and behavior of the locomotor circuit of Caenorhabditis elegans.

The neurotransmitter gamma-aminobutyric acid (GABA) is depolarizing in the developing vertebrate brain, but in older animals switches to hyperpolarizing and becomes the major inhibitory neurotransmitter in adults. We discovered a similar developmental switch in GABA response in Caenorhabditis elegans and have genetically analyzed its mechanism and function in a well-defined circuit. Worm GABA neurons innervate body wall muscles to control locomotion. Activation of GABAA receptors with their agonist muscimol in newly hatched first larval (L1) stage animals excites muscle contraction and thus is depolarizing. At the mid-L1 stage, as the GABAergic neurons rewire onto their mature muscle targets, muscimol shifts to relaxing muscles and thus has switched to hyperpolarizing. This muscimol response switch depends on chloride transporters in the muscles analogous to those that control GABA response in mammalian neurons: the chloride accumulator sodium-potassium-chloride-cotransporter-1 (NKCC-1) is required for the early depolarizing muscimol response, while the two chloride extruders potassium-chloride-cotransporter-2 (KCC-2) and anion-bicarbonate-transporter-1 (ABTS-1) are required for the later hyperpolarizing response. Using mutations that disrupt GABA signaling, we found that neural circuit development still proceeds to completion but with an ∼6-hr delay. Using optogenetic activation of GABAergic neurons, we found that endogenous GABAA signaling in early L1 animals, although presumably depolarizing, does not cause an excitatory response. Thus a developmental depolarizing-to-hyperpolarizing shift is an ancient conserved feature of GABA signaling, but existing theories for why this shift occurs appear inadequate to explain its function upon rigorous genetic analysis of a well-defined neural circuit.

The role of GABA in the regulation of GnRH neurons.

Gonadotropin-releasing hormone (GnRH) neurons form the final common pathway for the central regulation of reproduction. Gamma-amino butyric acid (GABA) has long been implicated as one of the major players in the regulation of GnRH neurons. Although GABA is typically an inhibitory neurotransmitter in the mature adult central nervous system, most mature GnRH neurons show the unusual characteristic of being excited by GABA. While many reports have provided much insight into the contribution of GABA to the activity of GnRH neurons, the precise physiological role of the excitatory action of GABA on GnRH neurons remains elusive. This brief review presents the current knowledge of the role of GABA signaling in GnRH neuronal activity. We also discuss the modulation of GABA signaling by neurotransmitters and neuromodulators and the functional consequence of GABAergic inputs to GnRH neurons in both the physiology and pathology of reproduction.

The spatiotemporal segregation of GAD forms defines distinct GABA signaling functions in the developing mouse olfactory system and provides novel insights into the origin and migration of GnRH neurons.

Gamma-aminobutyric acid (GABA) has a dual role as an inhibitory neurotransmitter in the adult central nervous system (CNS) and as a signaling molecule exerting largely excitatory actions during development. The rate-limiting step of GABA synthesis is catalyzed by two glutamic acid decarboxylase isoforms GAD65 and GAD67 coexpressed in the GABAergic neurons of the CNS. Here we report that the two GADs show virtually nonoverlapping expression patterns consistent with distinct roles in the developing peripheral olfactory system. GAD65 is expressed exclusively in undifferentiated neuronal progenitors confined to the proliferative zones of the sensory vomeronasal and olfactory epithelia In contrast GAD67 is expressed in a subregion of the nonsensory epithelium/vomeronasal organ epithelium containing the putative Gonadotropin-releasing hormone (GnRH) progenitors and GnRH neurons migrating from this region through the frontonasal mesenchyme into the basal forebrain. Only GAD67+, but not GAD65+ cells accumulate detectable GABA. We further demonstrate that GAD67 and its embryonic splice variant embryonic GAD (EGAD) concomitant with GnRH are dynamically regulated during GnRH neuronal migration in vivo and in two immortalized cell lines representing migratory (GN11) and postmigratory (GT1-7) stage GnRH neurons, respectively. Analysis of GAD65/67 single and double knock-out embryos revealed that the two GADs play complementary (inhibitory) roles in GnRH migration ultimately modulating the speed and/or direction of GnRH migration. Our results also suggest that GAD65 and GAD67/EGAD characterized by distinct subcellular localization and kinetics have disparate functions during olfactory system development mediating proliferative and migratory responses putatively through specific subcellular GABA pools.

Determining the in vivo transverse relaxation time of GABA in the human brain at 7T

To measure in vivo transverse relaxation times (T2 ) of gamma-aminobutyric acid (GABA) at 7T using the experimental spectral-editing method. Experiments were performed at 7T in a 10 mM GABA phantom to determine the intrinsic TE-dependence of the edited signal. Then the same method was applied with editing-based suppression of coedited macromolecular signals to five healthy volunteers to determine T2 of GABA in vivo. From in vivo data acquired at multiple echo times, the in vivo GABA T2 relaxation time was estimated to be 63 ± 19 msec. We present a measurement of the T2 of edited GABA signal at 7T by first using phantom measurements to determine the echo time-dependence of edited signal. The method is purely experimental and does not rely on prior knowledge of coupling constants or simulation of realistic experiments. J. Magn. Reson. Imaging 2013;38:1224-1229. © 2013 Wiley Periodicals, Inc.

Evolution of neurotransmitter gamma-aminobutyric acid, glutamate and their receptors

Gamma-aminobutyric acid (GABA) and glutamate are two important amino acid neurotransmitters widely present in the nervous systems of mammals, insects, round worm, and platyhelminths, while their receptors are quite diversified across different animal phyla. However, the evolutionary mechanisms between the two conserved neurotransmitters and their diversified receptors remain elusive, and antagonistic interactions between GABA and glutamate signal transduction systems, in particular, have begun to attract significant attention. In this review, we summarize the extant results on the origin and evolution of GABA and glutamate, as well as their receptors, and analyze possible evolutionary processes and phylogenetic relationships of various GABAs and glutamate receptors. We further discuss the evolutionary history of Excitatory/Neutral Amino Acid Transporter (EAAT), a transport protein, which plays an important role in the GABA-glutamate "yin and yang" balanced regulation. Finally, based on current advances, we propose several potential directions of future research.

Effects of anesthetic regimes on inflammatory responses in a rat model of acute lung injury

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter through activation of GABA receptors. Volatile anesthetics activate type-A (GABA(A)) receptors resulting in inhibition of synaptic transmission. Lung epithelial cells have been recently found to express GABA(A) receptors that exert anti-inflammatory properties. We hypothesized that the volatile anesthetic sevoflurane (SEVO) attenuates lung inflammation through activation of lung epithelial GABA(A) receptors. Sprague-Dawley rats were anesthetized with SEVO or ketamine/xylazine (KX). Acute lung inflammation was induced by intratracheal instillation of endotoxin, followed by mechanical ventilation for 4 h at a tidal volume of 15 mL/kg without positive end-expiratory pressure (two-hit lung injury model). To examine the specific effects of GABA, healthy human lung epithelial cells (BEAS-2B) were challenged with endotoxin in the presence and absence of GABA with and without addition of the GABA(A) receptor antagonist picrotoxin. Anesthesia with SEVO improved oxygenation and reduced pulmonary cytokine responses compared to KX. This phenomenon was associated with increased expression of the π subunit of GABA(A) receptors and glutamic acid decarboxylase (GAD). The endotoxin-induced cytokine release from BEAS-2B cells was attenuated by the treatment with GABA, which was reversed by the administration of picrotoxin. Anesthesia with SEVO suppresses pulmonary inflammation and thus protects the lung from the two-hit injury. The anti-inflammatory effect of SEVO is likely due to activation of pulmonary GABA(A) signaling pathways.

Abstract 4938: A global landscape of transcriptional interactions and regulations in lung cancer

Abstract Lung cancer is the most common cancer in the world and is the leading cause of cancer-related deaths. Despite of decades’ intensive research, only a few driver genes have been identified and the exact regulatory mechanisms of lung cancer development and progression still remain elusive. The poor understanding of this deadly cancer prevents us from developing effective methods for early detection and personalized therapeutics. This study aims to reconstruct multiscale genome-wide transcriptional networks to elucidate the global patterns of transcriptional interactions and regulations for development and metastasis of lung cancer and to provide new insights into the disease through discovery of novel pathways and drivers. We compiled multiple large scale genomic studies of lung cancer. Gene coexpression networks were first reconstructed to identify gene modules (clusters) comprised of highly interacting genes. A module with unknown function along with the modules enriched for extracellular matrix organization, immune response, epidermis development and DNA replication/mitotic cell cycle are most predictive of survival. Meanwhile, causal Bayesian networks were also constructed to derive a more granular view of the relationships and directionality between genes. The coexpression and Bayesian networks were then integrated by projecting the co-expression modules onto the BNs to identify putative causal regulators (key drivers) within each module based on their interconnectivity and predicted impact on the rest of the module. About 200 driver genes including known oncogenes ATRX, BRCA1, BUB1B, CREB1, LCK, RECQL4 and SFPQ, were revealed. To further identify genomic alterations and key pathways account for metastasis of lung cancer, we applied a recently developed Wavelet based Analysis of Copy number alteration by Expression (WACE) algorithm to infer copy number variation sites and combined it with Bayesian networks to identify putative key drivers of the genomic alterations in metastasis. One hundred forty nine amplified regions and 91 deleted regions were identified. The amplified and deleted regions are most significantly enriched for gamma-aminobutyric acid signaling and MHCII-mediated immunity pathways, respectively. Twenty one key drivers including CHEK1, a key gene in DNA damage pathway associated with multiple cancers, and NME1, a known metastasis suppressor gene in breast cancer, were identified. The amplified regions are most enriched in the module with unknown function and they share three drivers (ACTR6, CEP68 and RPAP3). To our knowledge, this is the first effort to systematically reconstruct multiscale transcriptional networks and identify drivers for lung cancer. The global map of the gene-gene interactions and regulations as well as the inferred driver genes for both development and invasion of lung cancer will have a significant impact on lung cancer research and therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4938. doi:1538-7445.AM2012-4938

The Vasculature within the Paraventricular Nucleus of the Hypothalamus in Mice Varies as a Function of Development, Subnuclear Location, and GABA Signaling

The paraventricular nucleus of the hypothalamus (PVN) is a cell group that plays important roles in regulating sympathetic vasomotor tone, food intake, neuroendocrine and autonomic stress responses, and cardiovascular function. The developing PVN is surrounded by neuronal elements containing, and presumably secreting, gamma-aminobutyric acid (GABA). The vasculature of the adult PVN is notably denser than in other brain regions or in the PVN during perinatal development. To characterize the postnatal angiogenic process in mice, blood vessels were analyzed at P8, 20, and 50 in rostral, mid, and caudal divisions of the PVN in males and females. Vascular changes relative to disruption of the R1 subunit of the GABA(B) receptor were evaluated at P8 and P20. For defined regions of interest within the PVN there were age dependent increases in blood vessel lengths and branching from P8 to 20 to 50 with the most notable increases in the middle region. Loss of GABA(B) receptors did not influence vascular characteristics at P8 in any region, but by P20 there was significantly (20%) less blood vessel length and branching in the mid-PVN region vs. wild type. These findings suggest that the loss of GABA(B) signaling may lead to a late developing defect in angiogenesis. The loss of vascularity with defective GABA(B) signaling suggests that neurovascular relationships in the PVN may be an important locus for understanding disorders of the hypothalamic-pituitary-adrenal axis with potential impact for psychiatric mood disorders along with other comorbid disorders that may be regulated by cells in the PVN.

Using EEG to test the inhibitory mechanisms implicated in aggressive behaviour that rely on GABA function: Source analysis of N200 and P300 components

Extreme forms of aggression can have an adverse impact on society and those within it. The inhibitory neurotransmitter Gamma-Aminobutyric acid (GABA) has been associated with decreased levels of both aggression and impulsivity in animal and human research with frontal executive structures suppressing sub-cortical activity and impulsive behaviours. This thesis reviews the literature outlining the influence of GABA on event-related potentials and uses a go /no-go oddball paradigm, measured by electroencephalography, to index GABA signalling accordingly. Dipole modelling revealed that attenuations of the dorsolateral prefrontal cortex in production of the N200 and anterior cingulate cortex in P3a generation were key predictors of aggression and impulsivity respectively. It was concluded that poor GABAergic signalling in frontal regions and a subsequent inability to mediate sub-cortical impulses resulted in higher levels of trait aggression and impulsivity in a non-clinical population. These results provide a strong basis for future replications on a larger participant sample to test the stability of models proposed in this pilot research.

GABAergic signaling in primary lens epithelial and lentoid cells and its involvement in intracellular Ca2+ modulation

Primary lens epithelial cell (LEC) cultures derived from newborn (P0) and one-month-old (P30) mouse lenses were used to study GABA (gamma-aminobutyric acid) signaling expression and its effect on the intracellular Ca2+ ([Ca2+]i) level. We have found that these cultures express specific cellular markers for lens epithelial and fiber cells, all components of the functional GABA signaling pathway and GABA, thus recapitulating the developmental program of the ocular lens. Activation of both GABA-A and GABA-B receptors (GABAAR and GABABR) with the specific agonists muscimol and baclofen, respectively induces [Ca2+]i transients that could be blocked by the specific antagonists bicuculline and CGP55845 and were dependent on extracellular Ca2+. Bicuculline did not change the GABA-evoked Ca2+ responses in Ca2-containing buffers, but suppressed them significantly in Ca2+-free buffers suggesting the two receptors couple to convergent Ca2+ mobilization mechanisms with different extracellular Ca2+ sensitivity. Prolonged activation of GABABR induced wave propagation of the Ca2+ signal and persistent oscillations. The number of cells reacting to GABA or GABA+bicuculline in P30 mouse LEC cultures expressing predominantly the synaptic type GABAAR did not differ significantly from the number of reacting cells in P0 mouse LEC cultures. The GABA-induced Ca2+ transients in P30 (but not P0) mouse LEC could be entirely suppressed by co-application of bicuculline and CGP55845. The GABA-mediated Ca2+ signaling may be involved in a variety of Ca2+-dependent cellular processes during lens growth and epithelial cell differentiation.

Synaptic Signaling and Aberrant RNA Splicing in Autism Spectrum Disorders

Interactions between presynaptic and postsynaptic cellular adhesion molecules (CAMs) drive synapse maturation during development. These trans-synaptic interactions are regulated by alternative splicing of CAM RNAs, which ultimately determines neurotransmitter phenotype. The diverse assortment of RNAs produced by alternative splicing generates countless protein isoforms necessary for guiding specialized cell-to-cell connectivity. Failure to generate the appropriate synaptic adhesion proteins is associated with disrupted glutamatergic and gamma-aminobutyric acid signaling, resulting in loss of activity-dependent neuronal plasticity, and risk for developmental disorders, including autism. While the majority of genetic mutations currently linked to autism are rare variants that change the protein-coding sequence of synaptic candidate genes, regulatory polymorphisms affecting constitutive and alternative splicing have emerged as risk factors in numerous other diseases, accounting for an estimated 40–60% of general disease risk. Here, we review the relationship between aberrant RNA splicing of synapse-related genes and autism spectrum disorders.

Expression of GABAergic Receptors in Mouse Taste Receptor Cells

BackgroundMultiple excitatory neurotransmitters have been identified in the mammalian taste transduction, with few studies focused on inhibitory neurotransmitters. Since the synthetic enzyme glutamate decarboxylase (GAD) for gamma-aminobutyric acid (GABA) is expressed in a subset of mouse taste cells, we hypothesized that other components of the GABA signaling pathway are likely expressed in this system. GABA signaling is initiated by the activation of either ionotropic receptors (GABAA and GABAC) or metabotropic receptors (GABAB) while it is terminated by the re-uptake of GABA through transporters (GATs).Methodology/Principal FindingsUsing reverse transcriptase-PCR (RT-PCR) analysis, we investigated the expression of different GABA signaling molecules in the mouse taste system. Taste receptor cells (TRCs) in the circumvallate papillae express multiple subunits of the GABAA and GABAB receptors as well as multiple GATs. Immunocytochemical analyses examined the distribution of the GABA machinery in the circumvallate papillae. Both GABAA-and GABAB- immunoreactivity were detected in the peripheral taste receptor cells. We also used transgenic mice that express green fluorescent protein (GFP) in either the Type II taste cells, which can respond to bitter, sweet or umami taste stimuli, or in the Type III GAD67 expressing taste cells. Thus, we were able to identify that GABAergic receptors are expressed in some Type II and Type III taste cells. Mouse GAT4 labeling was concentrated in the cells surrounding the taste buds with a few positively labeled TRCs at the margins of the taste buds.Conclusions/SignificanceThe presence of GABAergic receptors localized on Type II and Type III taste cells suggests that GABA is likely modulating evoked taste responses in the mouse taste bud.

Individual Differences in Subconscious Motor Control Predicted by GABA Concentration in SMA

Subliminal visual stimuli affect motor planning, but the size of such effects differs greatly between individuals. Here, we investigated whether such variation may be related to neurochemical differences between people. Cortical responsiveness is expected to be lower under the influence of more of the main inhibitory neurotransmitter, GABA. Thus, we hypothesized that, if an individual has more GABA in the supplementary motor area (SMA)--a region previously associated with automatic motor control--this would result in smaller subliminal effects. We measured the reversed masked prime--or negative compatibility--effect, and found that it correlated strongly with GABA concentration, measured with magnetic resonance spectroscopy. This occurred specifically in the SMA region, and not in other regions from which spectroscopy measurements were taken. We replicated these results in an independent cohort: more GABA in the SMA region is reliably associated with smaller effect size. These findings suggest that, across individuals, the responsiveness of subconscious motor mechanisms is related to GABA concentration in the SMA.

Roles for gamma-aminobutyric acid in the development of the paraventricular nucleus of the hypothalamus.

The development of the hypothalamic paraventricular nucleus (PVN) involves several factors that work together to establish a cell group that regulates neuroendocrine functions and behaviors. Several molecular markers were noted within the developing PVN, including estrogen receptors (ER), neuronal nitric oxide synthase (nNOS), and brain-derived neurotrophic factor (BDNF). By contrast, immunoreactive gamma-aminobutyric acid (GABA) was found in cells and fibers surrounding the PVN. Two animal models were used to test the hypothesis that GABA works through GABA(A) and GABA(B) receptors to influence the development of the PVN. Treatment with bicuculline to decrease GABA(A) receptor signaling from embryonic day (E) 10 to E17 resulted in fewer cells containing immunoreactive (ir) ERalpha in the region of the PVN vs. control. GABA(B)R1 receptor subunit knockout mice were used to examine the PVN at P0 without GABA(B) signaling. In female but not male GABA(B)R1 subunit knockout mice, the positions of cells containing ir ERalpha shifted from medial to lateral compared with wild-type controls, whereas the total number of ir ERalpha-containing cells was unchanged. In E17 knockout mice, ir nNOS cells and fibers were spread over a greater area. There was also a significant decrease in ir BDNF in the knockout mice in a region-dependent manner. Changes in cell position and protein expression subsequent to disruption of GABA signaling may be due, in part, to changes in nNOS and BDNF signaling. Based on the current study, the PVN can be added as another site where GABA exerts morphogenetic actions in development.

Mutation of theDrosophilavesicular GABA transporter disrupts visual figure detection

The role of gamma amino butyric acid (GABA) release and inhibitory neurotransmission in regulating most behaviors remains unclear. The vesicular GABA transporter (VGAT) is required for the storage of GABA in synaptic vesicles and provides a potentially useful probe for inhibitory circuits. However, specific pharmacologic agents for VGAT are not available, and VGAT knockout mice are embryonically lethal, thus precluding behavioral studies. We have identified the Drosophila ortholog of the vesicular GABA transporter gene (which we refer to as dVGAT), immunocytologically mapped dVGAT protein expression in the larva and adult and characterized a dVGAT(minos) mutant allele. dVGAT is embryonically lethal and we do not detect residual dVGAT expression, suggesting that it is either a strong hypomorph or a null. To investigate the function of VGAT and GABA signaling in adult visual flight behavior, we have selectively rescued the dVGAT mutant during development. We show that reduced GABA release does not compromise the active optomotor control of wide-field pattern motion. Conversely, reduced dVGAT expression disrupts normal object tracking and figure-ground discrimination. These results demonstrate that visual behaviors are segregated by the level of GABA signaling in flies, and more generally establish dVGAT as a model to study the contribution of GABA release to other complex behaviors.

Reversal of Ketamine-Induced Working Memory Impairments by the GABA Aα2/3 Agonist TPA023

Ketamine has been used to model cognitive and behavioral symptoms of schizophrenia. Current hypotheses state that inadequate glutamatergic transmission in schizophrenia leads to a deficiency in gamma-aminobutyric acid (GABA)ergic inhibitory mechanisms and treatment with a GABA type A receptor subunits alpha2/alpha3 (GABA(Aalpha2/3)) modulator improved working memory performance in a preliminary study in patients. Here, we used ketamine to impair spatial working memory and disrupt behavior to examine the capacity for the GABA(Aalpha2/3) agonist 7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (TPA023) to reverse these symptoms. Rhesus monkeys received TPA023 (.7, 2.0, and 5 mg/kg; by mouth) or vehicle 45 minutes before ketamine (1.0-1.7 mg/kg; intramuscular) or saline in a semirandomized Latin square design. Behavioral observations were acquired at approximately 5 minutes, and spatial delayed response performance was tested at 15 minutes postinjection. Ketamine produced a profound impairment in spatial working memory in association with the emergence of hallucinatory-like behaviors. TPA023 at all doses blocked ketamine's cognitive-impairing ability but did not influence the behavioral symptoms. Acute GABA(Aalpha2/3) agonist administration reverses the working memory deficits induced by ketamine in primates. This finding indicates that the consequences of N-methyl-D-aspartate deficiency on the function of prefrontal circuits involved in working memory can be completely overcome by acute enhancement of GABA signaling.

GABA signals modulate neuronal production

Event Abstract Back to Event GABA signals modulate neuronal production Angelique Bordey1* 1 Yale School of Medicine, Department of Signal Processing, United States The neurotransmitter gamma-aminobutyric acid (GABA) acting at GABAA receptors is critical for multiple developmental processes such as cell proliferation, migration, neurite extension, and network integration. Recent work has emphasized the importance of GABA on postnatal neurogenesis including the hippocampal subgranular zone and the subventricular zone (SVZ). The SVZ is the largest neurogenic zone where 10,000-30,000 neurons are produced per day and integrate in the olfactory bulb network. In this region, GABA exerts a negative feedback on neural progenitor cell proliferation and regulates neuroblast migration and differentiation. However, the ultimate in vivo function of GABA on SVZ neurogenesis remains unknown. To address this issue, we took advantage of and manipulated the depolarizing action of GABA. GABA effect is thought to result from its depolarization-induced calcium increases in both SVZ astrocytes and neuroblasts. We used a RNA interference approach against the Na-K-2Cl co-transporter 1 (NKCC1), which allows Cl- influx in immature cells, to reduce or eliminate GABA depolarization. Short hairpin RNA (shRNA) and a fluorescent reporter (GFP or RFP) were introduced into neural progenitor cells using in vivo electroporation in neonates. Using electrophysiology and calcium imaging, we found that shRNA expression to knock down (KD) NKCC1 (noted NKCC1KD) led to a premature hyperpolarization in neuroblasts integrating into the olfactory bulb network. We also found that 40% fewer NKCC1KD neuroblasts reached the olfactory bulb. This effect was not due to cell apoptosis measured with activated caspase-3 staining or a defect in cell migration. Indeed, NKCC1KD neuroblasts migrated at the same speed as neuroblasts containing a control shRNA. Finally, newly integrated NKCC1KD neurons displayed morphological defects compared to control. In conclusion, modulating NKCC1 expression in vivo significantly decreases the numbers of newly born neurons in the olfactory bulb and alters their morphology. Since there is a lack of either apoptotic or migratory defects, there is likely a proliferation defect in the astrocyte-like stem cells, neuroblasts, or potentially both. Conference: EMBO workshop: Gaba Signalling and Brain Networks , Amsterdam, Netherlands, 30 Jun - 2 Jul, 2010. Presentation Type: Oral Presentation Topic: Talks Citation: Bordey A (2010). GABA signals modulate neuronal production. Conference Abstract: EMBO workshop: Gaba Signalling and Brain Networks . doi: 10.3389/conf.fnins.2010.15.00028 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 22 Jun 2010; Published Online: 22 Jun 2010. * Correspondence: Angelique Bordey, Yale School of Medicine, Department of Signal Processing, New Haven, United States, angelique.bordey@yale.edu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Angelique Bordey Google Angelique Bordey Google Scholar Angelique Bordey PubMed Angelique Bordey Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Defining the role of GABA in cortical development

Of the many signals in the developing nervous system, GABA (gamma-aminobutyric acid) has been shown to be one of the earliest neurotransmitters present. Unlike in the adult, where this transmitter acts synaptically to inhibit neurons, during development, GABA can depolarize progenitor cells and their progeny due to their high intracellular chloride concentration. This early form of GABA signalling may provide the main excitatory drive for the immature cortical network and play a central role in regulating cortical development. Many features of GABA signalling are conserved in different species and are recapitulated during neurogenesis in the adult brain, demonstrating the importance of this versatile molecule in driving cortical formation. Here, we present recent evidence supporting the multiple functions of GABA during embryonic development and adult neurogenesis, from regulating progenitor proliferation to influencing the migration and maturation of newborn neurons.

GABA increases Ca2+ in cerebellar granule cell precursors via depolarization: Implications for proliferation

The amino acids glutamate and gamma-aminobutyric acid (GABA) have primarily been characterized as the most prevalent excitatory and inhibitory, respectively, neurotransmitters in the vertebrate central nervous system. However, the role of these signaling molecules extends far beyond the synapse. GABA, glutamate, and their complement of receptors are essential signaling molecules that regulate developmental processes in both embryonic and young adult mammals. In this review, we describe the current knowledge on the role of GABA and glutamate in development, focusing on the perinatal cerebellum. We will then present novel data suggesting that GABA depolarizes granule cell precursors via GABA(A) receptors, which leads to calcium increases in these cells. Finally, we will consider the role of GABA and glutamate signaling on cell proliferation and perhaps neural cancers. From our review of the literature and these data, we hypothesize that GABA(A) receptors and metabotropic glutamate receptors may be a novel target for the pharmacological regulation of the cerebellar tumors, medulloblastomas.

Gamma‐aminobutyric acid (GABA)‐mediated neural connections in the Drosophila antennal lobe

Inhibitory synaptic connections mediated by gamma-aminobutyric acid (GABA) play important roles in the neural computation of the brain. To obtain a detailed overview of the neural connections mediated by GABA signals, we analyzed the distribution of the cells that produce and receive GABA in the Drosophila adult brain. Relatively small numbers of the cells, which form clusters in several areas of the brain, express the GABA synthesis enzyme Gad1. On the other hand, many cells scattered across the brain express ionotropic GABA(A) receptor subunits (Lcch3 and Rdl) and metabotropic GABA(B) receptor subtypes (GABA-B-R1, -2, and -3). To analyze the expression of these genes in distinct identified cell types, we focused on the antennal lobe, where GABAergic neurons play important roles in odor coding. By combining fluorescent in situ hybridization and immunolabeling against GFP expressed with cell-type-specific GAL4 driver strains, we quantified the percentage of the cells that produce or receive GABA for each cell type. GABA was synthesized in the middle antennocerebral tract (mACT) projection neurons and two types of local neurons. Among them, mACT neurons had few presynaptic sites in the antennal lobe, making the local neurons essentially the sole provider of GABA signals there. On the other hand, not only these local neurons but also all types of projection neurons expressed both ionotropic and metabotropic GABA receptors. Thus, even though inhibitory signals are released from only a few, specific types of local neurons, the signals are read by most of the neurons in the antennal lobe neural circuitry.