GABAergic Control Research Articles

GABAergic control of anxiety-potentiated responding to stimulus deviance

Event Abstract Back to Event GABAergic control of anxiety-potentiated responding to stimulus deviance Brian Cornwell1* and Christian Grillon2 1 Swinburne University of Technology, Brain and Psychological Sciences Research Centre, Australia 2 National Institute of Mental Health, Section on Neurobiology of Fear and Anxiety, United States Heightened vigilance and distractibility are key features of anxiety. Using a well-validated experimental model of state anxiety – threat of unpredictable shocks – we have shown in healthy individuals that threat-induced anxiety enhances cortical responding to stimulus deviance in a passive auditory oddball task. Enhanced cortical responding to subtle deviances in stimulation suggests that anxiety optimizes detection of environmental change irrespective of its significance. Recently, we investigated with whole-head MEG the effects of ?-aminobutyric acid (GABA)-ergic signal modulation on the anxiety-related enhancement of stimulus deviance responding. We specifically measured the acute effects of the benzodiazepine alprazolam (1 mg), which acts as a positive allosteric modulator at the GABAA receptor site, because of its well-known rapid anxiolytic action. Healthy participants (N=18) completed a passive auditory oddball task under threat (shocks at any time) and safe (no shocks) conditions in a randomized placebo-controlled crossover experiment. Adaptive MEG beamformer analyses were performed to map stimulus-elicited activity across the brain. Consistent with previous data, we found that threat potentiated stimulus-evoked responses within the core fronto-temporal cortical circuit mediating auditory deviance processing. Alprazolam, in addition to reducing subjective anxiety under threat, neutralized threat-potentiated responses, particularly in right inferior frontal gyrus (IFG; and left IFG to a lesser extent). Right IFG is thought to provide biasing signals to auditory cortices to enhance stimulus discrimination. Our findings suggest that threat amplifies these top-down prefrontal signals, and that this network process is under GABAergic control. This neurobiological change in healthy individuals during threat-induced anxiety may be linked to the chronic hypervigilance and exaggerated responding that is commonly exhibited in anxiety disorders. Keywords: Anxiety, Auditory Perception, Magnetoencephalography, GABA, inferior frontal gyrus Conference: XII International Conference on Cognitive Neuroscience (ICON-XII), Brisbane, Queensland, Australia, 27 Jul - 31 Jul, 2014. Presentation Type: Poster Topic: Emotional and Social Processes Citation: Cornwell B and Grillon C (2015). GABAergic control of anxiety-potentiated responding to stimulus deviance. Conference Abstract: XII International Conference on Cognitive Neuroscience (ICON-XII). doi: 10.3389/conf.fnhum.2015.217.00172 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: 19 Feb 2015; Published Online: 24 Apr 2015. * Correspondence: Dr. Brian Cornwell, Swinburne University of Technology, Brain and Psychological Sciences Research Centre, Melbourne, Australia, bcornwell@swin.edu.au 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 Brian Cornwell Christian Grillon Google Brian Cornwell Christian Grillon Google Scholar Brian Cornwell Christian Grillon PubMed Brian Cornwell Christian Grillon 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.

GABAergic control of depression-related brain states.

The GABAergic deficit hypothesis of major depressive disorders (MDDs) posits that reduced γ-aminobutyric acid (GABA) concentration in brain, impaired function of GABAergic interneurons, altered expression and function of GABA(A) receptors, and changes in GABAergic transmission dictated by altered chloride homeostasis can contribute to the etiology of MDD. Conversely, the hypothesis posits that the efficacy of currently used antidepressants is determined by their ability to enhance GABAergic neurotransmission. We here provide an update for corresponding evidence from studies of patients and preclinical animal models of depression. In addition, we propose an explanation for the continued lack of genetic evidence that explains the considerable heritability of MDD. Lastly, we discuss how alterations in GABAergic transmission are integral to other hypotheses of MDD that emphasize (i) the role of monoaminergic deficits, (ii) stress-based etiologies, (iii) neurotrophic deficits, and (iv) the neurotoxic and neural circuit-impairing consequences of chronic excesses of glutamate. We propose that altered GABAergic transmission serves as a common denominator of MDD that can account for all these other hypotheses and that plays a causal and common role in diverse mechanistic etiologies of depressive brain states and in the mechanism of action of current antidepressant drug therapies.

Gabaergic control of anxiety-like behavior, but not food intake, induced by ghrelin in the intermediate medial mesopallium of the neonatal chick

Ghrelin (Grh) is an endogenous ligand of the growth hormone secretagogue receptor. In neonatal chicks, central Ghr induces anxiogenic-like behavior but strongly inhibits food intake. The intermediate medial mesopallium (IMM) of the chick forebrain has been identified to be a site of the memory formation, and the modulation of the GABAA receptors that are present here modifies the expression of behavior. Thus, the GABAergic system may constitute a central pathway for Ghr action in regulating the processes of food intake and stress-related behaviors. Therefore, we investigated if the effect of systemic administration of bicuculline (GABAA receptor antagonist) and diazepam (benzodiazepine receptor agonist) on the anxiety in an Open Field test and inhibition in food intake induced by Grh (30pmol) when injected into IMM, were mediated by GABAergic transmission. In Open Field test, bicuculline was able to block the anxiogenic-like behavior induced by Ghr, whereas diazepam did not produce it. However, the co-administration of bicuculline or diazepam plus Ghr did not show any change in food intake at 30, 60 and 120min after injection compared to Ghr alone. Our results indicate for the first time that Ghr, injected into the forebrain IMM area, induces an anxiogenic-like behavior, which was blocked by bicuculline but not diazepam, thus suggesting that Ghr plays an important role in the response pattern to acute stressor, involving the possible participation of the GABAergic system. Nevertheless, as neither drug affected the hypophagia induced by intra-IMM Ghr, this suggests that it may be mediated by different mechanisms.

GABAρ subunits confer a bicuculline-insensitive component to GFAP+ cells of cerebellum.

GABA-A receptors mediating synaptic or extrasynaptic transmission are molecularly and functionally distinct, and glial cells are known to express a plethora of GABA-A subunits. Here we demonstrate that GFAP(+) cells of the granular layer of cerebellum express GABAρ subunits during early postnatal development, thereby conferring peculiar pharmacologic characteristics to GABA responses. Electron microscopy revealed the presence of GABAρ in the plasma membrane of GFAP(+) cells. In contrast, expression in the adult was restricted to Purkinje neurons and a subset of ependymal cells. Electrophysiological studies in vitro revealed that astrocytes express functional receptors with an EC50 of 52.2 ± 11.8 μM for GABA. The evoked currents were inhibited by bicuculline (100 μM) and TPMPA (IC50, 5.9 ± 0.6 μM), indicating the presence of a GABAρ component. Coimmunoprecipitation demonstrated protein-protein interactions between GABAρ1 and GABAα1, and double immunofluorescence showed that these subunits colocalize in the plasma membrane. Three populations of GABA-A receptors in astrocytes were identified: classic GABA-A, bicuculline-insensitive GABAρ, and GABA-A-GABAρ hybrids. Clusters of GABA-A receptors were distributed in the perinuclear space and along the processes of GFAP(+) cells. Time-lapse microscopy showed GABAρ2-GFP accumulation in clusters located in the soma and along the processes. The clusters were relatively immobile, with mean displacement of 9.4 ± 0.9 μm and a net distance traveled of 1-2 μm, owing mainly to directional movement or simple diffusion. Modulation of GABAρ dynamics may be a novel mechanism of extrasynaptic transmission regulating GABAergic control of GFAP(+) cells during early postnatal development.

Plasticity of GABAA receptor diffusion dynamics at the axon initial segment.

The axon initial segment (AIS), a site of action potential initiation, undergoes activity-dependent homeostatic repositioning to fine-tune neuronal activity. However, little is known about the behavior of GABAA receptors (GABAARs) at synapses made onto the axon and especially the AIS. Here, we study the clustering and lateral diffusion of GABAARs in the AIS under baseline conditions, and find that GABAAR lateral mobility is lower in the AIS than dendrites. We find differences in axonal clustering and lateral mobility between GABAARs containing the α1 or α2 subunits, which are known to localize differentially to the AIS. Interestingly, we find that chronic activity driving AIS repositioning does not alter GABAergic synapse location along the axon, but decreases GABAAR cluster size at the AIS. Moreover, in response to chronic depolarization, GABAAR diffusion is strikingly increased in the AIS, and not in dendrites, and this is coupled with a decrease in synaptic residency time of GABAARs at the AIS. We also demonstrate that activation of L-type voltage-gated calcium channels is important for regulating GABAAR lateral mobility at the AIS during chronic depolarization. Modulation of GABAAR diffusion dynamics at the AIS in response to prolonged activity may be a novel mechanism for regulating GABAergic control of information processing.

Stress-induced plasticity of GABAergic inhibition.

GABAergic neurotransmission is highly plastic, undergoing dynamic alterations in response to changes in the environment, such as following both acute and chronic stress. Stress-induced plasticity of GABAergic inhibition is thought to contribute to changes in neuronal excitability associated with stress, which is particularly relevant for stress-related disorders and seizure susceptibility. Here we review the literature demonstrating several mechanisms altering GABAergic inhibition associated with stress, including brain region-specific alterations in GABAA receptor (GABAAR) subunit expression, changes in chloride homeostasis, and plasticity at GABAergic synapses. Alterations in the expression of specific GABAAR subunits have been documented in multiple brain regions associated with acute or chronic stress. In addition, recent work demonstrates stress-induced alterations in GABAergic inhibition resulting from plasticity in intracellular chloride levels. Acute and chronic stress-induced dephosphorylation and downregulation of the K+/Cl− co-transporter, KCC2, has been implicated in compromising GABAergic control of corticotropin-releasing hormone (CRH) neurons necessary for mounting the physiological response to stress. Acute stress also unmasks the capacity for both long-term potentiation and long-term depression, in distinct temporal windows, at GABAergic synapses on parvocellular neuroendocrine cells (PNCs) in the paraventricular nucleus (PVN) of the hypothalamus. This review highlights the complexity in the plasticity of GABAergic neurotransmission associated with stress and the relationship to neuronal excitability, including alterations in GABAAR expression, synaptic plasticity at GABAergic synapses, and changes in chloride homeostasis.

Chronic stress impairs GABAergic control of amygdala through suppressing the tonic GABAA receptor currents.

BackgroundChronic stress is generally known to exacerbate the development of numerous neuropsychiatric diseases such as fear and anxiety disorders, which is at least partially due to the disinhibition of amygdala subsequent to the prolonged stress exposure. GABA receptor A (GABAAR) mediates the primary component of inhibition in brain and its activation produces two forms of inhibition: the phasic and tonic inhibition. While both of them are critically engaged in limiting the activity of amygdala, their roles in the amygdala disinhibition subsequent to chronic stress exposure are largely unknown.ResultsWe investigated the possible alterations of phasic and tonic GABAAR currents and their roles in the amygdala disinhibition subsequent to chronic stress. We found that both chronic immobilization and unpredictable stress led to long lasting loss of tonic GABAAR currents in the projection neurons of lateral amygdala. By contrast, the phasic GABAAR currents, as measured by the spontaneous inhibitory postsynaptic currents, were virtually unaltered. The loss of tonic inhibition varied with the duration of daily stress and the total days of stress exposure. It was prevented by pretreatment with metyrapone to block corticosterone synthesis or RU 38486, a glucocorticoid receptor antagonist, suggesting the critical involvement of glucocorticoid receptor activation. Moreover, chronic treatment with corticosterone mimicked the effect of chronic stress and reduced the tonic inhibition in lateral amygdala of control mice. The loss of tonic inhibition resulted in the impaired GABAergic gating on neuronal excitability in amygdala, which was prevented by metyrapone pretreatment.ConclusionsOur study suggests that enduring loss of tonic but not phasic GABAAR currents critically contributes to the prolonged amygdala disinhibition subsequent to chronic stress. We propose that the preferential loss of tonic inhibition may account for the development of stress-related neuropsychiatric diseases.

Pontine respiratory group neuronal discharge is modulated by powerful GABAergic tonic inhibition (712.7)

Neurons within the parabrachial (PB) complex appear to play a key role in controlling breathing frequency. Densely labeled GABA‐immunoreactive varicosities have been observed throughout the PB and the Kölliker‐Fuse (KF) nuclei of rats, however, the role of GABAergic control of PRG neurons is inadequately understood. To characterize GABAergic inhibition in the control of PRG discharge frequency (Fn) patterns, we analyzed the effects of microejected GABA‐A receptor antagonists bicuculline and picrotoxin on PRG neuronal activity in a decerebrate, vagotomized, ventilated and paralyzed canine model. Histograms (CTHs) triggered from the phrenic neurogram were used to quantify neuronal unit activity. Both antagonists produced marked increases in Fn (>80%) either alone or combined (sequentially ejected) in 80‐90% of PRG neurons. Activity throughout the cycle of phase spanning PRG neurons was increased and phasic portions of Fn showed gain modulation. Effects of both antagonists appear to be qualitatively and quantitatively similar. The results show that most PRG neurons are under strong endogenous GABAergic inhibition that attenuates their activity and is expected to markedly impact phase‐timing.Grant Funding Source: Supported by VA Medical Research Funds I01 BX000721‐01

Lateral habenula and the rostromedial tegmental nucleus innervate neurochemically distinct subdivisions of the dorsal raphe nucleus in the rat

The lateral habenula (LHb) is an epithalamic structure differentiated in a medial (LHbM) and a lateral division (LHbL). Together with the rostromedial tegmental nucleus (RMTg), the LHb has been implicated in the processing of aversive stimuli and inhibitory control of monoamine nuclei. The inhibitory LHb influence on midbrain dopamine neurons has been shown to be mainly mediated by the RMTg, a mostly GABAergic nucleus that receives a dominant input from the LHbL. Interestingly, the RMTg also projects to the dorsal raphe nucleus (DR), which also receives direct LHb projections. To compare the organization and transmitter phenotype of LHb projections to the DR, direct and indirect via the RMTg, we first placed injections of the anterograde tracer Phaseolus vulgaris leucoagglutinin into the LHb or the RMTg. We then confirmed our findings by retrograde tracing and investigated a possible GABAergic phenotype of DR-projecting RMTg neurons by combining retrograde tracing with in situ hybridization for GAD67. We found only moderate direct LHb projections to the DR, which mainly emerged from the LHbM and were predominantly directed to the serotonin-rich caudal DR. In contrast, RMTg projections to the DR were more robust, emerged from RMTg neurons enriched in GAD67 mRNA, and were focally directed to a distinctive DR subdivision immunohistochemically characterized as poor in serotonin and enriched in presumptive glutamatergic neurons. Thus, besides its well-acknowledged role as a GABAergic control center for the ventral tegmental area (VTA)-nigra complex, our findings indicate that the RMTg is also a major GABAergic relay between the LHb and the DR.

Lateral habenula and the rostromedial tegmental nucleus innervate neurochemically distinct subdivisions of the dorsal raphe nucleus in the rat

ABSTRACTThe lateral habenula (LHb) is an epithalamic structure differentiated in a medial (LHbM) and a lateral division (LHbL). Together with the rostromedial tegmental nucleus (RMTg), the LHb has been implicated in the processing of aversive stimuli and inhibitory control of monoamine nuclei. The inhibitory LHb influence on midbrain dopamine neurons has been shown to be mainly mediated by the RMTg, a mostly GABAergic nucleus that receives a dominant input from the LHbL. Interestingly, the RMTg also projects to the dorsal raphe nucleus (DR), which also receives direct LHb projections. To compare the organization and transmitter phenotype of LHb projections to the DR, direct and indirect via the RMTg, we first placed injections of the anterograde tracer Phaseolus vulgaris leucoagglutinin into the LHb or the RMTg. We then confirmed our findings by retrograde tracing and investigated a possible GABAergic phenotype of DR‐projecting RMTg neurons by combining retrograde tracing with in situ hybridization for GAD67. We found only moderate direct LHb projections to the DR, which mainly emerged from the LHbM and were predominantly directed to the serotonin‐rich caudal DR. In contrast, RMTg projections to the DR were more robust, emerged from RMTg neurons enriched in GAD67 mRNA, and were focally directed to a distinctive DR subdivision immunohistochemically characterized as poor in serotonin and enriched in presumptive glutamatergic neurons. Thus, besides its well‐acknowledged role as a GABAergic control center for the ventral tegmental area (VTA)–nigra complex, our findings indicate that the RMTg is also a major GABAergic relay between the LHb and the DR. J. Comp. Neurol. 522:1454–1484, 2014. © 2013 Wiley Periodicals, Inc.

Traumatic Brain Injury Increases Cortical Glutamate Network Activity by Compromising GABAergic Control

Traumatic brain injury (TBI) is a major risk factor for developing pharmaco-resistant epilepsy. Although disruptions in brain circuitry are associated with TBI, the precise mechanisms by which brain injury leads to epileptiform network activity is unknown. Using controlled cortical impact (CCI) as a model of TBI, we examined how cortical excitability and glutamatergic signaling was altered following injury. We optically mapped cortical glutamate signaling using FRET-based glutamate biosensors, while simultaneously recording cortical field potentials in acute brain slices 2-4 weeks following CCI. Cortical electrical stimulation evoked polyphasic, epileptiform field potentials and disrupted the input-output relationship in deep layers of CCI-injured cortex. High-speed glutamate biosensor imaging showed that glutamate signaling was significantly increased in the injured cortex. Elevated glutamate responses correlated with epileptiform activity, were highest directly adjacent to the injury, and spread via deep cortical layers. Immunoreactivity for markers of GABAergic interneurons were significantly decreased throughout CCI cortex. Lastly, spontaneous inhibitory postsynaptic current frequency decreased and spontaneous excitatory postsynaptic current increased after CCI injury. Our results suggest that specific cortical neuronal microcircuits may initiate and facilitate the spread of epileptiform activity following TBI. Increased glutamatergic signaling due to loss of GABAergic control may provide a mechanism by which TBI can give rise to post-traumatic epilepsy.

Retinal Input Directs the Recruitment of Inhibitory Interneurons into Thalamic Visual Circuits

Inhibitory interneurons (INs) critically control the excitability and plasticity of neuronal networks, but whether activity can direct INs into specific circuits during development is unknown. Here, we report that in the dorsal lateral geniculate nucleus (dLGN), which relays retinal input to the cortex, circuit activity is required for the migration, molecular differentiation, and functional integration of INs. We first characterize the prenatal origin and molecular identity of dLGN INs, revealing their recruitment from an Otx2(+) neuronal pool located in the adjacent ventral LGN. Using time-lapse and electrophysiological recordings, together with genetic and pharmacological perturbation of retinal waves, we show that retinal activity directs the navigation and circuit incorporation of dLGN INs during the first postnatal week, thereby regulating the inhibition of thalamocortical circuits. These findings identify an input-dependent mechanism regulating IN migration and circuit inhibition, which may account for the progressive recruitment of INs into expanding excitatory circuits during evolution.

Layer-Specific GABAergic Control of Distinct Gamma Oscillations in the CA1 Hippocampus

The temporary interaction of distinct gamma oscillators effects binding, association, and information routing. How independent gamma oscillations are generated and maintained by pyramidal cells and interneurons within a cortical circuit remains unknown. We recorded the spike timing of identified parvalbumin-expressing basket cells in the CA1 hippocampus of anesthetized rats and simultaneously detected layer-specific gamma oscillations using current-source-density analysis. Spike timing of basket cells tuned the phase and amplitude of gamma oscillations generated around stratum pyramidale, where basket cells selectively innervate pyramidal cells with GABAergic synapses. Basket cells did not contribute to gamma oscillations generated at the apical tuft of pyramidal cells. This gamma oscillation was selectively modulated by a subset of local GABAergic interneurons and by medial entorhinal cortex layer 3 neurons. The generation of independent and layer-specific gamma oscillations, implemented onto hippocampal pyramidal cells along their somato-dendritic axis, can be explained by selective axonal targeting and precisely controlled temporal firing of GABAergic interneurons.

Alteration of Striatal Dopamine Levels Under Various Partial Pressure of Oxygen in Pre-convulsive and Convulsive Phases in Freely-Moving rats

The purpose of this study was to investigate the change in the striatal dopamine (DA) level in freely-moving rat exposed to different partial pressure of oxygen (from 1 to 5ATA). Some works have suggested that DA release by the substantia nigra pars compacta (SNc) neurons in the striatum could be disturbed by hyperbaric oxygen (HBO) exposure, altering therefore the basal ganglia activity. Such changes could result in a change in glutamatergic and GABAergic control of the dopaminergic neurons into the SNc. Such alterations could provide more information about the oxygen-induced seizures observed at 5ATA in rat. DA-sensitive electrodes were implanted into the striatum under general anesthesia. After 1week rest, awaked rats were exposed to oxygen-nitrogen mixture at a partial pressure of oxygen of 1, 2, 3, 4 and 5ATA. DA level was monitored continuously (every 3min) by in vivo voltammetry before and during HBO exposure. HBO induced a decrease in DA level in relationship to the increase in partial pressure of oxygen from 1ATA to 4ATA (-15% at 1ATA, -30% at 2ATA, -40% at 3ATA, -45% at 4ATA), without signs of oxygen toxicity. At 5ATA, DA level strongly decreases (-75%) before seizure which occurred after 27min±7 HBO exposure. After the epileptic seizure the decrease in DA level disappeared. These changes and the biphasic effect of HBO were discussed in function of HBO action on neurochemical regulations of the nigro striatal pathway.

Seizure-induced disinhibition of the HPA axis increases seizure susceptibility

Stress is the most commonly reported precipitating factor for seizures. The proconvulsant actions of stress hormones are thought to mediate the effects of stress on seizure susceptibility. Interestingly, epileptic patients have increased basal levels of stress hormones, including corticotropin-releasing hormone (CRH) and corticosterone, which are further increased following seizures. Given the proconvulsant actions of stress hormones, we proposed that seizure-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis may contribute to future seizure susceptibility. Consistent with this hypothesis, our data demonstrate that pharmacological induction of seizures in mice with kainic acid or pilocarpine increases circulating levels of the stress hormone, corticosterone, and exogenous corticosterone administration is sufficient to increase seizure susceptibility. However, the mechanism(s) whereby seizures activate the HPA axis remain unknown. Here we demonstrate that seizure-induced activation of the HPA axis involves compromised GABAergic control of CRH neurons, which govern HPA axis function. Following seizure activity, there is a collapse of the chloride gradient due to changes in NKCC1 and KCC2 expression, resulting in reduced amplitude of sIPSPs and even depolarizing effects of GABA on CRH neurons. Seizure-induced activation of the HPA axis results in future seizure susceptibility which can be blocked by treatment with an NKCC1 inhibitor, bumetanide, or blocking the CRH signaling with Antalarmin. These data suggest that compromised GABAergic control of CRH neurons following an initial seizure event may cause hyperexcitability of the HPA axis and increase future seizure susceptibility.

The parvalbumin-positive interneurons in the mouse dentate gyrus express GABAA receptor subunits alpha1, beta2, and delta along their extrasynaptic cell membrane

Neuronal circuitries in the hippocampus are involved in navigation and memory and are controlled by major networks of GABAergic interneurons. Parvalbumin (PV)-expressing interneurons in the dentate gyrus (DG) are identified as fast-spiking cells, playing a crucial role in network oscillation and synchrony. The inhibitory modulation of these interneurons is thought to be mediated mainly through GABAA receptors, the major inhibitory neurotransmitter receptors in the brain. Here we show that all PV-positive interneurons in the granular/subgranular layer (GL/SGL) of the mouse DG express high levels of the GABAA receptor δ subunit. PV-containing interneurons in the hilus and the molecular layer, however, express the δ subunit to a lower extent. Only 8% of the somatostatin-containing interneurons express the δ subunit, whereas calbindin- or calretinin-containing interneurons in the DG seem not to express the GABAA receptor δ subunit at all. Hence, these cells receive a GABAergic control different from that of PV-containing interneurons in the GL/SGL. Experiments investigating a possible co-expression of GABAA receptor α1, α2, α3, α4, α5, β1, β2, β3, or γ2 subunits with PV and δ subunits indicated that α1 and β2 subunits are co-expressed with δ subunits along the extrasynaptic membranes of PV-interneurons. These results suggest a robust tonic GABAergic control of PV-containing interneurons in the GL/SGL of the DG via δ subunit-containing receptors. Our data are important for better understanding of the neuronal circuitries in the DG and the role of specific cell types under pathological conditions.

Compartmentalization of GABAergic Inhibition by Dendritic Spines

γ-aminobutyric acid-mediated (GABAergic) inhibition plays a critical role in shaping neuronal activity in the neocortex. Numerous experimental investigations have examined perisomatic inhibitory synapses, which control action potential output from pyramidal neurons. However, most inhibitory synapses in the neocortex are formed onto pyramidal cell dendrites, where theoretical studies suggest they may focally regulate cellular activity. The precision of GABAergic control over dendritic electrical and biochemical signaling is unknown. By using cell type-specific optical stimulation in combination with two-photon calcium (Ca(2+)) imaging, we show that somatostatin-expressing interneurons exert compartmentalized control over postsynaptic Ca(2+) signals within individual dendritic spines. This highly focal inhibitory action is mediated by a subset of GABAergic synapses that directly target spine heads. GABAergic inhibition thus participates in localized control of dendritic electrical and biochemical signaling.

GABAergic control of critical developmental periods for anxiety- and depression-related behavior in mice.

Vulnerability for anxiety and depressive disorders is thought to have origins in early life and is increasingly recognized to involve deficits in GABAergic neurotransmission. Mice that were rendered heterozygous for the γ2 subunit gene of GABAA receptors (GABAARs) show behavioral, cognitive, neuroendocrine and pharmacologic features expected of a mouse model of melancholic anxious depression, including reduced survival of adult-born hippocampal neurons. Here we embarked on elucidating the developmental substrate underlying this phenotype, focusing on the Elevated Plus Maze and Forced Swim Test as relevant behavioral paradigms. In a first series of experiments using hemizygous tamoxifen-induced genetic inactivation of a floxed γ2 genomic locus we show that reducing the gene dosage at postnatal days (P)13/14 but not P27/28 results in altered behavior in both of these tests in adulthood, reminiscent of the anxious-depressive phenotype previously described for global heterozygous mice. However, in contrast to global heterozygous mice, the behavioral changes induced by γ2 subunit knockdown at P13/14 occurred without changes in adult hippocampal neurogenesis, indicating that altered neurogenesis is not an absolute prerequisite for anxiety- and depression-related behavior in this model. In a separate series of experiments using a pharmacological approach, acute but transient potentiation of GABAARs with diazepam uncovered distinct developmental vulnerabilities for altered behavior in the Elevated Plus Maze and Forced Swim Test, respectively. Specifically, diazepam given during P10-16 but not during later weeks resulted in increased anxiety-like behavior in adulthood, while diazepam administered during P29-35 but not earlier nor later resulted in increased immobility behavior in adulthood. We conclude that anxiety-like behavior in the Elevated Plus Maze and behavioral despair-like immobility in the Forced Swim Test are controlled by separate postnatal critical periods characterized by distinct developmental sensitivity to manipulation of GABAergic transmission via γ2 subunit-containing GABAARs.

GABAergic control of central serotonergic neurotransmission – role of GABAB receptors and possible implication in the antidepressant action of ketamine

GABAergic control of central serotonergic neurotransmission – role of GABAB receptors and possible implication in the antidepressant action of ketamine

Chaoborus and Gasterosteus Anti-Predator Responses in Daphnia pulex Are Mediated by Independent Cholinergic and Gabaergic Neuronal Signals

Many prey species evolved inducible defense strategies that protect effectively against predation threats. Especially the crustacean Daphnia emerged as a model system for studying the ecology and evolution of inducible defenses. Daphnia pulex e.g. shows different phenotypic adaptations against vertebrate and invertebrate predators. In response to the invertebrate phantom midge larvae Chaoborus (Diptera) D. pulex develops defensive morphological defenses (neckteeth). Cues originating from predatory fish result in life history changes in which resources are allocated from somatic growth to reproduction. While there are hints that responses against Chaoborus cues are transmitted involving cholinergic neuronal pathways, nothing is known about the neurophysiology underlying the transmission of fish related cues. We investigated the neurophysiological basis underlying the activation of inducible defenses in D. pulex using induction assays with the invertebrate predator Chaoborus and the three-spined stickleback Gasterosteus aculeatus. Predator-specific cues were combined with neuro-effective substances that stimulated or inhibited the cholinergic and gabaergic nervous system. We show that cholinergic-dependent pathways are involved in the perception and transmission of Chaoborus cues, while GABA was not involved. Thus, the cholinergic nervous system independently mediates the development of morphological defenses in response to Chaoborus cues. In contrast, only the inhibitory effect of GABA significantly influence fish-induced life history changes, while the application of cholinergic stimulants had no effect in combination with fish related cues. Our results show that cholinergic stimulation mediates signal transmission of Chaoborus cues leading to morphological defenses. Fish cues, which are responsible for predator-specific life history adaptations involve gabaergic control. Our study shows that both pathways are independent and thus potentially allow for adjustment of responses to variable predation regimes.