GABAergic Deficits Research Articles

GABAergic deficits and schizophrenia-like behaviors in a mouse model carrying patient-derived neuroligin-2 R215H mutation

Schizophrenia (SCZ) is a severe mental disorder characterized by delusion, hallucination, and cognitive deficits. We have previously identified from schizophrenia patients a loss-of-function mutation Arg215→His215 (R215H) of neuroligin 2 (NLGN2) gene, which encodes a cell adhesion molecule critical for GABAergic synapse formation and function. Here, we generated a novel transgenic mouse line with neuroligin-2 (NL2) R215H mutation. The single point mutation caused a significant loss of NL2 protein in vivo, reduced GABAergic transmission, and impaired hippocampal activation. Importantly, R215H KI mice displayed anxiety-like behavior, impaired pre-pulse inhibition (PPI), cognition deficits and abnormal stress responses, recapitulating several key aspects of schizophrenia-like behaviors. Our results demonstrate a significant impact of a single point mutation NL2 R215H on brain functions, providing a novel animal model for the study of schizophrenia and neuropsychiatric disorders.

256. Targeting GABAergic SST-Positive Interneurons Deficits: Implications for Cognitive and Mood Symptoms in Depression and Other Brain Disorders

256. Targeting GABAergic SST-Positive Interneurons Deficits: Implications for Cognitive and Mood Symptoms in Depression and Other Brain Disorders

S14. DNA METHYLATION CHANGES IN GABAERGIC AND GLUTAMATERGIC MARKERS IN EARLY SCHIZOPHRENIA

BackgroundGABAergic and glutamatergic systems play an important role in the neurobiology of schizophrenia, and changes in their markers are reported in both postmortem human brain and in animal models. Recent studies have demonstrated that abnormalities in DNA methylation may underlie the alterations in various indicators of GABAergic and glutamatergic functions in schizophrenia. As our group previously found decreased NR2 protein plasma levels and downregulation of parvalbumin (PVALB) mRNA in first episode of psychosis (FEP) patients, we hypothesised that changes in DNA methylation may be responsible for these indicators of glutamatergic and GABAergic deficits in FEP patients.MethodsBlood samples were collected from patients in FEP (n = 35) after their first contact with the mental health assistance, siblings (n = 21) and population-based controls (n = 35). Bisulfite conversion and pyrosequencing were used to determine methylation levels in 4 CpG sites in promoter sequence of PVALB and 5 CpG sites at GRIN2B (gene which encodes NR2).ResultsWe found hypermethylation at a CpG site within the PVALB promoter sequence in patients and their siblings compared to population-based control group (p< 0.001) while overall hypomethylation was found in the 5 CpGs analysed within GRIN2B promoter sequence (p < 0.01).DiscussionOur PVALB findings are consistent with our previous studies showing that PVALB promoter methylation is elevated in schizophrenia and, additionally this is the first evidence showing changes in GRIN2B promoter methylation in psychosis. These results together suggest that these epigenetic findings may relate to the reduction of protein expression of indicators of glutamate and GABA systems seen in this disease.

Increased DNA methylation in the parvalbumin gene promoter is associated with methamphetamine dependence.

The parvalbumin (PV)-containing subgroup of GABAergic neurons is particularly affected in schizophrenia and animal models of psychosis, including after methamphetamine (METH) administration. We investigated whether METH dependence and METH-induced psychosis may involve an effect on DNA methylation of the PVALB promoter. The methylation of a PVALB promoter sequence was determined in 100 METH-dependent and 102 control subjects using pyrosequencing. A significant increase in PVALB methylation was observed in METH dependence and METH-induced psychosis. No significant effect on long interspersed nucleotide element-1 methylation, a measure of global DNA methylation, was observed. These results demonstrate a specific association between elevated PVALB methylation and METH-induced psychosis. This finding may contribute to the GABAergic deficits associated with METH dependence.

Mutation-induced loss of APP function causes GABAergic depletion in recessive familial Alzheimer\u2019s disease: analysis of Osaka mutation-knockin mice

The E693Δ (Osaka) mutation in APP is linked to familial Alzheimer’s disease. While this mutation accelerates amyloid β (Aβ) oligomerization, only patient homozygotes suffer from dementia, implying that this mutation is recessive and causes loss-of-function of amyloid precursor protein (APP). To investigate the recessive trait, we generated a new mouse model by knocking-in the Osaka mutation into endogenous mouse APP. The produced homozygous, heterozygous, and non-knockin littermates were compared for memory, neuropathology, and synaptic plasticity. Homozygotes showed memory impairment at 4 months, whereas heterozygotes did not, even at 8 months. Immunohistochemical and biochemical analyses revealed that only homozygotes displayed intraneuronal accumulation of Aβ oligomers at 8 months, followed by abnormal tau phosphorylation, synapse loss, glial activation, and neuron loss. These pathologies were not observed at younger ages, suggesting that a certain mechanism other than Aβ accumulation underlies the memory disturbance at 4 months. For the electrophysiology studies at 4 months, high-frequency stimulation evoked long-term potentiation in all mice in the presence of picrotoxin, but in the absence of picrotoxin, such potentiation was observed only in homozygotes, suggesting their GABAergic deficit. In support of this, the levels of GABA-related proteins and the number of dentate GABAergic interneurons were decreased in 4-month-old homozygotes. Since APP has been shown to play a role in dentate GABAergic synapse formation, the observed GABAergic depletion is likely associated with an impairment of the APP function presumably caused by the Osaka mutation. Oral administration of diazepam to homozygotes from 6 months improved memory at 8 months, and furthermore, prevented Aβ oligomer accumulation, indicating that GABAergic deficiency is a cause of memory impairment and also a driving force of Aβ accumulation. Our findings suggest that the Osaka mutation causes loss of APP function, leading to GABAergic depletion and memory disorder when wild-type APP is absent, providing a mechanism of the recessive heredity.

청소년기 동물모델에서 구속 스트레스로 유발된 불안, 우울행동에 미치는 영향

Purpose: Some of the adolescent drinks more sugar-sweetened beverages. However, there is little evidence on the effect of eating behavior on emotional state and neurochemical changes under stress, especially on the levels of typical inhibitory neurotransmitters and gamma-aminobutyric acid. This article demonstrates that sucrose or saccharin drink reduces stress-related behavior responses and GABAergic deficits in adolescent rats. Methods: We randomly assigned 7-weeks-old Sprague-Dawley male rats to three groups: control group (Control), restraint stress only group (Stress), and restraint stress with unrestricted access to saccharin solution (Saccharin) and sucrose solution (Sucrose) as a positive control. We evaluated both anxious and depressive moods using an open field test and forced swim test, respectively. Using western blot analyses, the expression of a GABA-synthesizing enzyme, glutamate decarboxylase-67 (GAD67) and GABAergic markers, including calbindin and parvalbumin was assessed in the prefrontal cortex and the amygdala. Results: We found that both the drinks alleviated anxiety and depressive moods, induced significant attenuation in GAD67 level, and reduced calbindin level under stress in the prefrontal cortex and the amygdala. Conclusion: The results provide an understanding of the effect of sucrose or saccharin drink on stress-related responses. We propose the consumption of sweet drinks as a plausible strategy to alleviate stress-related alterations in adolescents. Key Words: Sugar-sweetened beverages; Artificially sweetened beverage; Gamma-aminobutyric acid; Adolescent; Emotions Key Words: 가당 음료; ì²­ì†Œë „; ìŠ¤íŠ¸ë ˆìŠ¤; ê°ì •; GABA성 ì‹ ê²½ì„¸í¬

Role of gamma-aminobutyric acid ergic activation in pathology of −dopamine-2 receptors model of Parkinsonism in mice

BACKGROUND: Blocking of dopamine-2 receptors (D2R) in the brain showed motor symptoms seen in Parkinsonism. Since D2R is excitatory in the brain and blocking it is like inhibition. This work is designed to show if activating gamma aminobutyric acid (GABA) system in the brain contributes to the pathogenesis of Parkinsonism seen in–D2R model of Parkinsonism. MATERIALS AND METHODS: Twenty male adult albino mice were randomly divided into four groups (Veh, −D2R, +GABA, and −D2R + GABA). Veh. animals were given 0.04 mL of normal saline, −D2R were given 10 mg/kg body weight (BW) of haloperidol for 14 days, +GABA were given 10 mg/kg BW of diazepam for 7 days and −D2R + GABA were given 10 mg/kg BW of haloperidol for 14 days with subsequent 10 mg/kg BW of diazepam for 7 days. Each group contains 5 animals and all treatment was done intraperitoneally. Motor activity of the animals was assessed using rotarod, Y-maze for spatial memory and elevated plus maze for anxiety and locomotion. At the end of treatment, the animals were anesthetized using ketamine and perfused transcardially with formal saline. Brains were then excised and fixed in formal saline. The prefrontal cortex (PFC) and hippocampus were processed for histological study using hematoxylin and eosin stain and immunohistochemistry for Lewy bodies. Data were expressed as mean ± standard error of mean and analyzed using analysis of variance with Tukey post hoc test significant level was set at P RESULTS: Motor activity was significantly reduced in all treated groups (−D2R, +GABA and −D2R/+GABA) compared to the control (Veh) as they all have lower latency of fall and arm entries. Y-maze result shows that spatial memory was significantly reduced in –D2R and −D2R/+GABA groups but not + GABA. Anxiety-related behavior was high in all treated groups compared to control. Cellular distortion was observed in the PFC and hippocampus of all treated groups with −D2R/+GABA group having a high level of distortion. Lewy bodies accumulation was absent in the brain regions observed from all the groups. CONCLUSIONS: GABAergic activation aids motor and memory deficit and marked brain pathology in −D2R model of Parkinsonism.

Disinhibition of somatostatin-positive GABAergic interneurons results in an anxiolytic and antidepressant-like brain state

Major depressive disorder (MDD) is associated with reduced concentrations of γ-aminobutyric acid (GABA) that are normalized by antidepressant therapies. Moreover, depressive-like phenotypes of GABAA receptor mutant mice can be reversed by treatment with conventional antidepressants drugs, as well as by subanesthetic doses of ketamine. Thus GABAergic deficits may causally contribute to depressive disorders, while antidepressant therapies may enhance GABAergic synaptic transmission. Here we tested the hypothesis that sustained enhancement of GABAergic transmission alone is sufficient to elicit antidepressant-like behavior, using disinhibition of GABAergic interneurons. We focused on somatostatin-positive (SST+) GABAergic interneurons because of evidence that their function is compromised in MDD. To disinhibit SST+ interneurons, we inactivated the γ2 subunit gene of GABAA receptors selectively in these neurons (SSTCre:γ2f/f mice). Loss of inhibitory synaptic input resulted in increased excitability of SST+ interneurons. In turn, pyramidal cell targets of SST+ neurons showed an increased frequency of spontaneous inhibitory postsynaptic currents. The behavior of SSTCre:γ2f/f mice mimicked the effects of anxiolytic and antidepressant drugs in a number of behavioral tests, without affecting performance in a spatial learning- and memory-dependent task. Finally, brain extracts of SSTCre:γ2f/f mice showed decreased phosphorylation of the eukaryotic elongation factor eEF2, reminiscent of the effects of ketamine. Importantly, these effects occurred without altered activity of the mammalian target of rapamycin pathway nor did they involve altered expression of SST. However, they were associated with reduced Ca2+/calmodulin-dependent auto-phosphorylation of eEF2 kinase, which controls the activity of eEF2 as its single target. Thus enhancing GABAergic inhibitory synaptic inputs from SST+ interneurons to pyramidal cells and corresponding chronic reductions in the synaptic excitation:inhibition ratio represents a novel strategy for antidepressant therapies that reproduces behavioral and biochemical end points of rapidly acting antidepressants.

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

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

Bidirectional Homeostatic Regulation of a Depression-Related Brain State by Gamma-Aminobutyric Acidergic Deficits and Ketamine Treatment

BackgroundMajor depressive disorder is increasingly recognized to involve functional deficits in both gamma-aminobutyric acid (GABA)ergic and glutamatergic synaptic transmission. To elucidate the relationship between these phenotypes, we used GABAA receptor γ2 subunit heterozygous (γ2+/−) mice, which we previously characterized as a model animal with construct, face, and predictive validity for major depressive disorder. MethodsTo assess possible consequences of GABAergic deficits on glutamatergic transmission, we quantitated the cell surface expression of N-methyl-D-aspartate (NMDA)-type and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors and the function of synapses in the hippocampus and medial prefrontal cortex of γ2+/− mice. We also analyzed the effects of an acute dose of the experimental antidepressant ketamine on all these parameters in γ2+/− versus wild-type mice. ResultsModest defects in GABAergic synaptic transmission of γ2+/− mice resulted in a strikingly prominent homeostatic-like reduction in the cell surface expression of NMDA-type and AMPA-type glutamate receptors, along with prominent functional impairment of glutamatergic synapses in the hippocampus and medial prefrontal cortex. A single subanesthetic dose of ketamine normalized glutamate receptor expression and synaptic function of γ2+/− mice to wild-type levels for a prolonged period, along with antidepressant-like behavioral consequences selectively in γ2+/− mice. The GABAergic synapses of γ2+/− mice were potentiated by ketamine in parallel but only in the medial prefrontal cortex. ConclusionsDepressive-like brain states that are caused by GABAergic deficits involve a homeostatic-like reduction of glutamatergic transmission that is reversible by an acute, subanesthetic dose of ketamine, along with regionally selective potentiation of GABAergic synapses. The data merge the GABAergic and glutamatergic deficit hypotheses of major depressive disorder.

Estrogens Suppress a Behavioral Phenotype in Zebrafish Mutants of the Autism Risk Gene, CNTNAP2

Autism spectrum disorders (ASDs) are a group of devastating neurodevelopmental syndromes that affect up to 1 in 68 children. Despite advances in the identification of ASD risk genes, the mechanisms underlying ASDs remain unknown. Homozygous loss-of-function mutations in Contactin Associated Protein-like 2 (CNTNAP2) are strongly linked to ASDs. Here we investigate the function of Cntnap2 and undertake pharmacological screens to identify phenotypic suppressors. We find that zebrafish cntnap2 mutants display GABAergic deficits, particularly in the forebrain, and sensitivity to drug-induced seizures. High-throughput behavioral profiling identifies nighttime hyperactivity in cntnap2 mutants, while pharmacological testing reveals dysregulation of GABAergic and glutamatergic systems. Finally, we find that estrogen receptor agonists elicit a behavioral fingerprint anti-correlative to that of cntnap2 mutants and show that the phytoestrogen biochanin A specifically reverses the mutant behavioral phenotype. These results identify estrogenic compounds as phenotypic suppressors and illuminate novel pharmacological pathways with relevance to autism.

Frequency-Dependent Corticostriatal Disinhibition Resulting from Chronic Dopamine Depletion: Role of Local Striatal cGMP and GABA-AR Signaling.

The onset of motor deficits in parkinsonism is thought to result from dopamine (DA) loss-induced corticostriatal disruption and the development of excessive cortico-basal ganglia synchronization. To gain insights into the mechanisms underlying such corticostriatal dysfunction, we conducted local field potential (LFP) recordings in rats and measured how striatal manipulations of DA, cyclic guanosine monophosphate (cGMP), and gamma-aminobutyric acid- A receptor (GABA-AR) signaling impact corticostriatal transmission at specific oscillatory frequencies. Results indicate that the degree of 6-hydroxydopamine-induced DA lesion and subsequent changes in striatal DA, cGMP, and GABA-AR signaling contribute to impair LFP suppression such that the DA-depleted striatum becomes more permissive to cortically driven oscillations at 10-20 Hz, and to a lesser extent, at 40 Hz. Notably, the corticostriatal dysfunction at 40 Hz emerged only when the degree of chronic DA lesion surpassed 90%, which coincides with the appearance of severe forelimb stepping deficits. Collectively, these results indicate that several mechanisms contribute to suppress LFP within the 10-20 Hz range, yet a critical level of striatal GABAergic activity is required for sustaining corticostriatal inhibition at 40 Hz. Both the degree and chronicity of DA lesion are major contributing factors to the severity of motor and striatal GABAergic deficits that could only be reversed by strengthening local GABA-AR function.

Rescue of deficient amygdala tonic γ-aminobutyric acidergic currents in the Fmr-/y mouse model of fragile X syndrome by a novel γ-aminobutyric acid type A receptor-positive allosteric modulator.

Alterations in the ratio of excitatory to inhibitory transmission are emerging as a common component of many nervous system disorders, including autism spectrum disorders (ASDs). Tonic γ-aminobutyric acidergic (GABAergic) transmission provided by peri- and extrasynaptic GABA type A (GABAA ) receptors powerfully controls neuronal excitability and plasticity and, therefore, provides a rational therapeutic target for normalizing hyperexcitable networks across a variety of disorders, including ASDs. Our previous studies revealed tonic GABAergic deficits in principal excitatory neurons in the basolateral amygdala (BLA) in the Fmr1(-/y) knockout (KO) mouse model fragile X syndrome. To correct amygdala deficits in tonic GABAergic neurotransmission in Fmr1(-/y) KO mice, we developed a novel positive allosteric modulator of GABAA receptors, SGE-872, based on endogenously active neurosteroids. This study shows that SGE-872 is nearly as potent and twice as efficacious for positively modulating GABAA receptors as its parent molecule, allopregnanolone. Furthermore, at submicromolar concentrations (≤1 μM), SGE-872 is selective for tonic, extrasynaptic α4β3δ-containing GABAA receptors over typical synaptic α1β2γ2 receptors. We further find that SGE-872 strikingly rescues the tonic GABAergic transmission deficit in principal excitatory neurons in the Fmr1(-/y) KO BLA, a structure heavily implicated in the neuropathology of ASDs. Therefore, the potent and selective action of SGE-872 on tonic GABAA receptors containing α4 subunits may represent a novel and highly useful therapeutic avenue for ASDs and related disorders involving hyperexcitability of neuronal networks.

Abnormal subcellular localization of GABAA receptor subunits in schizophrenia brain.

Inhibitory neurotransmission is primarily mediated by γ-aminobutyric acid (GABA) activating synaptic GABA type A receptors (GABAAR). In schizophrenia, presynaptic GABAergic signaling deficits are among the most replicated findings; however, postsynaptic GABAergic deficits are less well characterized. Our lab has previously demonstrated that although there is no difference in total protein expression of the α1–6, β1–3 or γ2 GABAAR subunits in the superior temporal gyrus (STG) in schizophrenia, the α1, β1 and β2 GABAAR subunits are abnormally N-glycosylated. N-glycosylation is a posttranslational modification that has important functional roles in protein folding, multimer assembly and forward trafficking. To investigate the impact that altered N-glycosylation has on the assembly and trafficking of GABAARs in schizophrenia, this study used western blot analysis to measure the expression of α1, α2, β1, β2 and γ2 GABAAR subunits in subcellular fractions enriched for endoplasmic reticulum (ER) and synapses (SYN) from STG of schizophrenia (N=16) and comparison (N=14) subjects and found evidence of abnormal localization of the β1 and β2 GABAAR subunits and subunit isoforms in schizophrenia. The β2 subunit is expressed as three isoforms at 52 kDa (β252 kDa), 50 kDa (β250 kDa) and 48 kDa (β248 kDa). In the ER, we found increased total β2 GABAAR subunit (β2ALL) expression driven by increased β250 kDa, a decreased ratio of β248 kDa:β2ALL and an increased ratio of β250 kDa:β248 kDa. Decreased ratios of β1:β2ALL and β1:β250 kDa in both the ER and SYN fractions and an increased ratio of β252 kDa:β248 kDa at the synapse were also identified in schizophrenia. Taken together, these findings provide evidence that alterations of N-glycosylation may contribute to GABAergic signaling deficits in schizophrenia by disrupting the assembly and trafficking of GABAARs.

Novel Findings from CNVs Implicate Inhibitory and Excitatory Signaling Complexes in Schizophrenia

SummaryWe sought to obtain novel insights into schizophrenia pathogenesis by exploiting the association between the disorder and chromosomal copy number (CNV) burden. We combined data from 5,745 cases and 10,675 controls with other published datasets containing genome-wide CNV data. In this much-enlarged sample of 11,355 cases and 16,416 controls, we show for the first time that case CNVs are enriched for genes involved in GABAergic neurotransmission. Consistent with non-genetic reports of GABAergic deficits in schizophrenia, our findings now show disrupted GABAergic signaling is of direct causal relevance, rather than a secondary effect or due to confounding. Additionally, we independently replicate and greatly extend previous findings of CNV enrichment among genes involved in glutamatergic signaling. Given the strong functional links between the major inhibitory GABAergic and excitatory glutamatergic systems, our findings converge on a broad, coherent set of pathogenic processes, providing firm foundations for studies aimed at dissecting disease mechanisms.

Hairy/Enhancer-of-Split MEGANE and Proneural MASH1 Factors Cooperate Synergistically in Midbrain GABAergic Neurogenesis.

GABAergic neurons are the primary inhibitory cell type in the mature brain and their dysfunction is associated with important neurological conditions like schizophrenia and anxiety. We aimed to discover the underlying mechanisms for dorsal/ventral midbrain GABAergic neurogenesis. Previous work by us and others has provided crucial insights into the key function of Mgn and Mash1 genes in determining GABAergic neurotransmitter fate. Induction of dorsal midbrain GABAergic neurons does not take place at any time during development in either of the single mutant mice. However, GABAergic neurons in the ventral midbrain remained unchanged. Thus, the similarities in MB-GABAergic phenotype observed in the Mgn and Mash1 single mutants suggest the existence of other factors that take over the function of MGN and MASH1 in the ventral midbrain or the existence of different molecular mechanisms. We show that this process essentially depends on heterodimers and homodimers formed by MGN and MASH1 and deciphered the in vivo relevance of the interaction by phenotypic analysis of Mgn/Mash1 double knockout and compound mice. Furthermore, the combination of gain- and loss-of-function experiments in the developing midbrain showed co-operative roles for Mgn and Mash1 genes in determining GABAergic identity. Transcription factors belonging to the Enhancer-of-split-related and proneural families have long been believed to counterpart each other’s function. This work uncovers a synergistic cooperation between these two families, and provides a novel paradigm for how these two families cooperate for the acquisition of MB-GABAergic neuronal identity. Understanding their molecular mechanisms is essential for cell therapy strategies to amend GABAergic deficits.

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.

Defects in dendrite and spine maturation and synaptogenesis associated with an anxious-depressive-like phenotype of GABAA receptor-deficient mice

Mice that were rendered heterozygous for the γ2 subunit of GABAA receptors (γ2+/− mice) have been characterized extensively as a model for major depressive disorder. The phenotype of these mice includes behavior indicative of heightened anxiety, despair, and anhedonia, as well as defects in hippocampus-dependent pattern separation, HPA axis hyperactivity and increased responsiveness to antidepressant drugs. The γ2+/− model thereby provides strong support for the GABAergic deficit hypothesis of major depressive disorder. Here we show that γ2+/− mice additionally exhibit specific defects in late stage survival of adult-born hippocampal granule cells, including reduced complexity of dendritic arbors and impaired maturation of synaptic spines. Moreover, cortical γ2+/− neurons cultured in vitro show marked deficits in GABAergic innervation selectively when grown under competitive conditions that may mimic the environment of adult-born hippocampal granule cells. Finally, brain extracts of γ2+/− mice show a numerical but insignificant trend (p = 0.06) for transiently reduced expression of brain derived neurotrophic factor (BDNF) at three weeks of age, which might contribute to the previously reported developmental origin of the behavioral phenotype of γ2+/− mice. The data indicate increasing congruence of the GABAergic, glutamatergic, stress-based and neurotrophic deficit hypotheses of major depressive disorder.This article is part of the Special Issue entitled ‘GABAergic Signaling in Health and Disease’.

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

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

α-Melanocyte stimulating hormone prevents GABAergic neuronal loss and improves cognitive function in Alzheimer's disease.

In Alzheimer's disease (AD), appropriate excitatory-inhibitory balance required for memory formation is impaired. Our objective was to elucidate deficits in the inhibitory GABAergic system in the TgCRND8 mouse model of AD to establish a link between GABAergic dysfunction and cognitive function. We sought to determine whether the neuroprotective peptide α-melanocyte stimulating hormone (α-MSH) attenuates GABAergic loss and thus improves cognition. TgCRND8 mice with established β-amyloid peptide pathology and nontransgenic littermates were treated with either α-MSH or vehicle via daily intraperitoneal injections for 28 d. TgCRND8 mice exhibited spatial memory deficits and altered anxiety that were rescued after α-MSH treatment. The expression of GABAergic marker glutamic acid decarboxylase 67 (GAD67) and the number of GABAergic GAD67+ interneurons expressing neuropeptide Y and somatostatin are reduced in the hippocampus in vehicle-treated TgCRND8 mice. In the septohippocampal pathway, GABAergic deficits are observed before cholinergic deficits, suggesting that GABAergic loss may underlie behavior deficits in vehicle-treated TgCRND8 mice. α-MSH preserves GAD67 expression and prevents loss of the somatostatin-expressing subtype of GABAergic GAD67+ inhibitory interneurons. Without decreasing β-amyloid peptide load in the brain, α-MSH improves spatial memory in TgCRND8 mice and prevents alterations in anxiety. α-MSH modulated the excitatory-inhibitory balance in the brain by restoring GABAergic inhibition and, as a result, improved cognition in TgCRND8 mice.