Expression of GABAA α2-, β1- and ɛ-receptors are altered significantly in the lateral cerebellum of subjects with schizophrenia, major depression and bipolar disorder

Fatemi, S. Hossein; Folsom, Timothy D.; Rooney, Robert J.; Thuras, Paul

doi:10.1038/tp.2013.64

Cited by 106 publications

(100 citation statements)

References 103 publications

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“…We found that Gabarapl1 expression was increased by chronic stress in the PFC and NAc, consistent with results in human MDD in which expression is increased in Brodmann area 9 (BA9), BA10, BA20, and BA46 [84, 85]. Consistent with what we observed for the effects of stress on Gabra2 expression in the PFC and NAc, subjects with MDD have increased Gabra2 expression in the cerebellum [86]. While single-nucleotide polymorphisms (SNPs) in the Gabbr2 gene are associated with MDD, human postmortem studies have not found altered expression of this gene in the brain (e.g., [85, 87]).…”

Section: Discussionsupporting

confidence: 88%

Sex-Specific Effects of Stress on Mood-Related Gene Expression

et al. 2019

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Women are twice as likely as men to be diagnosed with major depressive disorder (MDD). Recent studies report distinct molecular changes in depressed men and women across mesocorticolimbic brain regions. However, it is unclear which sex-related factors drive distinct MDD-associated pathology. The goal of this study was to use mouse experimental systems to investigate sex-specific mechanisms underlying the distinct molecular profiles of MDD in men and women. We used unpredictable chronic mild stress to induce an elevated anxiety-/depressive-like state and “four core genotypes” (FCG) mice to probe for sex-specific mechanisms. As predicted, based on previous implications in mood, stress impacted the expression of several dopamine-, GABA-, and glutamate-related genes. Some of these effects, specifically in the prefrontal cortex, were genetic sex-specific, with effects in XX mice but not in XY mice. Stress also impacted gene expression differently across the mesocorticolimbic circuit, with increased expression of mood-related genes in the prefrontal cortex and nucleus accumbens, but decreased expression in basolateral amygdala. Our results suggest that females are sensitive to the effects of chronic stress, partly due to their genetic sex, independent of gonadal hormones. Furthermore, these results point to the prefrontal cortex as the node in the mesocorticolimbic circuitry with the strongest female-specific effects.

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Section: Discussionsupporting

confidence: 88%

Sex-Specific Effects of Stress on Mood-Related Gene Expression

et al. 2019

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“…GABA A receptors are widely distributed in the brain and are the primary channels through which GABA inhibits the excitability of neurons in the central nervous system (24,25). Abnormalities in GABA function have been postulated for many years in bipolar disorder and are supported by the observation of decreased CSF GABA in bipolar patients (26), as well as alterations in GABA subunit ratios in the postmortem brain (27). Positive allosteric modulators of GABA A receptors (benzodiazepines) are used adjunctively in the treatment of mania, a key aspect of BD.…”

Section: Discussionmentioning

confidence: 99%

Rare variants in neuronal excitability genes influence risk for bipolar disorder

Ament

Szelinger

Glusman

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

166

135

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We sequenced the genomes of 200 individuals from 41 families multiply affected with bipolar disorder (BD) to identify contributions of rare variants to genetic risk. We initially focused on 3,087 candidate genes with known synaptic functions or prior evidence from genomewide association studies. BD pedigrees had an increased burden of rare variants in genes encoding neuronal ion channels, including subunits of GABA A receptors and voltage-gated calcium channels. Four uncommon coding and regulatory variants also showed significant association, including a missense variant in GABRA6. Targeted sequencing of 26 of these candidate genes in an additional 3,014 cases and 1,717 controls confirmed rare variant associations in ANK3, CACNA1B, CACNA1C, CACNA1D, CACNG2, CAMK2A, and NGF. Variants in promoters and 5′ and 3′ UTRs contributed more strongly than coding variants to risk for BD, both in pedigrees and in the case-control cohort. The genes and pathways identified in this study regulate diverse aspects of neuronal excitability. We conclude that rare variants in neuronal excitability genes contribute to risk for BD. by episodes of mania and depression (1). Episodes of mania are marked by elevated or alternatively irritable mood, grandiosity, racing thoughts, rapid speech, diminished need for sleep, and risk-taking behavior. Depression includes sadness, low energy and motivation, decreased ability to experience pleasure, insomnia, and appetite changes. Psychosis with hallucinations and delusions can occur in either state. BD affects 1-2% of the US population, and if untreated, up to 15% of patients die from suicide. Twin and family studies suggest that heritable causes explain 60-80% of lifetime risk for BD (2), with an approximate eightfold relative risk in the siblings of BD probands (3). Several common genetic markers have shown significant and replicable associations in genome-wide association studies (GWASs), including a region near a voltage-gated calcium channel, CACNA1C, and another near a synaptic scaffolding gene, ANK3 (4). Additive effects of common loci detectable on commercially available genomic arrays may be used to predict about 25% of the risk for BD (5), but typically the function and exact location of the causative variants linked to these loci is unknown.Rare variants may explain additional risk for BD. It is possible that one or a few rare variants of large effect dramatically increase disease risk, resulting in an inheritance model resembling monogenic inheritance in a given family. However, four exomesequencing and whole-genome sequencing (WGS) studies of BD pedigrees have detected few, if any, plausible variants of large effect (6-9). An alternative oligogenic model posits that different combinations of several uncommon or rare variants of moderate effect cluster in affected individuals and collectively cause disease.To test the hypothesis that rare variants contribute to risk for BD, we sequenced the genomes of 200 individuals from 41 multiply affected BD pedigrees of European ancestry. We seque...

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“…GABA A receptor subunit gene polymorphisms are differentially associated with risk for other mental disorders such as alcohol dependence (69), MDD, bipolar disorder and schizophrenia (70). In animal models, mice genetically designed to lack the δ subunit do not exhibit ALLO's paradoxical effects at the GABA A receptor during puberty as do wild-type mice (62).…”

Section: Introductionmentioning

confidence: 99%

Ovarian Hormone Fluctuation, Neurosteroids, and HPA Axis Dysregulation in Perimenopausal Depression: A Novel Heuristic Model

Gordon¹,

Girdler²,

Meltzer‐Brody³

et al. 2015

AJP

221

148

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Objective In this conceptual review, we propose a novel mechanistic candidate in the etiology of depression with onset in the menopause transition (a.k.a. perimenopausal depression) involving alterations in stress-responsive pathways, induced by ovarian hormone fluctuation. Methods The relevant literature in perimenopausal depression was reviewed, including its prevalence, predictors, and treatment with estrogen therapy. Subsequently, the growing evidence from animal models and clinical research in other reproductive mood disorders was synthesized to describe a heuristic model of perimenopausal depression development. Results The rate of major depressive disorder and of clinically meaningful elevations in depressive symptoms increases two- to threefold during the menopause transition. While the mechanisms by which ovarian hormone fluctuation might impact mood are poorly understood, growing evidence from basic and clinical research suggests that fluctuations in ovarian hormones and their derived neurosteroids result in altered GABAergic regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Our heuristic model suggests that for some women, failure of the GABAA receptor to regulate overall GABAergic tone in the face of shifting levels of these neurosteroids may induce HPA axis dysfunction, thereby increasing sensitivity to stress, and generating a period of greater vulnerability to depression. Conclusions The proposed model provides a basis for understanding the mechanisms by which the changing hormonal environment of the menopause transition may interact with the psychosocial environment of mid-life to contribute to perimenopausal depression risk. Future research investigating this model may inform the development of novel pharmacological treatments for perimenopausal depression and related disorders such as postpartum depression and premenstrual dysphoric disorder.

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Expression of GABAA α2-, β1- and ɛ-receptors are altered significantly in the lateral cerebellum of subjects with schizophrenia, major depression and bipolar disorder

Cited by 106 publications

References 103 publications

Sex-Specific Effects of Stress on Mood-Related Gene Expression

Sex-Specific Effects of Stress on Mood-Related Gene Expression

Rare variants in neuronal excitability genes influence risk for bipolar disorder

Ovarian Hormone Fluctuation, Neurosteroids, and HPA Axis Dysregulation in Perimenopausal Depression: A Novel Heuristic Model

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