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

ABSTRACT: Major 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 ?2 subunit heterozygous (?2(+/-)) mice, which we previously characterized as a model animal with construct, face, and predictive validity for major depressive disorder.To 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 ?2(+/-) mice. We also analyzed the effects of an acute dose of the experimental antidepressant ketamine on all these parameters in ?2(+/-) versus wild-type mice.Modest defects in GABAergic synaptic transmission of ?2(+/-) 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 ?2(+/-) mice to wild-type levels for a prolonged period, along with antidepressant-like behavioral consequences selectively in ?2(+/-) mice. The GABAergic synapses of ?2(+/-) mice were potentiated by ketamine in parallel but only in the medial prefrontal cortex.Depressive-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.

SUBMITTER: Ren Z

PROVIDER: S-EPMC4983262 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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

Ren Zhen Z Pribiag Horia H Jefferson Sarah J SJ Shorey Matthew M Fuchs Thomas T Stellwagen David D Luscher Bernhard B

Biological psychiatry 20160213 6

<h4>Background</h4>Major 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.<h4>Methods</h4>To assess possible consequences of GABAergic defi ...[more]

PMID: 27062563

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Project description:BACKGROUND:The gamma-aminobutyric acid (GABA) Type A receptor deficits that are induced by global or forebrain-specific heterozygous inactivation of the gamma2 subunit gene in mouse embryos result in behavior indicative of trait anxiety and depressive states. By contrast, a comparable deficit that is delayed to adolescence is without these behavioral consequences. Here we characterized gamma2-deficient mice with respect to hypothalamic-pituitary-adrenal (HPA) axis abnormalities and antidepressant drug responses. METHODS:We analyzed the behavioral responses of gamma2(+/-) mice to desipramine and fluoxetine in novelty suppressed feeding, forced swim, tail suspension, and sucrose consumption tests as well as GABA(A) receptor deficit- and antidepressant drug treatment-induced alterations in serum corticosterone. RESULTS:Baseline corticosterone concentrations in adult gamma2-deficient mice were elevated independent of whether the genetic lesion was induced during embryogenesis or delayed to adolescence. However, the manifestation of anxious-depressive behavior in different gamma2-deficient mouse lines was correlated with early onset HPA axis hyperactivity during postnatal development. Chronic but not subchronic treatment of gamma2(+/-) mice with fluoxetine or desipramine normalized anxiety-like behavior in the novelty suppressed feeding test. Moreover, desipramine had antidepressant-like effects in that it normalized HPA axis function and depression-related behavior of gamma2(+/-) mice in the forced swim, tail suspension, and sucrose consumption tests. By contrast, fluoxetine was ineffective as an antidepressant and failed to normalize HPA axis function. CONCLUSIONS:Developmental deficits in GABAergic inhibition in the forebrain cause behavioral and endocrine abnormalities and selective antidepressant drug responsiveness indicative of anxious-depressive disorders such as melancholic depression, which are frequently characterized by HPA axis hyperactivity and greater efficacy of desipramine versus fluoxetine.

Project description:BACKGROUND: The selective serotonin reuptake inhibitor fluoxetine (FLX) is widely used to treat depression and anxiety disorders, but cellular mechanisms underlying the antidepressant effect of FLX remain largely unknown. The generally accepted effect of chronic FLX treatment is increased adult neurogenesis in the hippocampal dentate gyrus. It was recently demonstrated that FLX treatments can reverse the established neuronal maturation of granule cells in the hippocampal dentate gyrus and of gamma-aminobutyric acidergic (GABAergic) interneurons in the basolateral amygdala. However, it is not clear whether this dematuration effect of FLX occurs in other brain regions. Thus, in this study, we used immunohistological analysis to assess the effect of FLX treatment on GABAergic interneurons in the medial frontal cortex (mFC) and reticular thalamic nucleus (RTN). RESULTS: Immunofluorescence analysis for perineuronal nets (PNNs), which is a marker of neuronal maturation, and for parvalbumin, calretinin, and somatostatin, which are markers for specific GABAergic interneuron type, showed lower number of parvalbumin-positive (+) cells and PNN+/parvalbumin+?cells in the mFC of FLX-treated mice compared to vehicle-treated mice. However, FLX treatment had no effect on the number of cells expressing calretinin and somatostatin in the mFC. In the RTN, the number of PNN+?cells and parvalbumin+?cells was unaltered by FLX treatments. Furthermore, the number of total GABA+?cells and apoptotic cells in the mFC was similar between vehicle- and FLX-treated mice, suggesting that FLX treatment did not induce cell death in this region. Rather, our findings suggest that the decreased number of parvalbumin+?cells in the mFC was due to a decreased expression of parvalbumin proteins in the interneurons. CONCLUSIONS: This study indicates that FLX decreases the levels of parvalbumin, a mature marker of fast-spiking interneurons, and PNNs in parvalbumin+ interneurons in the mFC, suggesting that FLX treatment induces a dematuration of this type of neurons. Induction of a juvenile-like state in fast-spiking inhibitory interneurons in these regions might be involved in the therapeutic mechanism of this antidepressant drug and/or some of its adverse effects.

Dataset Information

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

Publications

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

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