Abstract
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.
Highlights
Extensive comorbidity among major depressive disorder (MDD) and anxiety disorders suggests related disease etiologies [1,2]
We have presented the combined results of two independent studies assessing postnatal developmental periods during which perturbations of GABAergic transmission via c2-containing GABAA receptors (GABAARs) affect anxiety- and emotion-related behavior in adulthood
Irreversible TAM-induced knockdown of the GABAAR c2 subunit gene dosage identified a postnatal two-week period during which induction of a permanent GABAergic deficit led to increased anxiety- and depression-related behavioral measures in adulthood
Summary
Extensive comorbidity among major depressive disorder (MDD) and anxiety disorders suggests related disease etiologies [1,2]. Reduced brain concentrations of the inhibitory neurotransmitter c-aminobutyric acid (GABA) and altered function or reduced expression of its principal receptors (GABAARs) are increasingly implicated in both types of disorders [3]. GABAARs serve as the principal receptors mediating neural inhibition in the brain. They are heteropentameric chloride channels composed of a1-6, b1-3, c1-3, d, e, p, h, and r1-3 subunits [4]. Mice that are heterozygous for the c2 subunit gene (gabrg, c2+/2) exhibit anxious-depression-related behavior, including cognitive, cellular, neuroendocrine and pharmacological alterations expected of a mouse model of melancholic major depression [7,8,9].
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