An investigation of the molecular and cellular substrates of anxiety and depression-like disorders

In humans, heightened trait anxiety is a vulnerability factor for diverse psychiatric disorders, especially generalized anxiety disorder (GAD) and major depression. Besides multiple genetic factors, environmental factors such as early life stress are believed to increase vulnerability for anxiety and mood disorders. Early life stress has been shown to modulate the stress response in adulthood through changes in gene expression and changes in neurotransmitter systems. Stress, including especially early life stress, is also a potent inhibitor of adult hippocampal neurogenesis, a mechanism that has been implicated in the etiology of depression. Conversely, deficits in neurotransmission, including neurotransmission by gamma-aminobutyric acid (GABA), in the cortex and hippocampus are implicated in the etiology of anxiety and depressive disorders. GABA type A (GABAA) receptors are key control elements of anxiety states based on the anxiolytic properties of benzodiazepines (BZs), which act as allosteric GABAA receptor agonists.; Heterozygous deletion of the gamma2 subunit of GABAA receptors results in modest but significant deficits in BZ binding sites as well as altered channel conductance, deficits in trafficking and clustering of GABA A receptors at postsynaptic sites. However, there is no change in the number of GABA binding sites indicating that the number of GABAA receptors was unaltered in these mice. This subtle deficit in GABAA receptors is associated with behavioral, pharmacological and cognitive alterations indicative of elevated trait anxiety. The gamma2+/- mice exhibit neophobia and marked behavioral avoidance to natural or learned stressors. This phenotype is reversed to wildtype (wt) levels following BZ treatment reflecting sensitivity of pathologically anxious patients to anxiolytics. Altered behavior of gamma2+/- mice is associated with cognitive deficits including enhanced 1-s trace conditioning and impaired ambiguous cue conditioning but unimpaired spatial memory.; In the present thesis, cell-type-specific and developmentally controlled inactivation of the gamma2 subunit gene was used to further analyze the mechanism underlying anxiety-like behavior of gamma2+/- mice. Recombination of a 'floxed' gamma2 subunit (fgamma2) allele in either of two different Cre-expressing mouse lines results in a reduction of GABAA receptors specifically in glutamatergic neurons of the forebrain. In adulthood, Emx1Cre x fgamma2/+ and CaMKIICre2834 x fgamma2/+ mice exhibited comparable deficits in BZ binding in the forebrain. Specifically, both mouse lines showed substantial reductions in BZ binding in the forebrain, including the cortex, CA1 region of the hippocampus and striatum, with less severe deficits in the amygdala and the dentate gyrus. However, in Emx1Cre mice Cre-mediated recombination occurs in immature glutamatergic neurons of the embryonic and adult forebrain while in CaMKIICre2834 mice recombination is developmentally delayed to mature neurons of the adult brain.; The GABAA receptor deficits in immature glutamatergic neurons of the embryonic forebrain resulted in heightened anxiety-like behavior similar of that seen previously in gamma2+/- mice. This included increased risk assessment behavior and neophobia in paradigms without an implicit threat and increased avoidance to naturally aversive stimuli. In addition, Emx1Cre x fgamma2/+ mice and gamma2+/- mice showed increased behavioral inhibition in paradigms with predictive validity for antidepressant drug effects in humans. By contrast, the developmentally delayed GABA A receptor deficit of CaMKIICre x fgamma2/+ mice was without behavioral effect. Thus, the first three weeks of life represent a GABAA receptor dependent critical period in the establishment of normal emotionality of mice.; In addition to behavioral deficits, gamma2 subunit inactivation in immature forebrain glutamatergic neurons was associated with significant deficits in adult hippocampal neurogenesis. Dec...