Trait anxiety describes a personality trait characterized by an elevated basal level of anxiety that represents a vulnerability factor for anxiety disorders and various forms of depression. Anxiety-disorders that afflict humans include generalized anxiety disorder (GAD), panic, diverse phobias and posttraumatic stress disorder (PTSD) which, together, are among the most frequent and costly psychiatric illnesses. The longterm goal of our research is to elucidate the molecular and cellular mechanisms underlying anxiety disorders. GABA-A receptors are widely recognized to hold a gatekeeper function in the modulation of anxiety state, especially in GAD and panic disorder. Mice with a heterozygous mutation of the GABA-A receptor gamma 2 subunit gene have been established as an animal model of that anxiety that exbits behavioral and cogntive deficits reminiscent of GAD in humans. Conditional deletion of this gene in pyramidal forebrain neurons during embryogenesis but not in adolescent mice leads to excessive trait anxiety in adults. In agreement with a developmental mechanism underlying trait anxiety, gamma 2 subunit heterozygous mice exhibit reduced hippocampal neurogenesis and serotonergic transmission. Based on these observations we hypothesize (I) that trait anxiety is due to the loss of specific types of hippocampal neurons during development. We further hypothesize (II) that the GABA-A receptor deficit leads to a deficit in serotonergic transmission that contributes to the manifestation of trait anxiety. We also predict (III) that treatment of young mutant mice with antidepressant and neurogenesis-enhancing drugs prevents development of trait anxiety in adults. Finally, (IV) we hypothesize that GABA-A receptor deficits in the hippocampus and cerebral cortex act independently of deficits in the amygdala to establish an anxiety-like phenotype. Together these studies will greatly advance our undestanding of the mechanism underlying anxiety and depressive disorders.
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