INVESTIGATION OF THE BRAIN SUBSTRATES OF ANXIOUS DEPRESSION
Open Access
- Author:
- Shen, Qiuying
- Graduate Program:
- Biochemistry, Microbiology, and Molecular Biology
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- June 06, 2011
- Committee Members:
- Bernhard Luscher, Dissertation Advisor/Co-Advisor
Bernhard Luscher, Committee Chair/Co-Chair
Douglas Cavener, Committee Member
Wendy Hanna Rose, Committee Member
Debashis Ghosh, Committee Member
Jeffrey Maurice Peters, Committee Member
Robert Paulson, Committee Member - Keywords:
- HPA axis
GABA
anxious depression
critical period - Abstract:
- Major depressive disorder (MDD) exhibits extensive comorbidity with anxiety and poorly predictable responsiveness to different types of antidepressant drugs. In particular, melancholic MDD shows great reductions in GABA, aberrant function of the hypothalamic-pituitary-adrenal (HPA) axis as well as characteristics of anxious depression. Mice that are heterozygous for the γ2 subunit gene of GABAARs (γ2+/−) exhibit a modest functional deficit in GABAARs, yet they have been shown to recapitulate behavioral, pharmacological, and cognitive alterations reminiscent of anxiety disorders. In addition, this phenotype of γ2+/− mice includes increased behavioral passivity under stressful conditions, as expected of an animal model of mood disorders. Conditional knockdown of the γ2 subunit in the embryonic telencephalon was shown to result in anxious-depressive behavior similar to that of γ2+/- mice that carry the mutation in the germ line. By contrast, a comparable forebrain-specific γ2 subunit deficit that was delayed to the fourth postnatal week and limited to mature neurons was without anxiety- or depressive-like consequences. These findings are consistent with evidence that the vulnerability for anxiety and mood disorders is established early in life, and that they represent developmental disorders. In this thesis I embarked on further analyzing the brain substrate of anxious depression. In particular, I investigated putative HPA axis deficits and the behavioral and endocrine responsiveness of γ2+/− mice to treatment with serotonin (5-HT)- and norepinephrine (NE)-selective reuptake inhibitors. In addition, I investigated the critical developmental periods responsible for anxious depressive like behavior of γ2+/− mice in adulthood We found that the baseline corticosterone concentration of adult γ2-deficient mice was elevated independent of whether the genetic lesion was induced during embryogenesis or delayed to adolescence. However, the manifestation of anxious-depressive behavior in different γ2-deficient mouse lines was correlated with early onset HPA axis hyperactivity during postnatal development. Chronic but not subchronic treatment of γ2+/- mice with fluoxetine or desipramine normalized the anxiety-like phenotype in the novelty suppressed feeding test. Moreover, desipramine had antidepressant-like effects in that it normalized HPA axis function and depression-related behavior of γ2+/- 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. Collectively, these data indicate that developmental deficits in GABAergic inhibition may 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. Towards elucidating the developmental substrate of pathological anxiety and depression, we first used a chemically inducible knockout strategy to irreversibly reduce the GABAAR γ2 subunit gene dosage at different time points of postnatal brain development. Second, we used potentiation of GABAAR function with diazepam in γ2-deficient and WT mice to disturb normal activity-dependent brain development during defined temporal windows (critical developmental periods). Reducing the function of GABAARs by hemizygous inactivation of the γ2 gene at postnatal day (P)13/14 but not P27/28 was sufficient to induce anxious-depressive-like behavior in adulthood. Potentiation of GABAARs by treatment of wild-type mice with diazepam from P10-21 and P29-35 had selective anxiogenic- and depressant-like effects, respectively on behavior in adulthood. In addition, diazepam treatment from P10-21 had antidepressant-like effects on behavior in adulthood independent of genotype. Collectively, the data indicate that anxiety- and depression-related behavioral traits of γ2+/- mice are independently controlled by distinct postnatal critical periods that are sensitive to both genetic impairment and pharmacological potentiation of GABAergic transmission via γ2 subunit-containing GABAARs.