Defects in dendrite and spine maturation and synaptogenesis associated with an anxious-depressive-like phenotype of GABA(A) receptor-deficient mice

Mice that were rendered heterozygous for the gamma 2 subunit of GABAA receptors (gamma 2(+)/(-) mice) have been characterized extensively as a model for major depressive disorder. The phenotype of these mice includes behavior indicative of heightened anxiety, despair, and anhedonia, as well as defects in hippocampus-dependent pattern separation, HPA axis hyperactivity and increased responsiveness to antidepressant drugs. The gamma 2(+)/-model thereby provides strong support for the GABAergic deficit hypothesis of major depressive disorder. Here we show that gamma 2(+)/(-) mice additionally exhibit specific defects in late stage survival of adult-born hippocampal granule cells, including reduced complexity of dendritic arbors and impaired maturation of synaptic spines. Moreover, cortical gamma 2(+)/(-) neurons cultured in vitro show marked deficits in GABAergic innervation selectively when grown under competitive conditions that may mimic the environment of adult-born hippocampal granule cells. Finally, brain extracts of gamma 2(+)/(-) mice show a numerical but insignificant trend (p = 0.06) for transiently reduced expression of brain derived neurotrophic factor (BDNF) at three weeks of age, which might contribute to the previously reported developmental origin of the behavioral phenotype of gamma 2(+)/(-) mice. The data indicate increasing congruence of the GABAergic, glutamatergic, stress-based and neurotrophic deficit hypotheses of major depressive disorder.(C) 2014 Elsevier Ltd. All rights reserved.