GABAergic control of adult hippocampal neurogenesis in relation to behavior indicative of trait anxiety and depression states

John C. Earnheart, Claude Schweizer, Florence Crestani, Takuji Iwasato, Shigeyoshi Itohara, Hanns Mohler, Bernhard Luscher

Research output: Contribution to journalArticlepeer-review

156 Scopus citations

Abstract

Stressful experiences in early life are known risk factors for anxiety and depressive illnesses, and they inhibit hippocampal neurogenesis and the expression of GABAA receptors in adulthood. Conversely, deficits in GABAergic neurotransmission and reduced neurogenesis are implicated in the etiology of pathological anxiety and diverse mood disorders. Mice that are heterozygous for the γ2 subunit of GABAA receptors exhibit a modest functional deficit in mainly postsynaptic GABAA receptors that is associated with a behavioral, cognitive, and pharmacological phenotype indicative of heightened trait anxiety. Here we used cell type-specific and developmentally controlled inactivation of the γ2 subunit gene to further analyze the mechanism and brain substrate underlying this phenotype. Heterozygous deletion of the γ2 subunit induced selectively in immature neurons of the embryonic and adult forebrain resulted in reduced adult hippocampal neurogenesis associated with heightened behavioral inhibition to naturally aversive situations, including stressful situations known to be sensitive to antidepressant drug treatment. Reduced adult hippocampal neurogenesis was associated with normal cell proliferation, indicating a selective vulnerability of postmitotic immature neurons to modest functional deficits in γ2 subunit-containing GABAA receptors. In contrast, a comparable forebrain-specific GABAA receptor deficit induced selectively in mature neurons during adolescence lacked neurogenic and behavioral consequences. These results suggest that modestly reduced GABA A receptor function in immature neurons of the developing and adult brain can serve as a common molecular substrate for deficits in adult neurogenesis and behavior indicative of anxious and depressive-like mood states.

Original languageEnglish (US)
Pages (from-to)3845-3854
Number of pages10
JournalJournal of Neuroscience
Volume27
Issue number14
DOIs
StatePublished - Apr 4 2007

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

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