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The Journal of Neuroscience, April 4, 2007, 27(14):3845-3854; doi:10.1523/JNEUROSCI.3609-06.2007

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Behavioral/Systems/Cognitive
GABAergic Control of Adult Hippocampal Neurogenesis in Relation to Behavior Indicative of Trait Anxiety and Depression States

John C. Earnheart,¹ Claude Schweizer,¹ Florence Crestani,³ Takuji Iwasato,⁴ Shigeyoshi Itohara,⁴ Hanns Mohler,³ and Bernhard Lüscher^1,2

¹Departments of Biology and Biochemistry and Molecular Biology and Penn State Neuroscience Institute, Penn State University, University Park, Pennsylvania 16802, ²Department of Psychiatry, Penn State College of Medicine, Hershey, Pennsylvania 17033, ³Institute of Pharmacology and Toxicology, University of Zurich and Swiss Federal Institute of Technology Zurich, 8092 Zurich, Switzerland, ⁴Laboratory for Behavioral Genetics, RIKEN Brain Science Institute, Wako-shi, Saitama, 351-0198, Japan

Correspondence should be addressed to Dr. Bernhard Luscher, Departments of Biology, Biochemistry and Molecular Biology, and Psychiatry, 301 Life Sciences Building, Penn State University, University Park, PA 16802. Email: bxl25{at}psu.edu

Stressful experiences in early life are known risk factors for anxiety and depressive illnesses, and they inhibit hippocampal neurogenesis and the expression of GABA_A 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 2 subunit of GABA_A receptors exhibit a modest functional deficit in mainly postsynaptic GABA_A 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 2 subunit gene to further analyze the mechanism and brain substrate underlying this phenotype. Heterozygous deletion of the 2 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 2 subunit-containing GABA_A receptors. In contrast, a comparable forebrain-specific GABA_A 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.

Key words: anxiety disorder; mood; conditional knock-out mice; brain development; mouse behavior; hippocampal neurogenesis; inhibitory synaptogenesis; Cre-loxP; depression; stress

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Received Aug. 19, 2006; revised Feb. 18, 2007; accepted Feb. 24, 2007.

Correspondence should be addressed to Dr. Bernhard Luscher, Departments of Biology, Biochemistry and Molecular Biology, and Psychiatry, 301 Life Sciences Building, Penn State University, University Park, PA 16802. Email: bxl25{at}psu.edu

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