GABAergic control of adult hippocampal neurogenesis in relation to behavior indicative of trait anxiety and depression states.
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 gamma2 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 gamma2 subunit gene to further analyze the mechanism and brain substrate underlying this phenotype. Heterozygous deletion of the gamma2 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 gamma2 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.
Earnheart
John C
JC
Department of Biology and Penn State Neuroscience Institute, Penn State University, University Park, Pennsylvania 16802, USA.
Schweizer
Claude
C
Crestani
Florence
F
Iwasato
Takuji
T
Itohara
Shigeyoshi
S
Mohler
Hanns
H
Lüscher
Bernhard
B
D000818:Animals; D001007:Anxiety / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D002454:Cell Differentiation / Q000502:physiology; D003866:Depressive Disorder / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D011963:Receptors, GABA-A / Q000378:metabolism*
D011963:Receptors, GABA-A