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

机译：与表明性格焦虑和抑郁状态的行为有关的成年海马神经发生的GABA能控制

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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.
机译：早年的压力经历是焦虑和抑郁症的已知危险因素，在成年后会抑制海马神经发生和GABA（A）受体的表达。相反，GABA能神经传递的缺陷和神经发生的减少与病理性焦虑和多种情绪障碍的病因有关。 GABA（A）受体的gamma2亚基杂合的小鼠主要在突触后GABA（A）受体中表现出适度的功能缺陷，这与表明性状焦虑加剧的行为，认知和药理学表型有关。在这里，我们使用了特定于细胞类型且由发育控制的gamma2亚基基因失活来进一步分析该表型的机制和大脑底物。在胚胎和成年前脑的未成熟神经元中选择性诱导的γ2亚基的杂合缺失导致成年海马神经发生减少，并伴有对自然厌恶情况的行为抑制作用增强，包括已知对抗抑郁药物治疗敏感的应激情况。成人海马神经发生减少与正常细胞增殖有关，表明有丝分裂后未成熟神经元对含gamma2亚基的GABA（A）受体的适度功能缺陷的选择性脆弱性。相反，在青春期成熟神经元中选择性诱导的可比较的前脑特异性GABA（A）受体缺乏神经原性和行为后果。这些结果表明，在发育中和成年大脑的未成熟神经元中适度降低的GABA（A）受体功能可以作为成年人神经发生缺陷和表现出焦虑和抑郁样情绪状态的行为的常见分子底物。

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