GABAergic control of adult hippocampal neurogenesis in relation to behavior indicative of trait anxiety and depression states
GABAergic control of adult hippocampal neurogenesis in relation to behavior indicative of trait anxiety and depression states
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DOI：
10.1523/jneurosci.3609-06.2007
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发表时间：
2007-04-04
影响因子：
5.3
通讯作者：
Luscher, Bernhard
中科院分区：
文献类型：
--
作者：
Earnheart, John C.;Schweizer, Claude;Luscher, Bernhard
早期生活中的压力经历是已知的焦虑和抑郁疾病的危险因素，它们抑制海马神经发生和成年期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各种情绪障碍的病因有关。GABA(A)受体γ(2)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，这与行为、认知和药理学表型相关，表明性状焦虑升高。在这里，我们使用细胞类型特异性和发育控制的伽马2亚基基因失活来进一步分析这种表型的机制和脑底物。在胚胎和成人前脑的未成熟神经元中选择性诱导γ - 2亚基的杂合缺失导致成人海马神经发生减少，这与对自然厌恶情况的行为抑制增强有关，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有γ - 2亚基的GABA(a)受体的适度功能缺陷具有选择性易感性。相比之下，青春期成熟神经元选择性诱导的类似的前脑特异性GABA(a)受体缺陷缺乏神经源性和行为后果。这些结果表明，在发育和成人大脑的未成熟神经元中，适度减少的GABA(A)受体功能可能是成人神经发生和行为缺陷的共同分子底物，表明焦虑和抑郁样情绪状态。
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 gamma(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 gamma 2 subunit gene to further analyze the mechanism and brain substrate underlying this phenotype. Heterozygous deletion of the gamma 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 situationsknownto 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 gamma 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.