Erbb4 Deletion from Medium Spiny Neurons of the Nucleus Accumbens Core Induces Schizophrenia-Like Behaviors via Elevated GABAA Receptor α1 Subunit Expression
Erbb4 Deletion from Medium Spiny Neurons of the Nucleus Accumbens Core Induces Schizophrenia-Like Behaviors via Elevated GABAA Receptor α1 Subunit Expression
复制标题
伏核核心中型多棘神经元的 Erbb4 删除通过升高的 GABAA 受体 α1 亚基表达诱导精神分裂症样行为。
DOI：
10.1523/jneurosci.3948-16.2017
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发表时间：
2017-08-02
影响因子：
5.3
通讯作者：
Li, Xiao-Ming
中科院分区：
文献类型：
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作者：
Geng, Hong-Yan;Zhang, Jing;Li, Xiao-Ming
中型多棘神经元 (MSN) 是纹状体中主要的 GABA 能投射神经元，与精神分裂症等许多神经精神疾病有关，但其潜在机制仍不清楚。我们发现，伏隔核（NAc）核心（而非背内侧纹状体）的MSN中Erbb4（一种精神分裂症风险基因）的缺陷，会显着诱发雄性小鼠的精神分裂症样行为，例如多动、异常埋弹珠行为、社交新奇识别受损和感觉运动门控功能受损。通过免疫组织化学、蛋白质印迹、RNA干扰、电生理学和行为测试研究，我们发现这些现象是由GABAA受体α1亚基（GABAARα1）表达增加介导的，从而增强了MSN上的抑制性突触传递。这些结果表明，NAc 核心 MSN 中的 Erbb4 可能通过调节 GABA 能传递而促进精神分裂症的发病机制，并因此提出了 GABAAR α 1 作为精神分裂症新治疗靶点的可能性。
Medium spiny neurons (MSNs), the major GABAergic projection neurons in the striatum, are implicated in many neuropsychiatric diseases such as schizophrenia, but the underlying mechanisms remain unclear. Wefound that a deficiency in Erbb4, a schizophrenia risk gene, in MSNs of the nucleus accumbens (NAc) core, but not the dorsomedial striatum, markedly induced schizophrenia-like behaviors such as hyperactivity, abnormal marble-burying behavior, damaged social novelty recognition, and impaired sensorimotor gating function in male mice. Using immunohistochemistry, Western blot, RNA interference, electrophysiology, and behavior test studies, we found that these phenomena were mediated by increased GABAA receptor alpha 1 subunit(GABAAR alpha 1) expression, which enhanced inhibitory synaptic transmission on MSNs. These results suggest that Erbb4 in MSNs of the NAc core may contribute to the pathogenesis of schizophrenia by regulating GABAergic transmission and raise the possibility that GABAAR alpha 1 may therefore serve as a new therapeutic target for schizophrenia.