Hippocampal α5 subunit-containing GABAA receptors modulate the expression of prepulse inhibition
Hippocampal α5 subunit-containing GABAA receptors modulate the expression of prepulse inhibition
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DOI：
10.1038/sj.mp.4001554
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发表时间：
2005-02-01
影响因子：
11
通讯作者：
Yee, BK
中科院分区：
文献类型：
--
作者：
Hauser, J;Rudolph, U;Yee, BK
前脉冲抑制（PPI）是指低强度前脉冲刺激减弱对后续惊吓脉冲刺激的反射反应的现象。海马体以及其他结构被认为在 PPI 表达的调节中发挥着重要作用。在α5(H105R)突变小鼠中，海马中含有α5亚基的GABA(A)受体的表达降低。在此，我们报告 α5(H105R) 突变小鼠的 PPI 减弱，自发运动活性增加。这些影响在两性中都很明显。因此，含有 α5 亚基的 GABA(A) 受体位于突触外，被认为介导强直抑制，是 PPI 表达和运动探索的重要调节因子。对精神分裂症患者大脑的尸检分析一致揭示了海马体发育起源的结构异常。鉴于已知精神分裂症患者表现出 PPI 缺陷，此类异常可能包括 α5 GABA(A) 受体功能或分布的紊乱。我们的数据进一步强调，需要考虑使用α5选择性反向激动剂治疗海马相关的记忆功能障碍，以防止此类化合物可能与感觉运动门控缺陷产生不利相关。
Prepulse inhibition (PPI) refers to the phenomenon in which a low-intensity prepulse stimulus attenuates the reflexive response to a succeeding startle-eliciting pulse stimulus. The hippocampus, among other structures, is believed to play an important role in the modulation of PPI expression. In alpha5(H105R) mutant mice, the expression of the alpha5 subunit-containing GABA(A) receptors in the hippocampus is reduced. Here, we report that PPI was attenuated, and spontaneous locomotor activity was increased in alpha5( H105R) mutant mice. These effects were apparent in both genders. Thus, alpha5 subunit-containing GABA(A) receptors, which are located extrasynaptically and are thought to mediate tonic inhibition, are important regulators of the expression of PPI and locomotor exploration. Post-mortem analyses of schizophrenia brains have consistently revealed structural abnormalities of a developmental origin in the hippocampus. There may be a possibility that such abnormalities include disturbance of alpha5 GABA(A) receptor function or distribution, given that schizophrenia patients are known to exhibit a PPI deficit. Our data further highlight that the potential use of alpha5-selective inverse agonists to treat hippocampal-related mnemonic dysfunction needs to be considered against the possibility that such compounds may be adversely associated with deficient sensorimotor gating.