Schizophrenia risk gene CAV1 is both pro-psychotic and required for atypical antipsychotic drug actions in vivo.
Schizophrenia risk gene CAV1 is both pro-psychotic and required for atypical antipsychotic drug actions in vivo.
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DOI：
10.1038/tp.2011.35
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发表时间：
2011-08-16
影响因子：
6.8
通讯作者：
Roth BL
中科院分区：
文献类型：
--
作者：
Allen JA;Yadav PN;Setola V;Farrell M;Roth BL
Caveolin-1（Cav-1）是一种重要的支架蛋白，通过将信号分子分配到膜微区来调节受体信号级联。CAV 1基因的破坏最近被确定为与精神分裂症相关的罕见结构变异。虽然Cav-1基因敲除（KO）小鼠没有表现出基线行为中断，Cav-1基因敲除小鼠，类似于精神分裂症患者，表现出对拟精神病N-甲基-天冬氨酸受体拮抗剂苯环己哌啶（PCP）的敏感性增加。因此，PCP破坏前脉冲抑制（PPI）和PCP诱导的小鼠自发活动都增强了基因缺失的Cav-1。有趣的是，Cav-1的基因缺失使得非典型抗精神病药物氯氮平和奥氮平以及5-HT 2A选择性拮抗剂M100907在使PCP诱导的PPI破坏正常化方面无效。我们还发现，Cav-1基因缺失减弱5-HT 2A诱导的c-Fos和c-Fos-1在小鼠额叶皮层的表达，也减少5-HT 2A介导的Ca 2+动员在原代皮层神经元培养。5-HT 2A激动剂（2，5-二甲氧基-4-碘苯丙胺）的行为效应（包括头部抽搐反应和PPI的破坏）也通过Cav-1的遗传缺失而减弱，这表明Cav-1对于5-HT 2A受体的反向激动剂（即，非典型抗精神病药物）和激动剂作用都是必需的。这项研究表明，破坏CAV 1基因-一种罕见的结构变异与精神分裂症-不仅是亲精神病，但也削弱了非典型抗精神病药物的作用。
Caveolin-1 (Cav-1) is a scaffolding protein important for regulating receptor signaling cascades by partitioning signaling molecules into membrane microdomains. Disruption of the CAV1 gene has recently been identified as a rare structural variant associated with schizophrenia. Although Cav-1 knockout (KO) mice displayed no baseline behavioral disruptions, Cav-1 KO mice, similar to schizophrenic individuals, exhibited increased sensitivity to the psychotomimetic N-methyl--aspartate receptor antagonist phencyclidine (PCP). Thus, PCP disruption of prepulse inhibition (PPI) and PCP-induced mouse locomotor activity were both enhanced by genetic deletion of Cav-1. Interestingly, genetic deletion of Cav-1 rendered the atypical antipsychotics clozapine and olanzapine and the 5-HT2A-selective antagonist M100907 ineffective at normalizing PCP-induced disruption of PPI. We also discovered that genetic deletion of Cav-1 attenuated 5-HT2A-induced c-Fos and egr-1 expression in mouse frontal cortex and also reduced 5-HT2A-mediated Ca2+ mobilization in primary cortical neuronal cultures. The behavioral effects of the 5-HT2A agonist (2,5-dimethoxy-4-iodoamphetamine) including head twitch responses and disruption of PPI were also attenuated by genetic deletion of Cav-1, indicating that Cav-1 is required for both inverse agonist (that is, atypical antipsychotic drug) and agonist actions at 5-HT2A receptors. This study demonstrates that disruption of the CAV1 gene—a rare structural variant associated with schizophrenia—is not only pro-psychotic but also attenuates atypical antipsychotic drug actions.
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DOI：
10.1196/annals.1300.008
发表时间：
2003-01-01
期刊：
GLUTAMATE AND DISORDERS OF COGNITION AND MOTIVATION
影响因子：
--
作者：
Farber, NB
通讯作者：
Farber, NB
影响因子：
25
作者：
Mukai, Jun;Dhilla, Alefiya;Drew, Liam J.;Stark, Kimberly L.;Cao, Luxiang;MacDermott, Amy B.;Karayiorgou, Maria;Gogos, Joseph A.
通讯作者：
Gogos, Joseph A.
影响因子：
9.9
作者：
Fernandez, Esperanza;Collins, Mark O.;Uren, Rachel T.;Kopanitsa, Maksym V.;Komiyama, Noboru H.;Croning, Mike D. R.;Zografos, Lysimachos;Armstrong, J. Douglas;Choudhary, Jyoti S.;Grant, Seth G. N.
通讯作者：
Grant, Seth G. N.
影响因子：
7.6
作者：
LAHTI, AC;KOFFEL, B;TAMMINGA, CA
通讯作者：
TAMMINGA, CA
影响因子：
5.3
作者：
Boulware, Marissa I.;Kordasiewicz, Holly;Mermelstein, Paul G.
通讯作者：
Mermelstein, Paul G.