Kassan Adam, Egawa Junji, Zhang Zheng, Almenar-Queralt Angels, Nguyen Quynh My, Lajevardi Yasaman, Kim Kaitlyn, Posadas Edmund, Jeste Dilip V, Roth David M, Patel Piyush M, Patel Hemal H, Head Brian P
Department of Anesthesiology, University of California San Diego, La Jolla, California.
VA San Diego Healthcare System, San Diego, California.
J Neurophysiol. 2017 Jan 1;117(1):436-444. doi: 10.1152/jn.00481.2016. Epub 2016 Nov 2.
Schizophrenia is a debilitating psychiatric disorder manifested in early adulthood. Disrupted-in-schizophrenia-1 (DISC1) is a susceptible gene for schizophrenia (Hodgkinson et al. 2004; Millar et al. 2000; St Clair et al. 1990) implicated in neuronal development, brain maturation, and neuroplasticity (Brandon and Sawa 2011; Chubb et al. 2008). Therefore, DISC1 is a promising candidate gene for schizophrenia, but the molecular mechanisms underlying its role in the pathogenesis of the disease are still poorly understood. Interestingly, caveolin-1 (Cav-1), a cholesterol binding and scaffolding protein, regulates neuronal signal transduction and promotes neuroplasticity. In this study we examined the role of Cav-1 in mediating DISC1 expression in neurons in vitro and the hippocampus in vivo. Overexpressing Cav-1 specifically in neurons using a neuron-specific synapsin promoter (SynCav1) increased expression of DISC1 and proteins involved in synaptic plasticity (PSD95, synaptobrevin, synaptophysin, neurexin, and syntaxin 1). Similarly, SynCav1-transfected differentiated human neurons derived from induced pluripotent stem cells (hiPSCs) exhibited increased expression of DISC1 and markers of synaptic plasticity. Conversely, hippocampi from Cav-1 knockout (KO) exhibited decreased expression of DISC1 and proteins involved in synaptic plasticity. Finally, SynCav1 delivery to the hippocampus of Cav-1 KO mice and Cav-1 KO neurons in culture restored expression of DISC1 and markers of synaptic plasticity. Furthermore, we found that Cav-1 coimmunoprecipitated with DISC1 in brain tissue. These findings suggest an important role by which neuron-targeted Cav-1 regulates DISC1 neurobiology with implications for synaptic plasticity. Therefore, SynCav1 might be a potential therapeutic target for restoring neuronal function in schizophrenia.
NEW & NOTEWORTHY: The present study is the first to demonstrate that caveolin-1 can regulate DISC1 expression in neuronal models. Furthermore, the findings are consistent across three separate neuronal models that include rodent neurons (in vitro and in vivo) and human differentiated neurons derived from induced pluripotent stem cells. These findings justify further investigation regarding the modulatory role by caveolin on synaptic function and as a potential therapeutic target for the treatment of schizophrenia.
精神分裂症是一种在成年早期出现的使人衰弱的精神障碍。精神分裂症相关基因1（DISC1）是精神分裂症的一个易感基因（霍奇金森等人，2004年；米勒等人，2000年；圣克莱尔等人，1990年），与神经元发育、大脑成熟和神经可塑性有关（布兰登和泽瓦，2011年；查布等人，2008年）。因此，DISC1是精神分裂症一个很有前景的候选基因，但其在疾病发病机制中作用的分子机制仍知之甚少。有趣的是，小窝蛋白-1（Cav-1）是一种胆固醇结合和支架蛋白，可调节神经元信号转导并促进神经可塑性。在本研究中，我们研究了Cav-1在体外神经元和体内海马体中介导DISC1表达的作用。使用神经元特异性突触素启动子（SynCav1）在神经元中特异性过表达Cav-1可增加DISC1以及参与突触可塑性的蛋白质（PSD95、突触小泡蛋白、突触素、神经连接蛋白和 syntaxin 1）的表达。同样，用SynCav1转染的源自诱导多能干细胞（hiPSC）的分化人类神经元表现出DISC1和突触可塑性标志物表达增加。相反，Cav-1基因敲除（KO）小鼠的海马体中DISC1以及参与突触可塑性蛋白质的表达降低。最后，将SynCav1导入Cav-1 KO小鼠的海马体和培养的Cav-1 KO神经元中可恢复DISC1和突触可塑性标志物的表达。此外，我们发现Cav-1在脑组织中与DISC1进行共免疫沉淀。这些发现表明神经元靶向的Cav-1在调节DISC1神经生物学方面具有重要作用，对突触可塑性有影响。因此，SynCav1可能是恢复精神分裂症患者神经元功能的潜在治疗靶点。
本研究首次证明小窝蛋白-1可在神经元模型中调节DISC1表达。此外，这些发现适用于三种不同的神经元模型，包括啮齿动物神经元（体外和体内）以及源自诱导多能干细胞的人类分化神经元。这些发现证明有必要进一步研究小窝蛋白对突触功能的调节作用以及作为治疗精神分裂症的潜在治疗靶点。
