Disrupted-in-Schizophrenia 1 (DISC1) regulates spines of the glutamate synapse via Rac1.
Disrupted-in-Schizophrenia 1 (DISC1) regulates spines of the glutamate synapse via Rac1.
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DOI：
10.1038/nn.2487
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发表时间：
2010-03
影响因子：
25
通讯作者：
Sawa, Akira
中科院分区：
文献类型：
--
作者：
Hayashi-Takagi, Akiko;Takaki, Manabu;Graziane, Nick;Seshadri, Saurav;Murdoch, Hannah;Dunlop, Allan J.;Makino, Yuichi;Seshadri, Anupamaa J.;Ishizuka, Koko;Srivastava, Deepak P.;Xie, Zhong;Baraban, Jay M.;Houslay, Miles D.;Tomoda, Toshifumi;Brandon, Nicholas J.;Kamiya, Atsushi;Yan, Zhen;Penzes, Peter;Sawa, Akira
突触棘是一种动态结构，调节神经元的反应性和可塑性。在这里，我们描述了精神分裂症的危险因素，精神分裂症中的中断1(DISC1)，在维持脊柱形态和功能方面的作用。我们发现DISC1锚定Kalirin-7(Kal-7)，从而调节Kal-7对rac1的访问，从而控制在大脑皮层培养和活体大脑中对NMDA受体激活做出反应的rac1激活的持续时间和强度。这就解释了为什么rac1及其激活剂(Kal-7)作为脊柱增大的关键介质，以及rac1的结构性激活减小脊柱大小。这一新的机制可能是精神分裂症患者经常报告的谷氨酸能神经传递障碍的基础，该障碍可导致树突棘的改变，从而导致脑功能的重大病理变化。此外，“信号体”的概念涉及疾病相关因素，如DISC1和谷氨酸，这很可能有助于精神分裂症的多因素和多基因特征。
Synaptic spines are dynamic structures that regulate neuronal responsiveness and plasticity. Here we describe a role for the schizophrenia risk factor, Disrupted-in-Schizophrenia 1 (DISC1), in the maintenance of spine morphology and function. We show that DISC1 anchors Kalirin-7 (Kal-7) thereby regulating access of Kal-7 to Rac1 and so controlling the duration and intensity of Rac1 activation in response to NMDA receptor activation in cortical culture as well as in vivo brain. This offers explanation for why Rac1 and its activator (Kal-7) serve as key mediators of spine enlargement and that constitutive Rac1 activation decreases spine size. This novel mechanism likely underlies disturbances in glutamatergic neurotransmission frequently reported in schizophrenia that can lead to alteration of dendritic spines with consequential major pathological changes in brain function. Furthermore, the concept of a “signalosome” involving disease-associated factors, such as DISC1 and glutamate, may well contribute to the multifactorial and polygenetic characteristics of schizophrenia.
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影响因子：
4.1
作者：
Bolger, Graeme B.;Baillie, George S.;Houslay, Miles D.
通讯作者：
Houslay, Miles D.
影响因子：
16.2
作者：
Holtmaat, AJGD;Trachtenberg, JT;Svoboda, K
通讯作者：
Svoboda, K
影响因子：
11
作者：
Camargo, L. M.;Collura, V.;Brandon, N. J.
通讯作者：
Brandon, N. J.
DOI：
10.1073/pnas.0511189103
发表时间：
2006-03-07
影响因子：
11.1
作者：
Koike, H;Arguello, PA;Gogos, JA
通讯作者：
Gogos, JA
影响因子：
2.5
作者：
Kirkpatrick, Brian;Xu, Leyan;Roberts, Rosalinda C.
通讯作者：
Roberts, Rosalinda C.