TY - JOUR
T1 - Disrupted-in-Schizophrenia 1 (DISC1) regulates spines of the glutamate synapse via Rac1
AU - Hayashi-Takagi, Akiko
AU - Takaki, Manabu
AU - Graziane, Nick
AU - Seshadri, Saurav
AU - Murdoch, Hannah
AU - Dunlop, Allan J.
AU - Makino, Yuichi
AU - Seshadri, Anupamaa J.
AU - Ishizuka, Koko
AU - Srivastava, Deepak P.
AU - Xie, Zhong
AU - Baraban, Jay M.
AU - Houslay, Miles D.
AU - Tomoda, Toshifumi
AU - Brandon, Nicholas J.
AU - Kamiya, Atsushi
AU - Yan, Zhen
AU - Penzes, Peter
AU - Sawa, Akira
N1 - Funding Information:
We thank Y. Lema and P. Talalay for help with manuscript preparation, A. Gruber, P. O’Donnell, P.F. Worley, R.L. Huganir, J.D. Rothstein, N. Shahani, H. Ujike, S. Kuroda, H. Bito and M. Nuriya for scientific discussions and J. Gogos, R.A. Cerione, H. Cline and A. Jeromin for providing us with reagents. This work was supported by grants from the US National Institutes of Health (MH-084018, MH-069853 and MH-088753 to A.S., MH-071316 to P.P., and MH-084233 and NS-048911 to Z.Y.), as well as by grants from Stanley (A.S.), Cure Huntington’s Disease Initiative (A.S.), HighQ (A.S.), S & R Foundation (A.S.), RUSK (A.S.), National Alliance for Research on Schizophrenia and Depression (A.S., A.H.-T., A.K. and P.P.), National Alliance for Autism Research (P.P.), Uehara (A.H.-T. and M.T.), Medical Research Council (G0600765 to M.D.H.) and the European Union (LSHB-CT-2006-037189 to M.D.H.).
PY - 2010/3
Y1 - 2010/3
N2 - Synaptic spines are dynamic structures that regulate neuronal responsiveness and plasticity. We examined the role of the schizophrenia risk factor DISC1 in the maintenance of spine morphology and function. We found that DISC1 anchored Kalirin-7 (Kal-7), regulating access of Kal-7 to Rac1 and controlling the duration and intensity of Rac1 activation in response to NMDA receptor activation in both cortical cultures and rat brain in vivo. These results explain why Rac1 and its activator (Kal-7) serve as important mediators of spine enlargement and why constitutive Rac1 activation decreases spine size. This mechanism likely underlies disturbances in glutamatergic neurotransmission that have been 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.
AB - Synaptic spines are dynamic structures that regulate neuronal responsiveness and plasticity. We examined the role of the schizophrenia risk factor DISC1 in the maintenance of spine morphology and function. We found that DISC1 anchored Kalirin-7 (Kal-7), regulating access of Kal-7 to Rac1 and controlling the duration and intensity of Rac1 activation in response to NMDA receptor activation in both cortical cultures and rat brain in vivo. These results explain why Rac1 and its activator (Kal-7) serve as important mediators of spine enlargement and why constitutive Rac1 activation decreases spine size. This mechanism likely underlies disturbances in glutamatergic neurotransmission that have been 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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U2 - 10.1038/nn.2487
DO - 10.1038/nn.2487
M3 - Article
C2 - 20139976
AN - SCOPUS:77649192502
SN - 1097-6256
VL - 13
SP - 327
EP - 332
JO - Nature Neuroscience
JF - Nature Neuroscience
IS - 3
ER -