Disrupted-in-Schizophrenia 1 (DISC1) regulates spines of the glutamate synapse via Rac1

Akiko Hayashi-Takagi; Manabu Takaki; Nick Graziane; Saurav Seshadri; Hannah Murdoch; Allan J. Dunlop; Yuichi Makino; Anupamaa J. Seshadri; Koko Ishizuka; Deepak P. Srivastava; Zhong Xie; Jay M. Baraban; Miles D. Houslay; Toshifumi Tomoda; Nicholas J. Brandon; Atsushi Kamiya; Zhen Yan; Peter Penzes; Akira Sawa

doi:10.1038/nn.2487

Disrupted-in-Schizophrenia 1 (DISC1) regulates spines of the glutamate synapse via Rac1

Akiko Hayashi-Takagi, Manabu Takaki, Nick Graziane, Saurav Seshadri, Hannah Murdoch, Allan J. Dunlop, Yuichi Makino, Anupamaa J. Seshadri, Koko Ishizuka, Deepak P. Srivastava, Zhong Xie, Jay M. Baraban, Miles D. Houslay, Toshifumi Tomoda, Nicholas J. Brandon, Atsushi Kamiya, Zhen Yan, Peter Penzes, Akira Sawa

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Abstract

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.

Original language	English (US)
Pages (from-to)	327-332
Number of pages	6
Journal	Nature Neuroscience
Volume	13
Issue number	3
DOIs	https://doi.org/10.1038/nn.2487
State	Published - Mar 2010

All Science Journal Classification (ASJC) codes

General Neuroscience

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10.1038/nn.2487

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Hayashi-Takagi, A., Takaki, M., Graziane, N., Seshadri, S., Murdoch, H., Dunlop, A. J., Makino, Y., Seshadri, A. J., Ishizuka, K., Srivastava, D. P., Xie, Z., Baraban, J. M., Houslay, M. D., Tomoda, T., Brandon, N. J., Kamiya, A., Yan, Z., Penzes, P., & Sawa, A. (2010). Disrupted-in-Schizophrenia 1 (DISC1) regulates spines of the glutamate synapse via Rac1. Nature Neuroscience, 13(3), 327-332. https://doi.org/10.1038/nn.2487

@article{5924c564db0b495bb6bf16a1a76839a8,

title = "Disrupted-in-Schizophrenia 1 (DISC1) regulates spines of the glutamate synapse via Rac1",

abstract = "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.",

author = "Akiko Hayashi-Takagi and Manabu Takaki and Nick Graziane and Saurav Seshadri and Hannah Murdoch and Dunlop, {Allan J.} and Yuichi Makino and Seshadri, {Anupamaa J.} and Koko Ishizuka and Srivastava, {Deepak P.} and Zhong Xie and Baraban, {Jay M.} and Houslay, {Miles D.} and Toshifumi Tomoda and Brandon, {Nicholas J.} and Atsushi Kamiya and Zhen Yan and Peter Penzes and Akira Sawa",

note = "Funding Information: We thank Y. Lema and P. Talalay for help with manuscript preparation, A. Gruber, P. O{\textquoteright}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{\textquoteright}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.).",

year = "2010",

month = mar,

doi = "10.1038/nn.2487",

language = "English (US)",

volume = "13",

pages = "327--332",

journal = "Nature Neuroscience",

issn = "1097-6256",

publisher = "Nature Research",

number = "3",

}

Hayashi-Takagi, A, Takaki, M, Graziane, N, Seshadri, S, Murdoch, H, Dunlop, AJ, Makino, Y, Seshadri, AJ, Ishizuka, K, Srivastava, DP, Xie, Z, Baraban, JM, Houslay, MD, Tomoda, T, Brandon, NJ, Kamiya, A, Yan, Z, Penzes, P & Sawa, A 2010, 'Disrupted-in-Schizophrenia 1 (DISC1) regulates spines of the glutamate synapse via Rac1', Nature Neuroscience, vol. 13, no. 3, pp. 327-332. https://doi.org/10.1038/nn.2487

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 -

Disrupted-in-Schizophrenia 1 (DISC1) regulates spines of the glutamate synapse via Rac1

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