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

Hayashi-Takagi, A. et al. (2010) Disrupted-in-Schizophrenia 1 (DISC1) regulates spines of the glutamate synapse via Rac1. Nature Neuroscience, 13(3), pp. 327-332. (doi: 10.1038/nn.2487)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Murdoch, Dr Hannah and Houslay, Professor Miles and Dunlop, Dr Allan
• Authors: 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., and Sawa, A.
• Subjects: R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
• College/School: College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
• Journal Name: Nature Neuroscience
• Publisher: Nature Publishing Group
• ISSN: 1097-6256
• ISSN (Online): 1546-1726
• Published Online: 07 February 2010

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Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
42157	1	thera-cAMP: identification of therapeutic molecules to target compartmentalised cAMP signalling networks in human disease	Miles Houslay	European Commission (EC)	UNSPECIFIED	Institute of Neuroscience and Psychology
43830	1	Phosphodiesterase-4 isoforms - intracellular targeting, regulation and potential therapeutic targets	Miles Houslay	Medical Research Council (MRC)	G0600765	Institute of Neuroscience and Psychology