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

Research output: Contribution to journalArticle

285 Citations (Scopus)

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 languageEnglish
Pages (from-to)327-332
Number of pages6
JournalNature Neuroscience
Volume13
Issue number3
DOIs
Publication statusPublished - Mar 1 2010
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

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