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

Nature Neuroscience volume 13, pages 327–332 (2010)Cite this article

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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.

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Figure 1: Short-term knockdown of DISC1 elicits spine enlargement in rat primary cortical neurons.
Figure 2: Protein interaction of DISC1 and Kal-7 regulates spine morphology in rat primary cortical neurons.
Figure 3: Augmentation of Kal-7–PSD-95 protein binding by DISC1 in rat primary cortical neurons.
Figure 4: Protein interaction of DISC1–Kal-7–PSD-95 influenced by activation of the NMDA-type glutamate receptor.
Figure 5: Regulation of Rac1 activity via signalosome of DISC1–Kal-7.
Figure 6: Long-term disturbance of DISC expression leads to spine shrinkage in rat primary cortical neurons.
Figure 7: Long-term suppression of DISC1 leads to spine shrinkage in slices and brains in vivo.

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Acknowledgements

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.).

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Authors and Affiliations

  1. Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Akiko Hayashi-Takagi, Manabu Takaki, Saurav Seshadri, Anupamaa J Seshadri, Koko Ishizuka, Atsushi Kamiya & Akira Sawa

  2. Department of Physiology and Biophysics, University at Buffalo, State University of New York, Buffalo, New York, USA

    Nick Graziane & Zhen Yan

  3. Neuroscience and Molecular Pharmacology, Faculty of Biomedical and Life Sciences, University of Glasgow, Glasgow, UK

    Hannah Murdoch, Allan J Dunlop & Miles D Houslay

  4. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Yuichi Makino, Jay M Baraban & Akira Sawa

  5. Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

    Deepak P Srivastava, Zhong Xie & Peter Penzes

  6. Beckman Research Institute of the City of Hope, Duarte, California, USA

    Toshifumi Tomoda

  7. Pfizer, Princeton, New Jersey, USA

    Nicholas J Brandon

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Contributions

A.H.-T., M.T., N.G., S.S., H.M., A.J.D. and T.T. conducted the experiments. Y.M., A.J.S., K.I., D.P.S. and Z.X. provided assistance for the experiments. J.M.B., M.D.H., T.T., N.J.B., A.K., Z.Y. and P.P. contributed to experimental design. A.H.-T., M.D.H., N.J.B. and A.S. wrote the manuscript. A.S. led the overall experimental design of the entire project.

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Correspondence to Akira Sawa.

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Hayashi-Takagi, A., Takaki, M., Graziane, N. et al. Disrupted-in-Schizophrenia 1 (DISC1) regulates spines of the glutamate synapse via Rac1. Nat Neurosci 13, 327–332 (2010). https://doi.org/10.1038/nn.2487

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