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

By Akiko Hayashi-Takagi, M. Takaki, N. Graziane, S. Seshadri, H. Murdoch, Allan J. Dunlop, Y. Makino, Anupamaa J. Seshadri, K. Ishizuka, D. Srivastava and 9 more. 2010

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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.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

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Citations in the corpus

Maturation and integration of adult born hippocampal neurons: signal convergence onto small Rho GTPases (2013, background): “A study in primary neurons in vitro found that DISC1 anchors the Rac1-GEF Kalirin-7 to the postsynaptic density, and regulates local Rac1 activity and spine morphology downstream of NMDAR activation (Hayashi-Takagi et al., 2010).”
PAKs inhibitors ameliorate schizophrenia-associated dendritic spine deterioration in vitro and in vivo during late adolescence (2014, methodology): “DISC1 interacts with many proteins, and its regulatory roles in synaptic plasticity may be multiple (10, 12, 19, 20).”
Dendritic spine pathology in neuropsychiatric disorders (2011, background): “Long-term DISC1 knockdown in cortical neurons reduces spine are”