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

Nature neuroscience | Mar 18, 2010

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.

Pubmed ID: 20139976 RIS Download

Mesh terms: Animals | Cells, Cultured | Cerebral Cortex | Dendritic Spines | Excitatory Postsynaptic Potentials | Gene Knockdown Techniques | Glutamic Acid | Guanine Nucleotide Exchange Factors | Nerve Tissue Proteins | Neurons | RNA Interference | Rats | Rats, Sprague-Dawley | Receptors, AMPA | Receptors, N-Methyl-D-Aspartate | Signal Transduction | Synapses | Time Factors | Tissue Culture Techniques | rac1 GTP-Binding Protein

Data used in this publication

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Associated grants

  • Agency: NIMH NIH HHS, Id: RC1 MH088753-01
  • Agency: NIMH NIH HHS, Id: MH-069853
  • Agency: NIMH NIH HHS, Id: R01 MH069853-01A1
  • Agency: NIMH NIH HHS, Id: R01 MH069853
  • Agency: NIMH NIH HHS, Id: P20 MH084018-01
  • Agency: NIMH NIH HHS, Id: P20 MH084018-010001
  • Agency: Medical Research Council, Id: G0600765
  • Agency: NIMH NIH HHS, Id: MH-084018
  • Agency: NINDS NIH HHS, Id: NS-048911
  • Agency: NIMH NIH HHS, Id: R01 MH084233-05
  • Agency: NINDS NIH HHS, Id: R01 NS048911-01
  • Agency: NIMH NIH HHS, Id: R01 MH084233
  • Agency: NINDS NIH HHS, Id: R01 NS048911
  • Agency: NIMH NIH HHS, Id: MH-084233
  • Agency: NIMH NIH HHS, Id: RC1 MH088753
  • Agency: NIMH NIH HHS, Id: R01 MH071316-01A1
  • Agency: NIMH NIH HHS, Id: MH-071316
  • Agency: NIMH NIH HHS, Id: P20 MH084018
  • Agency: NIMH NIH HHS, Id: MH-088753
  • Agency: NIMH NIH HHS, Id: R01 MH071316

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