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

Nat Neurosci. 2010 Mar;13(3):327-32. doi: 10.1038/nn.2487. Epub 2010 Feb 7.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Disc1 protein, rat
  • Guanine Nucleotide Exchange Factors
  • Kalrn protein, rat
  • Nerve Tissue Proteins
  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate
  • Glutamic Acid
  • Rac1 protein, rat
  • rac1 GTP-Binding Protein
  • glutamate receptor ionotropic, AMPA 1