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Biol Psychiatry. 2014 Mar 1;75(5):414-24. doi: 10.1016/j.biopsych.2013.06.009. Epub 2013 Jul 29.

Regulation of N-methyl-D-aspartate receptors by disrupted-in-schizophrenia-1.

Author information

  • 1Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, New York.
  • 2Pfizer Neuroscience Research Unit, Cambridge, Massachusetts.
  • 3Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland.
  • 4Department of Neuropathology, University of Düsseldorf Medical School, Düsseldorf, Germany.
  • 5Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, New York. Electronic address: zhenyan@buffalo.edu.

Abstract

BACKGROUND:

Genetic studies have implicated disrupted-in-schizophrenia-1 (DISC1) as a risk factor for a wide range of mental conditions, including schizophrenia. Because N-methyl-D-aspartate receptor (NMDAR) dysfunction has been strongly linked to the pathophysiology of these conditions, we examined whether the NMDAR is a potential target of DISC1.

METHODS:

DISC1 was knocked down with a small inference RNA. NMDAR-mediated currents were recorded and NMDAR expression was measured.

RESULTS:

We found that cellular knockdown of DISC1 significantly increased NMDAR currents in cortical cultures, which were accompanied by an increase in the expression of NMDAR subunit, GluN2A. NMDAR-mediated synaptic response in prefrontal cortical pyramidal neurons was also increased by DISC1 knockdown in vivo. The effect of DISC1 knockdown on NMDAR currents in cortical cultures was blocked by protein kinase A (PKA) inhibitor, occluded by PKA activator, and prevented by phosphodiesterase 4 inhibitor. Knockdown of DISC1 caused a significant increase of cyclic adenosine monophosphate response element-binding protein (CREB) activity. Inhibiting CREB prevented the DISC1 deficiency-induced increase of NMDAR currents and GluN2A clusters.

CONCLUSIONS:

Our results suggest that DISC1 exerts an important impact on NMDAR expression and function through a phosphodiesterase 4/PKA/CREB-dependent mechanism, which provides a potential molecular basis for the role of DISC1 in influencing NMDAR-dependent cognitive and emotional processes.

Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

KEYWORDS:

CREB; DISC1; GluN2A; NMDA receptors; PKA; schizophrenia

Comment in

PMID:
23906531
[PubMed - indexed for MEDLINE]
PMCID:
PMC3864617
[Available on 2015/3/1]
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