title: Regulation of N-methyl-D-aspartate receptors by disrupted-in-schizophrenia-1.
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.
authors.affiliation: Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wei
authors.affiliation: Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY, USA.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Graziane
authors.affiliation: Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY, USA.
authors.forename: Haitao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhong
authors.affiliation: Pfizer Neuroscience Research Unit, Cambridge, MA, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY, USA.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Liu
authors.affiliation: Dept. of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Akiko
authors.initials: A
authors.lastname: Hayashi-Takagi
authors.affiliation: Dept. of Neuropathology, University of Düsseldorf Medical School, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Korth
authors.affiliation: Dept. of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Akira
authors.initials: A
authors.lastname: Sawa
authors.affiliation: Pfizer Neuroscience Research Unit, Cambridge, MA, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Brandon
authors.affiliation: Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yan
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005625:Frontal Lobe / Q000166:cytology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D016202:N-Methylaspartate / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D014162:Transfection
chemical_list: C412476:DISC1 protein, human; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate
keywords: CREB; DISC1; GluN2A; NMDA receptors; PKA; schizophrenia
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