title: Changes in cortical N-methyl-D-aspartate receptors and post-synaptic density protein 95 in schizophrenia, mood disorders and suicide.
abstract: OBJECTIVE
  In humans, depending on dose, blocking the N-methyl-D-aspartate receptor (NMDAR) with ketamine can cause psychomimetic or antidepressant effects. The overall outcome for drugs such as ketamine depends on dose and the number of its available binding sites in the central nervous system, and to understand something of the latter variable we measure NMDAR in the frontal pole, dorsolateral prefrontal, anterior cingulate and parietal cortices from people with schizophrenia, bipolar disorder, major depressive disorders and age/sex matched controls.
  
  
  METHODS
  We measured levels of NMDARs (using [(3)H]MK-801 binding) and NMDAR sub-unit mRNAs (GRINs: using in situ hybridisation) as well as post-synaptic density protein 95 (anterior cingulate cortex only; not major depressive disorders: an NMDAR post-synaptic associated protein) in bipolar disorder, schizophrenia and controls.
  
  
  RESULTS
  Compared to controls, levels of NMDAR were lower in the outer laminae of the dorsolateral prefrontal cortex (-17%, p = 0.01) in people with schizophrenia. In bipolar disorder, levels of NMDAR binding (laminae IV-VI; -19%, p < 0.01) and GRIN2C mRNA (laminae I-VI; -27%, p < 0.05) were lower in the anterior cingulate cortex and NMDAR binding was lower in the outer lamina IV of the dorsolateral prefrontal cortex (-19%, p < 0.01). In major depressive disorders, levels of GRIN2D mRNA were higher in frontal pole (+22%, p < 0.05). In suicide completers, levels of GRIN2B mRNA were higher in parietal cortex (+20%, p < 0.01) but lower (-35%, p = 0.02) in dorsolateral prefrontal cortex while post-synaptic density protein 95 was higher (+26%, p < 0.05) in anterior cingulate cortex.
  
  
  CONCLUSIONS
  These data suggest that differences in cortical NMDAR expression and post-synaptic density protein 95 are present in psychiatric disorders and suicide completion and may contribute to different responses to ketamine.
authors.affiliation: Molecular Psychiatry Laboratory, The Florey Institute for Neuroscience and Mental Health, Parkville, VIC, Australia Psychiatric Neuropathology Laboratory, Department of Psychiatry, University of Melbourne, Parkville, VIC, Australia brian.dean@florey.edu.au.
authors.forename: Brian
authors.initials: B
authors.lastname: Dean
authors.affiliation: Molecular Psychiatry Laboratory, The Florey Institute for Neuroscience and Mental Health, Parkville, VIC, Australia Psychiatric Neuropathology Laboratory, Department of Psychiatry, University of Melbourne, Parkville, VIC, Australia.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Gibbons
authors.affiliation: Molecular Psychiatry Laboratory, The Florey Institute for Neuroscience and Mental Health, Parkville, VIC, Australia.
authors.forename: Simone
authors.initials: S
authors.lastname: Boer
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Akihito
authors.initials: A
authors.lastname: Uezato
authors.affiliation: Department of Psychiatry, University of Alabama Birmingham, Birmingham, AL, USA.
authors.forename: James
authors.initials: J
authors.lastname: Meador-Woodruff
authors.affiliation: Molecular Psychiatry Laboratory, The Florey Institute for Neuroscience and Mental Health, Parkville, VIC, Australia Psychiatric Neuropathology Laboratory, Department of Psychiatry, University of Melbourne, Parkville, VIC, Australia.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Scarr
authors.affiliation: Department of Psychiatry, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: McCullumsmith
mesh_terms: D000328:Adult; D015415:Biomarkers; D001714:Bipolar Disorder / Q000188:drug therapy / Q000235:genetics*; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000235:genetics*; D000076122:Disks Large Homolog 4 Protein; D005260:Female; D006179:Gyrus Cinguli / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D007649:Ketamine / Q000627:therapeutic use*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D017397:Prefrontal Cortex / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics*; D013405:Suicide
chemical_list: D015415:Biomarkers; C501444:DLG4 protein, human; D000076122:Disks Large Homolog 4 Protein; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine
keywords: NMDA; Schizophrenia; bipolar disorders; cortex; major depressive disorders