title: Postsynaptic Density-95 Isoform Abnormalities in Schizophrenia.
abstract: Postsynaptic density-95 (PSD-95) protein expression is dysregulated in schizophrenia in a variety of brain regions. We have designed experiments to examine PSD-95 mRNA splice variant expression in the dorsolateral prefrontal cortex from subjects with schizophrenia.
  
  
  
  We performed quantitative PCR and western blot analysis to measure PSD-95 expression in schizophrenia vs control subjects, rodent haloperidol treatment studies, rodent postmortem interval studies, and GluN1 knockdown (KD) mice vs controls.
  
  
  
  We found decreased mRNA expression of beta (t = 4.506, df = 383, P < .0001) and truncated (t = 3.378, df = 383, P = .0008) isoforms of PSD-95, whereas alpha was unchanged. Additionally, we found decreased PSD-95 protein expression in schizophrenia (t = 2.746, df = 71, P = .0076). We found no correlation between PSD-95 protein and alpha, beta, or truncated mRNA isoforms in schizophrenia. PSD-95 beta transcript was increased (t = 3.346, df = 14, P < .05) in the GluN1 KD mouse model of schizophrenia. There was an increase in PSD-95 alpha mRNA expression (t = 2.905, df = 16, P < .05) in rats following long-term haloperidol administration.
  
  
  
  Our findings describe a unique pathophysiology of specific PSD-95 isoform dysregulation in schizophrenia, chronic neuroleptic treatment, and a genetic lesion mouse model of drastically reduced N-methyl-d-aspartate receptor (NMDAR) complex expression. These data indicate that regulation of PSD-95 is multifaceted, may be isoform specific, and biologically relevant for synaptic signaling function. Specifically, NMDAR-mediated synaptic remodeling, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor trafficking and interaction may be impaired in schizophrenia by decreased PSD-95 beta and truncated expression (respectively). Further, increased PSD-95 beta transcript in the GluN1 KD mouse model poses a potential compensatory rescue of NMDAR-mediated function via increased postsynaptic throughput of the severely reduced GluN1 signal. Together, these data propose that disruption of excitatory signaling complexes through genetic (GluN1 KD), pharmacologic (antipsychotics), or disease (schizophrenia) mechanisms specifically dysregulates PSD-95 expression.
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, OH.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Funk
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
authors.forename: Catharine A
authors.initials: CA
authors.lastname: Mielnik
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, OH.
authors.forename: Rachael
authors.initials: R
authors.lastname: Koene
authors.affiliation: Personalis Inc., Menlo Park, CA.
authors.forename: Erin
authors.initials: E
authors.lastname: Newburn
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Ramsey
authors.affiliation: Human Brain Collection Core, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, MD.
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Lipska
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, OH.
authors.forename: Robert E
authors.initials: RE
authors.lastname: McCullumsmith
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein / Q000378:metabolism*; D005260:Female; D006220:Haloperidol / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009419:Nerve Tissue Proteins; D017397:Prefrontal Cortex / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism*; D022821:RNA Splice Sites; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate; D012559:Schizophrenia / Q000378:metabolism*
chemical_list: D014150:Antipsychotic Agents; D000076122:Disks Large Homolog 4 Protein; C121673:Gprin1 protein, mouse; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D022821:RNA Splice Sites; D016194:Receptors, N-Methyl-D-Aspartate; D006220:Haloperidol
keywords: PSD-95; isoform; mRNA; postmortem; protein; schizophrenia; splice variant