PMID- 28126896
OWN - NLM
STAT- MEDLINE
DCOM- 20180601
LR  - 20181113
IS  - 1745-1701 (Electronic)
IS  - 0586-7614 (Print)
IS  - 0586-7614 (Linking)
VI  - 43
IP  - 4
DP  - 2017 Jul 1
TI  - Postsynaptic Density-95 Isoform Abnormalities in Schizophrenia.
PG  - 891-899
LID - 10.1093/schbul/sbw173 [doi]
AB  - BACKGROUND: 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. METHODS: 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. RESULTS: 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. 
      CONCLUSIONS: 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 
      alpha-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.
CI  - (c) The Author 2017. Published by Oxford University Press on behalf of the Maryland 
      Psychiatric Research Center. All rights reserved. For permissions, please email: 
      journals.permissions@oup.com
FAU - Funk, Adam J
AU  - Funk AJ
AD  - Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati 
      College of Medicine, Cincinnati, OH.
FAU - Mielnik, Catharine A
AU  - Mielnik CA
AD  - Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, 
      Canada.
FAU - Koene, Rachael
AU  - Koene R
AD  - Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati 
      College of Medicine, Cincinnati, OH.
FAU - Newburn, Erin
AU  - Newburn E
AD  - Personalis Inc., Menlo Park, CA.
FAU - Ramsey, Amy J
AU  - Ramsey AJ
AD  - Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, 
      Canada.
FAU - Lipska, Barbara K
AU  - Lipska BK
AD  - Human Brain Collection Core, Division of Intramural Research Programs, National 
      Institute of Mental Health, National Institutes of Health, Bethesda, MD.
FAU - McCullumsmith, Robert E
AU  - McCullumsmith RE
AD  - Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati 
      College of Medicine, Cincinnati, OH.
LA  - eng
GR  - R01 MH094445/MH/NIMH NIH HHS/United States
GR  - R01 MH107487/MH/NIMH NIH HHS/United States
GR  - R21 MH107916/MH/NIMH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Schizophr Bull
JT  - Schizophrenia bulletin
JID - 0236760
RN  - 0 (Antipsychotic Agents)
RN  - 0 (Disks Large Homolog 4 Protein)
RN  - 0 (Gprin1 protein, mouse)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Protein Isoforms)
RN  - 0 (RNA Splice Sites)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - J6292F8L3D (Haloperidol)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Animals
MH  - Antipsychotic Agents/*pharmacology
MH  - Disease Models, Animal
MH  - Disks Large Homolog 4 Protein/*metabolism
MH  - Female
MH  - Haloperidol/*pharmacology
MH  - Humans
MH  - Male
MH  - Mice
MH  - Mice, Transgenic
MH  - Middle Aged
MH  - Nerve Tissue Proteins
MH  - Prefrontal Cortex/*metabolism
MH  - Protein Isoforms/*metabolism
MH  - *RNA Splice Sites
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, N-Methyl-D-Aspartate
MH  - Schizophrenia/*metabolism
PMC - PMC5472126
OTO - NOTNLM
OT  - PSD-95
OT  - isoform
OT  - mRNA
OT  - postmortem
OT  - protein
OT  - schizophrenia
OT  - splice variant
EDAT- 2017/01/28 06:00
MHDA- 2018/06/02 06:00
PMCR- 2018/07/01
CRDT- 2017/01/28 06:00
PHST- 2017/01/28 06:00 [pubmed]
PHST- 2018/06/02 06:00 [medline]
PHST- 2017/01/28 06:00 [entrez]
PHST- 2018/07/01 00:00 [pmc-release]
AID - sbw173 [pii]
AID - 10.1093/schbul/sbw173 [doi]
PST - ppublish
SO  - Schizophr Bull. 2017 Jul 1;43(4):891-899. doi: 10.1093/schbul/sbw173.