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. 2017 Jul 1;43(4):891-899.
doi: 10.1093/schbul/sbw173.

Postsynaptic Density-95 Isoform Abnormalities in Schizophrenia

Adam J Funk  1 , Catharine A Mielnik  2 , Rachael Koene  1 , Erin Newburn  3 , Amy J Ramsey  2 , Barbara K Lipska  4 , Robert E McCullumsmith  1
Affiliations

Postsynaptic Density-95 Isoform Abnormalities in Schizophrenia

Adam J Funk et al. Schizophr Bull. .

Abstract

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 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.

Keywords: PSD-95; isoform; mRNA; postmortem; protein; schizophrenia; splice variant.

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Figures

Fig. 1.
Fig. 1.
Decreased isoform-specific postsynaptic density-95 (PSD-95) mRNA expression in the dorsolateral prefrontal cortex (DLPFC) in schizophrenia. Quantitative PCR analysis of mRNA isolated from control (ctl, N = 210) and schizophrenia (scz, N = 175) subjects revealed decreased isoform-specific expression in the DLPFC in schizophrenia. No change was found with an assay that detected both alpha (α) and truncated (trunc) isoforms, while schizophrenia samples had decreased beta (β) (t = 4.7, df = 346.7, P < .05) and truncated isoform expression (t = 3.5, df = 373.5, P < .05). *P < .05.
Fig. 2.
Fig. 2.
Decreased postsynaptic density-95 (PSD-95) protein expression in the dorsolateral prefrontal cortex (DLPFC) in schizophrenia. Western blot analysis of protein isolated from control (C, N = 47) and schizophrenia (S, N = 26) subjects revealed decreased protein expression (t = 2.746, df = 71, P < .05) in the DLPFC from a subset of subjects used in the mRNA studies. (A) Graphed analysis of normalized PSD-95 protein expression. (B) Representative western blot, in duplicate for PSD-95 and β-tubulin. *P < .05.
Fig. 3.
Fig. 3.
Haloperidol-treated rats have increased postsynaptic density-95 alpha (PSD-95α) mRNA expression in frontal cortex. Quantitative PCR analysis of mRNA isolated from control (ctl, N = 9) and haloperidol (hal, N = 9) treated rats revealed increased PSD-95α expression (t = 2.9, df = 16, P < .05) in the frontal cortex. We found no changes in PSD-95 beta or gamma isoforms. *P < .05.
Fig. 4.
Fig. 4.
Analysis of the GluN1 NMDAR knockdown (KD) mouse model of schizophrenia. PSD-95 protein expression is unchanged in GluN1 KD mice (A, B). GluN1 KD (N = 5) mice have increased postsynaptic density-95 beta (PSD-95β) mRNA expression (t = 2.466, df = 7, P < .05) vs littermate wild-type (WT, N = 4) mice (C). *P < .05.
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