Postsynaptic density levels of the NMDA receptor NR1 subunit and PSD-95 protein in prefrontal cortex from people with schizophrenia.

Vibeke Sørensen Catts,Dominique Suzanne Derminio,Cynthia Shannon Weickert,Chang-Gyu Hahn

doi:10.1038/npjschz.2015.37

Vibeke Sørensen Catts, Dominique Suzanne Derminio + Show 2 more

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https://doi.org/10.1038/npjschz.2015.37

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Background:There is converging evidence of involvement of N-methyl-d-aspartate (NMDA) receptor hypofunction in the pathophysiology of schizophrenia. Our group recently identified a decrease in total NR1 mRNA and protein expression in the dorsolateral prefrontal cortex in a case-control study of individuals with schizophrenia (n=37/group). The NR1 subunit is critical to NMDA receptor function at the postsynaptic density, a cellular structure rich in the scaffolding protein, PSD-95. The extent to which the NMDA receptor NR1 subunit is altered at the site of action, in the postsynaptic density, is not clear.Aims:To extend our previous results by measuring levels of NR1 and PSD-95 protein in postsynaptic density-enriched fractions of prefrontal cortex from the same individuals in the case-control study noted above.Methods:Postsynaptic density-enriched fractions were isolated from fresh-frozen prefrontal cortex (BA10) and subjected to western blot analysis for NR1 and PSD-95.Results:We found a 20% decrease in NR1 protein (t(66)=−2.874, P=0.006) and a 30% decrease in PSD-95 protein (t(63)=−2.668, P=0.010) in postsynaptic density-enriched fractions from individuals with schizophrenia relative to unaffected controls.Conclusions:Individuals with schizophrenia have less NR1 protein, and therefore potentially fewer functional NMDA receptors, at the postsynaptic density. The associated decrease in PSD-95 protein at the postsynaptic density suggests that not only are glutamate receptors compromised in individuals with schizophrenia, but the overall spine architecture and downstream signaling supported by PSD-95 may also be deficient.

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There is converging evidence of involvement of N-methyl-D-aspartate (NMDA) receptor hypofunction in the pathophysiology of schizophrenia
Successful enrichment of the postsynaptic density (PSD) is indicated by the presence of increasing concentrations of PSD-95 in the ‘total fraction’ (T), synaptic membrane fraction’ (S) and the ‘PSD-enriched fraction’ (PSD) for both control (Figure 1a) and schizophrenia (Figure 1b) fractions
PSD-enriched fractions from people with schizophrenia had 20% less NR1 protein (t(66) = − 2.874, P = 0.006; Figures 3a and c) and 30% less PSD-95 protein (t(63) = − 2.668, P = 0.010; Figures 3b and d) than PSD-enriched fractions from controls

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Introduction

The majority of postmortem studies that find no statistically significant changes in NR1 protein levels or NMDA receptor ligand binding may not have been adequately powered to do so, contributing to conflicting results. There is converging evidence of involvement of N-methyl-D-aspartate (NMDA) receptor hypofunction in the pathophysiology of schizophrenia. Our group recently identified a decrease in total NR1 mRNA and protein expression in the dorsolateral prefrontal cortex in a case-control study of individuals with schizophrenia (n = 37/group). AIMS: To extend our previous results by measuring levels of NR1 and PSD-95 protein in postsynaptic density-enriched fractions of prefrontal cortex from the same individuals in the case-control study noted above. The associated decrease in PSD-95 protein at the postsynaptic density suggests that are glutamate receptors compromised in individuals with schizophrenia, but the overall spine architecture and downstream signaling supported by PSD-95 may be deficient

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