Molecular evidence of synaptic pathology in the CA1 region in schizophrenia
Matosin N, Fernandez F, Lum JS, Engel M, Andrews JL, Gassen NC, Wagner KV, Schmidt MV, Newell KA.
2(16022), npj Schizophrenia. 2016.
Abstract Alterations of postsynaptic density (PSD)95-complex proteins in schizophrenia ostensibly induce deficits in synaptic plasticity, the molecular process underlying cognitive functions. While some PSD95-complex proteins have been previously examined in the hippocampus in schizophrenia, the status of other equally important molecules is unclear. This is especially true in the cornu ammonis (CA)1 hippocampal subfield, a region that is critically involved in the pathophysiology of the illness. We thus performed a quantitative immunoblot experiment to examine PSD95 and several of its associated proteins in the CA1 region, using postmortem brain samples derived from schizophrenia subjects with age-, sex-, and postmortem interval (PMI)-matched controls (n=20/group). Our results indicate a substantial reduction in PSD95 protein expression (-61.8%). Further analysis showed additional alterations to the scaffold protein Homer1 (Homer1a: +42.9%, Homer1b/c: -24.6%), with a two-fold reduction in the ratio of Homer1b/c:Homer1a isoforms (p=0.011). Metabotropic glutamate receptor 1 (mGluR1) protein levels were significantly reduced (-32.7%), and Preso, a protein that supports interactions between Homer1 or PSD95 with mGluR1, was elevated (+83.3%). Significant reduction in synaptophysin (-27.8%) was also detected, which is a validated marker of synaptic density. These findings support the presence of extensive molecular abnormalities to PSD95 and several of its associated proteins in the CA1 region in schizophrenia, offering a small but significant step towards understanding how proteins in the PSD are altered in the schizophrenia brain, and their relevance to overall hippocampal and cognitive dysfunction in the illness.
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