Background: Dysfunction of the hippocampus in schizophrenia is ostensibly caused by aberrations of PSD95-complex proteins, which are molecules that regulate synaptic plasticity in this region. While some PSD95-complex proteins have been previously examined in the schizophrenia hippocampus, the status of other equally important molecules is still unclear. This is especially true in the CA1 hippocampal subfeld, a region that is critically involved in the pathophysiology of schizophrenia.
Methods: We thus performed a quantitative immunoblot
experiment to examine markers of synaptic plasticity and several PSD95-complex proteins in the CA1 region, using postmortem brain samples derived from schizophrenia subjects with age-, sex-, and PMI-matched controls (n=20/group).
Results: Our results indicated robust reductions in synaptophysin (-27.8%; p=0.001) and PSD95 (-61.8%; p<0.001), which are
validated markers of synaptic densities. We further report signifcant alterations to the important scaffold protein Homer1 (Homer1a: +42.9%, Homer1b/c: -24.6%; p<0.035), with a two-fold reduction in the ratio of Homer1b/c:Homer1a isoforms (p=0.011). Preso was robustly overexpressed (+83.3%; p<0.001); this is a scaffold protein that supports interactions between Homer1/ PSD95 and group I metabotropic glutamate receptors (mGluRs). mGluR1 was also signifcantly reduced (-32.7%; p<0.001).
Conclusions: Consolidated with our prior report of increased levels of mGluR5 and the scaffolding protein Tamalin in the same region and subjects, our results support the presence of molecular abnormalities to PSD95-complex proteins in schizophrenia. We hypothesize that these alterations contribute to disrupted synaptic plasticity and hippocampal dysfunction in the disorder. However, future studies are required to confrm possible changes to neuromorphology in this region.