Molecular evidence of synaptic pathology in the CA1 region in schizophrenia

Alterations of postsynaptic density (PSD)95-complex proteins in schizophrenia ostensibly induce deficits in synaptic plasticity, the molecular process underlying cognitive functions. Although 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 post mortem brain samples derived from schizophrenia subjects with age-, sex-, and post mortem interval-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 twofold 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 toward understanding how proteins in the PSD are altered in the schizophrenia brain, and their relevance to overall hippocampal and cognitive dysfunction in the illness. Neurotransmission: Post-synaptic abnormalities in the hippocampus People with schizophrenia have extensive molecular anomalies on the receiving end of synapses in a crucial part of the brain’s hippocampus. A team that included Natalie Matosin from the Max Planck Institute of Psychiatry in Munich, Germany, studied postmortem brain samples from 20 people with schizophrenia and 20 matched individuals with no history of psychiatric illness. They used immunoblotting techniques to quantify the expression levels of PSD-95 and several of its associated proteins in the CA1 region of the hippocampus. PSD-95 sits on the receiving side of neuronal connections, where it promotes the maturation and strengthening of excitatory synapses. The researchers found substantial r