Molecular Abnormalities in the Hippocampus in Schizophrenia

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Post mortem examination of human brain samples derived from individuals diagnosed with schizophrenia revealed widespread synaptic alterations in CA1 hippocampal subfield.
Post mortem examination of human brain samples derived from individuals diagnosed with schizophrenia revealed widespread synaptic alterations in CA1 hippocampal subfield.

Many “normal” learning and memory processes rely on the integrity and proper functioning of the hippocampus. Smaller hippocampal volume has previously been reported in patients diagnosed with schizophrenia, and hippocampus-dependent cognitive function is altered in these patients due to aberrant synaptic connectivity within the hippocampus and altered functional connectivity to other brain regions such as the prefrontal cortex. The hippocampal formation consists of 3 major subfields [cornu ammonis 1-3 (CA1-3)], as well as the dentate gyrus, the subiculum, and the entorhinal cortex.

Post mortem examination of human brain samples derived from 20 individuals diagnosed with schizophrenia revealed widespread molecular abnormalities in CA1 hippocampal subfield. Investigators affiliated with the Max Planck Institute of Psychiatry, Munich, Germany, the University of New South Wales, Sydney, Australia, the University of Wollongong, Australia, and the Australian Catholic University, Brisbane, published their findings in NPJ Schizophrenia.

After tissue collection, CA1 region was manually dissected, and researchers performed quantitative immunoblotting assay to gather densitometry values for PSD95, Homer1 (1a and 1b/c isoforms), Preso, mGluR1, and synaptophysin proteins.

Postsynaptic density 95 (PSD95) protein is required for synaptic formation, maturation, and plasticity at a postsynaptic density of excitatory synapses. Homer proteins regulate the function of mGluR1 (metabotropic glutamate receptor 1); Homer1b/c is predominantly localized in the CA1 region, whereas Homer1a is found at very low levels in hippocampal cells. Preso proteins regulate the density of dendritic spines and facilitate PSD95/Homer1 interactions. mGluR1 is a key regulator of synaptic plasticity that modulates glutamatergic neurotransmission [in the CA1 region, for example, mGluR1 is involved in long-term potentiation (LTP) and long-term depression (LTD)]. Synaptophysin is a presynaptic protein that is a useful marker for synaptic density.

“This study shows extensive disruption to PSD95 and several important PSD95-complex proteins in post mortem samples from the CA1 hippocampal region of schizophrenia subjects relative to matched controls,” the investigators wrote.

More specifically, the findings indicate that PSD95 protein levels were significantly reduced in CA1 region of individuals diagnosed with schizophrenia, as compared with those of controls (-64.84%; F(1,34) = 24.985, P < 0.001). Synaptophysin protein levels were also significantly reduced in CA1 region of individuals diagnosed with schizophrenia compared to those of controls (-27.84%; t(36) = -3.558, P = 0.001). "Considering 95% of PSD95 protein is localized to synapses and the levels of synaptophysin and PSD95 strongly correspond to synapse numbers, these data are strongly suggestive of reduced synapse number in the CA1 region of schizophrenia subjects," the authors noted.

Researchers assessed protein levels of Homer1 in the CA1 region and found a significant increase in Homer1a protein levels in schizophrenia subjects, relative to those of controls (+42.92%; F(1,34) = 9.751, P = 0.004). Conversely, they found a significant decrease in Homer1b/c protein levels in schizophrenia subjects (-24.55%; F(1,34) = 4.810, P = 0.035).

The findings indicate that Preso protein levels in the CA1 region were significantly higher in schizophrenia subjects, relative to those of controls (+83.30%; t(37) = 14.142, P < 0.001). And, Preso protein levels were associated with age of disease onset in individuals with schizophrenia (r=0.498, P = 0.030).

Total mGluR1 protein levels were significantly lower in schizophrenia subjects, relative to those of controls (-32.65%; F(1,30) = 14.586, P = 0.001).

“Although the mechanisms and morphological effects of these alterations were not explored,” the authors “speculate that changes in synaptic plasticity and/or neutrophil loss in the CA1 region in schizophrenia contribute to the increased activity and decreased volume of the hippocampus [that is] consistently observed in the disorder.”

Reference

Matosin N, Fernandez-Enright F, Lum JS, et al. Molecular evidence of synaptic pathology in the CA1 region in schizophrenia. NPJ Schizophrenia. 2016. doi: 10.1038/npjschz.2016.22.

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