Topic Overview:
Reductions in dendritic spines, the postsynaptic component of excitatory synapses, have been observed in multiple brain areas in schizophrenia (Sz) and are believed to underlie cortical processing deficits. Synaptic plasticity is regulated by synaptic protein network features, like protein trafficking and activity, both of which are mediated by posttranslational modifications (e.g., phosphorylation); and a significant number of Sz risk genes code for synaptic proteins. In cortical tissue from 50 Sz and 50 matched controls, MacDonald and colleagues used parallel microscopy, proteomic, and phosphoproteomic approaches to identify protein phosphorylations highly correlated with both dendritic spine loss and synaptic protein level alterations in Sz.

MacDonald and colleagues observed robust changes to phosphorylation levels of canonical postsynaptic proteins in Sz. WGCNA and cross-network analyses observed significant correlations among synaptosome, phosphorylation, and dendritic spine alterations in Sz. Phosphorylation sites on eight proteins were highly correlated with both synaptic protein alterations and spine loss. Of these eight proteins, all but one have well-documented roles in vesicular trafficking of postsynaptic glutamate receptors and/or regulating dendritic spines. When modeled in mice, one of these candidate phosphorylations (MAP2 S426E) decreased cortical dendritic spines numbers, further supporting a causal role for these phosphorylations in Sz pathology.

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