Synaptic Proteome Alterations in the Primary Auditory Cortex of Individuals With Schizophrenia.

Questions Are protein levels altered within synapses from the primary auditory cortex of individuals with schizophrenia and, if so, are these differences restricted to the synapse or present throughout the gray matter? Findings In this case-control study of 48 pairs of individuals with schizophrenia and matched control individuals, robust alterations were found in synaptic levels of mitochondrial and postsynaptic proteins, including glutamate and gamma-aminobutyric acid receptors, that were highly coregulated and not associated with underlying differences in total gray matter levels. Meaning These findings suggest a broad and highly coordinated rearrangement of the synaptic proteome in schizophrenia that is best explained by alterations in local synaptic, but not tissuewide, protein homeostasis. Importance Findings from unbiased genetic studies have consistently implicated synaptic protein networks in schizophrenia, but the molecular pathologic features within these networks and their contribution to the synaptic and circuit deficits thought to underlie disease symptoms remain unknown. Objective To determine whether protein levels are altered within synapses from the primary auditory cortex (A1) of individuals with schizophrenia and, if so, whether these differences are restricted to the synapse or occur throughout the gray matter. Design, Setting, and Participants This paired case-control study included tissue samples from individuals with schizophrenia obtained from the Allegheny County Office of the Medical Examiner. An independent panel of health care professionals made consensus DSM-IV diagnoses. Each tissue sample from an individual with schizophrenia was matched by sex, age, and postmortem interval with 1 sample from an unaffected control individual. Targeted mass spectrometry was used to measure protein levels in A1 gray matter homogenate and synaptosome preparations. All experimenters were blinded to diagnosis. Mass spectrometry data were collected from September 26 through November 4, 2016, and analyzed from November 3, 2016, to July 15, 2019. Main Outcomes and Measures Primary measures were homogenate and synaptosome protein levels and their coregulation network features. Hypotheses generated before data collection were (1) that levels of canonical postsynaptic proteins in A1 synaptosome preparations would differ between individuals with schizophrenia and controls and (2) that these differences would not be explained by changes in total A1 homogenate protein levels. Results Synaptosome and homogenate protein levels were investigated in 48 individuals with a schizophrenia diagnosis and 48 controls (mean age in both groups, 48 years [range, 17-83 years]); each group included 35 males (73%) and 13 females (27%). Robust alterations (statistical cutoff set at an adjusted Limma P < .05) were observed in synaptosome levels of canonical mitochondrial and postsynaptic proteins that were highly coregulated and not readily explained by postmortem interval, antipsychotic drug treatment, synaptosome yield, or underlying alterations in homogenate protein levels. Conclusions and Relevance These findings suggest a robust and highly coordinated rearrangement of the synaptic proteome. In line with unbiased genetic findings, alterations in synaptic levels of postsynaptic proteins were identified, providing a road map to identify the specific cells and circuits that are impaired in individuals with schizophrenia A1. This case-control study examines whether protein levels are altered within synapses from the primary auditory cortex of individuals with schizophrenia and, if so, whether these differences are restricted to the synapse or occur throughout the gray matter.