In vivo mapping of protein-protein interactions of schizophrenia risk factors generates an interconnected disease network.

Genetic analyses of schizophrenia (SCZ) patients have identified thousands of risk factors. In silico protein-protein interaction (PPI) network analysis has provided strong evidence that disrupted PPI networks underlie SCZ pathogenesis. In this study, we performed in vivo PPI analysis of several SCZ risk factors (i.e., Grin2b, Grm5, Gsk3b, Map2k1, Ppp1ca, Stx1a, Syngap1, and Syt1) in the rodent brain. Using endogenous antibody immunoprecipitations analyzed by liquid chromatography coupled to mass spectrometry, we constructed a SCZ network comprising 1612 unique PPI with a 5% FDR. Over 90% of the PPIs have not been previously reported. AlphaFold3 was employed to identify direct PPI interactors. Our SCZ PPI network was enriched with known SCZ risk factors, which supports the hypothesis that an accumulation of disturbances in selected PPI networks underlies SCZ. We used Stable Isotope Labeling in Mammals (SILAM) to quantitate phencyclidine (PCP) perturbations in the SCZ network and found that PCP weakened most PPI but also led to some enhanced or new PPI. These findings demonstrate that quantifying PPI in perturbed biological states can reveal alterations to network biology.