Abstract
Converging neuroimaging, genetic, and post-mortem evidence show a fundamental role of synaptic deficits in schizophrenia pathogenesis. However, the underlying molecular and cellular mechanisms that drive the onset and progression of synaptic pathology remain to be established. Here, we used synaptic density positron emission tomography (PET) imaging using the [(11)C]UCB-J radiotracer to reveal a prominent widespread pattern (p (FWE) < 0.05) of lower synaptic density in individuals with schizophrenia (n=29), compared to a large sample of healthy controls (n=93). We found that the spatial pattern of lower synaptic density in schizophrenia is spatially aligned (r (cca) = 0.67; p < 0.001) with higher normative distributions of GABA(A/BZ), 5HT(1B), 5HT(2A), and 5HT(6), and lower levels of CB(1) and 5HT(1A). Competing neighborhood deformation network models revealed that regional synaptic pathology strongly correlated with estimates predicted using a model constrained by both interregional structural connectivity and molecular similarity (.42 < r < .61; p (FWE) < 0.05). These data suggest that synaptic pathology in schizophrenia is jointly constrained by both global axonal connectivity and local molecular vulnerability. Simulation-based network diffusion models were used to identify regions that may represent the initial sources of pathology, nominating left prefrontal areas (p (FWE) < 0.05) as potential foci from which synaptic pathology initiates and propagates to molecularly similar areas. Overall, our findings provide in vivo evidence for widespread deficit in synaptic density in schizophrenia that is jointly constrained by axonal connectivity and molecular similarity between regions, and that synaptic deficits spread from initial source regions to axonally connected and molecularly similar territories.