Widespread synaptic density loss in schizophrenia follows molecular and network architecture

Converging neuroimaging, genetic, and post-mortem evidence highlights the fundamental role of synaptic density reductions in schizophrenia pathogenesis. However, the brain-wide spatial pattern of these alterations and the mechanisms underlying this patterning remain to be established. Here, using [¹¹C]UCB-J radiotracer positron emission tomography (PET) imaging in individuals with schizophrenia (n = 29) and healthy controls (n = 93), we find a prominent and widespread pattern of lower synaptic density (0.58 < Cohen's D < 1.47; p_FWE < 0.05) in patients. The left hemisphere is substantially more impacted than the right (Cohen's D = 1.14; p < 0.001), with frontal, temporal, cingulate, thalamic, striatal and hippocampal areas particularly affected. Synaptic density alterations were not spatially aligned with grey matter volume alterations indexed using anatomical Magnetic Resonance Imaging. Lower synaptic density in the left hemisphere is associated with higher normative concentrations of GABA_A/BZ, 5HT_2A, mGluR5 and 5HT_1B (r_cca = 0.68; p = 0.022). Simulation-based network diffusion models identified regions that may represent the initial sources of pathology, nominating left inferior frontal areas (p_FWE < 0.05) as potential foci from which synaptic pathology initiates and then propagates to structurally connected and molecularly similar areas. Overall, our findings provide in vivo evidence for widespread synaptic density deficits in schizophrenia that are left-lateralised, independent of grey matter volume alterations, aligned to specific neurochemical systems, and suggest that such synaptic pathology may propagate in a pattern consistent with axonal networks.