Dentate gyrus immaturity and region-specific synaptic and autophagy alterations across hippocampal subfields in schizophrenia.
BACKGROUND Hippocampal abnormalities are consistently observed in schizophrenia. We previously identified a histomorphological phenotype in the dentate gyrus (DG) suggestive of developmental arrest, alongside region-specific alterations in autophagy markers. However, how these features relate to synaptic organisation and neuronal maturity markers remains unclear. METHODS Post-mortem hippocampal tissue from older individuals with chronic schizophrenia (n = 10) and matched controls (n = 12) was examined using immunohistochemistry. Expression of synaptophysin and CD56 was assessed across the DG, CA4 (dentate hilus), and CA1, together with autophagy initiation proteins RB1CC1 and ATG16L1. Group differences were analysed using non-parametric tests, and exploratory correlation analyses were conducted across the cohort. RESULTS In control cases, the DG exhibited a distinct subgranular band-like pattern of synaptophysin immunoexpression consistent with organised synaptic architecture that was absent in schizophrenia. Schizophrenia cases showed a divergent synaptophysin pattern across hippocampal subfields, with reduced expression in the DG and CA4 but increased expression in CA1 (p = 0.003-0.007), while CD56 expression was higher across all regions (all p = 0.003). Autophagy markers showed complementary regional differences, with increased ATG16L1 in the DG (p = 0.048) and reduced RB1CC1 and ATG16L1 in CA1 (p = 0.009 and p = 0.003). Consistent with these regional differences, synaptophysin and CD56 expression showed strong inverse associations across hippocampal subfields, alongside region-dependent associations between synaptic, maturity-related, and autophagy-related markers. CONCLUSIONS These findings indicate regionally divergent alterations in synaptic organisation, neuronal maturity markers, and autophagy initiation signalling across hippocampal subfields in schizophrenia, consistent with the involvement of both neurodevelopmental and dynamic cellular processes and suggesting their potential convergence.