BackgroundRecent evidence brings autophagy, and specifically the RB1CC1 gene into sharp focus as aetiologically relevant to Schizophrenia. Our understanding of whether and how these genetic signatures translate to cellular functions remains limited. Material and methodsPost-mortem study of 10 individuals with Schizophrenia and 18 individuals without any neurological/psychiatric disorder, matched for age, sex, post-mortem-interval, pH and BRAAK score. Formalin-fixed, paraffin-embedded, 6 μm sections cut through segments of the anterior, middle and posterior left or right hippocampus were examined for histopathological differences and immunohistochemical expression of RB1CC1 and ATG16L1 proteins. ResultsDentate gyrus (DG) granule cells area (p = 0.005) and circularity (p = 0.012) were significantly lower among Schizophrenia vs. controls. Antipsychotics were associated with lower circularity (p = 0.007). RB1CC1 and ATG16L1 immunoexpression were positively correlated (p < 0.001) and significantly lower in the CA1 (p = 0.047, p = 0.005, respectively). RB1CC1 immunoexpression was significantly higher in the DG among Schizophrenia vs. controls (p = 0.047,). The latter was more pronounced among donors treated with antipsychotics. Lower ATG16L1 CA1 immunoreactivity was correlated with lower granule cell area (p < 0.001). ConclusionsFor the first time, we present histopathological evidence of morphological alterations in the DG of the human brain in Schizophrenia. We propose that these changes indicate DG developmental arrest, which is associated with diminished RB1CC1-ATG16L1-mediated autophagy initiation in the CA1. We suggest that this is a pathological process, whereas RB1CC1-ATG16L1 upregulation in the DG, and possibly in the CA4, may represent a compensatory/restorative mechanism. Antipsychotics may upregulate RB1CC1-ATG16L1 autophagy initiation. Larger studies are required to validate these findings and explore clinical correlations.
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