Cerebellar astrocytic alterations in depression

Accumulating evidence suggests dysfunction of cerebellar-cerebral circuits in depression. However, the potential cellular and molecular alterations associated with depression in the cerebellum remain largely uncharacterized. While postmortem findings in the cerebral cortex indicate astrocyte dysregulation in depressed individuals who died by suicide (DS), the extent to which depression potentially alters cerebellar astrocytes is not well understood. In this study, two canonical astrocyte markers, glial fibrillary acidic protein (GFAP) and aldehyde Dehydrogenase-1 Family member L1 (ALDH1L1) were used to quantify cerebellar astrocyte subtypes, Bergmann glia (BG) in the Purkinje cell layer (PCL), velate astrocytes in the granule cell layer (GCL), and fibrous astrocytes in the white matter (WM). Purkinje cells (PCs) were also quantified due to their close association with BG. To assess potential dysregulation of astrocyte communication, we examined connexins, channel proteins essential in forming a functional network between astrocytes. Astrocytic connexins were visualized using single molecule in situ hybridization targeting connexin 30 (Cx30) and connexin 43 (Cx43), followed by immunolabeling for ALDH1L1. Our analysis revealed significant increases in ALDH1L1+ astrocyte densities in DS specific to the PCL compared to control individuals. Astrocytic connexins were significantly downregulated in DS, with Cx43 showing marked reductions in both PCL and GCL. Overall, our findings suggest that BG in the PCL and velate astrocytes in the GCL are particularly vulnerable in the depressive phenotype. Furthermore, this study supports previous findings in the cerebral cortex and extends astrocytic dysfunction to the cerebellum suggesting a widespread disruption of astrocyte-mediated communication across the brain in depression.