EXAMINING THE CONSEQUENCES OF EARLY-LIFE ADVERSITY ON PERINEURONAL NETS IN THE CEREBELLUM: EVIDENCE FROM MICE AND HUMANS

Child abuse (CA) affects neurodevelopment and is a leading risk factor for psychiatric illness. We previously reported that severe CA is associated with increased density and maturity of perineuronal nets (PNNs) in the human ventromedial prefrontal cortex. PNNs are specialized extracellular matrix structures that surround certain neurons and regulate critical period closure. We recently characterized cerebellar PNNs in healthy humans, macaques and mice (Mpai et al., 2025, Cerebellum 24(6):168), though their vulnerability to early-life adversity (ELA) remains unclear. In the present study, we used immunofluorescence and fluorescence in situ hybridization to quantify PNNs and GABAergic (GAD1+), glutamatergic (SLC17A7+), and parvalbumin-expressing cells in the dentate nucleus of adult depressed suicides with, and without, a history of CA (n=15/group; DS-CA [12M] and DS [13M], respectively), compared to matched controls (n=15; 13M). Concurrently, we used a limited bedding and nesting (LBN) model of ELA in C57BL/6 mice (n=8; 4M) and compared them with standard-reared mice (n=9; 4M), using a similar approach. PNN densities did not differ between ELA and control mice in the deep cerebellar nuclei (all, p > 0.48). Similarly, preliminary results in humans (24/45 quantified) suggest no difference in PNN density between groups in the dentate nucleus. However, a decrease in GAD1+ (CTRL, n = 5,19.72 cells/mm²; DS, n = 11, 21.08 cells/mm²; and DS-CA, n = 8, 13.91 cells/mm²) and SLC17A7+ cells (CTRL, 25.37 cells/mm²; DS, 21.07 cells/mm²; and DS-CA,13.65 cells/mm²) was observed in DS-CA. Preliminary results suggest that not all PNNs are equally vulnerable to ELA in the CNS.