Characterization of Perineuronal Nets in the Human Cerebellum

Perineuronal nets (PNNs) are condensed extracellular matrix structures that regulate synaptic plasticity and neuronal stability. While their distribution and function have been well characterized in rodents, PNNs remain largely understudied in the human cerebellum. Here, we provide an anatomical characterization of PNNs in the post-mortem human cerebellum and compare their distribution and cellular phenotypes with those in mouse and macaque cerebellum. Using immunofluorescence for both Wisteria floribunda lectin (WFL) and aggrecan, we observed that PNNs in humans were exclusively localized in the deep cerebellar nuclei (DCN), with no detectable labelling in cerebellar cortex. In contrast, both macaques and mice exhibited PNNs in the DCN and cortex (granule cell layer), with interspecies differences in density and marker co-localization. Combining immunolabeling with fluorescence in situ hybridization for SLC17A7, GAD1, and PVALB, we found that in human and mouse DCN, PNNs predominantly surrounded excitatory, parvalbumin-expressing neurons, whereas in macaques, PV expression was absent from PNN-enwrapped excitatory cells. These findings highlight both conserved and divergent features of cerebellar PNNs, providing novel insights into the potential functional roles of these structures in human cerebellar circuitry, with implications for understanding cerebellar plasticity and disease vulnerability.