Glycosaminoglycan sugar side chains on perineuronal nets in the fastigial nucleus regulate motor skills

Perineuronal nets (PNNs), composed primarily of chondroitin sulfate proteoglycans with core proteins and glycosaminoglycan (GAG) side chains, are specialized extracellular matrices that modulate synaptic transmission. However, the specific function of PNNs in the cerebellum, particularly in the fastigial nucleus (FN), and their influence on motor skill regulation remains unclear. Here, we initially performed chemogenetic inactivation of the FN and confirmed that the activity of glutamatergic neurons in the FN is required for both gross and fine motor skills. We then demonstrated that motor skill tasks lead to modulation of PNN-GAGs in the FN of adult mice, as evidenced by fluorescent staining, while the mRNA levels of core proteins in PNNs remain unchanged. Upon enzymatic digestion of PNN-GAGs in the FN, treated mice exhibited improved motor performance and increased inhibitory synaptic terminals compared to controls. These findings suggest that PNNs in the FN play a crucial role in modulating motor skills.