A PRMT5-ANGPTL4 axis in brain endothelial cells regulates cerebellar inhibitory synaptogenesis and motor coordination

Here, we explored its roles in synaptic development and motor function and found a cerebrovascular signaling axis wherein endothelial arginine methyltransferase PRMT5 promoted proper inhibitory synaptogenesis and motor coordination in male mice. Cerebrovascular-specific deletion of Prmt5 in mice led to excessive inhibitory synaptic input onto Purkinje cells and progressive motor deficits.

Mechanistically, Prmt5 deficiency epigenetically upregulated the expression of the secreted angiocrine ANGPTL4 through reduced symmetric dimethylation of H3R8 and H4R3, along with increased H3K9 acetylation at the Angptl4 promoter. Angptl4 deletion in brain endothelium normalized inhibitory synaptic input onto Purkinje cells and restored motor coordination in Prmt5-deficient mice. The findings identify the endothelial PRMT5-ANGPTL4 axis as a key regulator of cerebellar inhibitory circuitry and motor function, highlighting cerebrovascular mechanisms as potential therapeutic targets for motor coordination disorders