PRMT5-Cacna1d axis maintains calcium homeostasis to regulate postnatal motor development in mice.

Abstract

Epigenetic regulation of neuronal calcium signaling during postnatal cortical development is critical for voluntary movement. Protein arginine methyltransferase 5 (PRMT5) acts as an epigenetic regulator that is involved in movement disorders, yet its underlying mechanism remains poorly understood. Here, we report that conditional knockout of Prmt5 in excitatory neurons (cKO^Nex) during motor cortex development leads to severe hyperactivity and shortened lifespan in mice. Transcriptomics analysis reveals that PRMT5 deficiency upregulated Cacna1d expression without affecting its alternative splicing. We demonstrate that PRMT5 directly binds to the Cacna1d promoter, and represses its expression via catalyzing H4R3me2s histone methylation. Electrophysiological studies showed deletion of Prmt5 increased calcium influx and neuronal excitability, resulting from elevated L-type voltage-gated calcium channel (Cav1.3) activity. The enhanced calcium level further leads to oxidative phosphorylation defects in neurons. Importantly, administration of the L-type channel blocker, nimodipine, rescues hyperactivity and neuronal hyper-excitability in vivo, as well as markedly extends the lifespan of cKO^Nex mice. Our findings establish a novel epigenetic mechanism wherein PRMT5-Cacna1d axis regulates neuronal excitability and motor development. These data provide new insights into the calcium channelopathy of movement disorders.