The protein arginine methyltransferase PRMT8 regulates actin polymerization that is crucial for dendritic spine maturation and social behavior

Abstract

Most excitatory synapses are located in the dendritic spines. Mature mushroom-shaped spines are crucial for memory consolidation, while immature long and thin filopodia may serve as the precursors of dendritic spines. Spine maturation requires neuronal activity and mRNAs trafficking for local protein translation. However, the functions of many dendritically localized transcripts remain uncharacterized. Interestingly, these include mRNAs that encode protein arginine methyltransferases (PRMTs). PRMTs catalyze arginine methylation, a protein post-translational modification (PTM) in the nucleus that regulates gene transcription and splicing. Among the nine PRMTs, PRMT8 is unique because of its anchorage to the plasma membrane and its brain-specific expression (Lee et al., 2005). PRMT8 also possesses the interesting properties of acting as both methyltransferase and phospholipase D (Kim et al., 2015). Recent studies have unraveled the significance of PRMT8 in memory formation (Penney et al., 2017), but the underlying cellular mechanism remains unclear. Here we demonstrate that PRMT8 is enriched in dendritic spines. The prmt8 mRNA is present in dendrites and the expression of PRMT8 protein in hippocampal neuron depends on spontaneous neuronal activity. The function of PRMT8 in regulating excitatory synapse development is determined through shRNA-mediated knockdown as well as PRMT8 knockout mice. Our findings indicate that PRMT8-mediated arginine methylation is a novel regulatory PTM at the synapse that controls dendritic spine maturation and localization of excitatory synapses.