The role of protein arginine methyltransferase 8 (PRMT8) in dendritic spine maturation and development of excitatory synapses in neurons

Abstract

Most excitatory synapses can be found on tiny membranous protrusions of dendrites called dendritic spines. Dendritic spine maturation is crucial for structural stability of excitatory synapses and proper brain functions. The morphologies of dendritic spines are heterogeneous based on their level of maturation. Mature mushroom spine possesses a large mushroom-shaped spine head for proper signaling cascades and important functions in the adult brain like memory consolidation. Immature spines include stubby spines, thin spines and long filopodia. Filopodia are important for searching for synaptic partners in the early stage of development to establish proper neuronal network. Delayed spine maturation and altered spine morphologies along development would cause neurological disorders like Fragile-X syndrome and Autism.

Neuronal activity and local protein synthesis are required for dendritic spine maturation. It is achieved by trafficking of specific mRNAs to the distal dendrites for translation. One of the dendritic transcripts is Prmt8 that encodes protein arginine methyltransferase 8 (PRMT8) for catalyzing arginine methylation, a form of protein post-translational modification. PRMT8 is special compared to the other PRMTs because its tissue expression is restricted mainly in the brain. Recent study has reported many arginine methylated synaptic proteins. Nevertheless, how protein arginine methylation mediates synapse development and the function of PRMT8 underlying dendritic spine maturation remains to be elucidated. Another dendritic transcript is Strn4 which encodes Striatin-4 (STRN4), a postsynaptic scaffold protein that bind to multiple signaling proteins. The functions of both PRMT8 and STRN4 in neuron remain elusive. It would be of immense interest to study the functions of STRN4 in the development of dendritic spines.

Here we found that both Prmt8 mRNA and PRMT8 protein are dendritically localized. Interestingly, the protein expression of PRMT8 depends on neuronal activity and is up-regulated during dendritic spine maturation along hippocampal development. PRMT8 promotes dendritic spine maturation through its protein arginine methyltransferase activity. Depletion of PRMT8 by short hairpin RNA results in increasing density of immature filopodia and mis-localization of excitatory synapses. Dendritic spine defects are also observed in Prmt8 gene knockout neurons in vitro, and mushroom spines become elongated in the Prmt8 knockout hippocampus in vivo. The spine defects caused by PRMT8 depletion is associated with reduced sociability in the knockout mice. Taken together, the findings reveal an important role of PRMT8 as an arginine methyltransferase in hippocampus for proper excitatory synapse localization and dendritic spine maturation that is required for social behaviour. We further demonstrated the local expression of STRN4 depends on NMDA receptor activation, and STRN4 functions to specifically maintain mushroom spines. Our findings have therefore identified PRMT8 and STRN4 as important players in the control of spine morphogenesis, yet they play distinct roles in dendritic spine development.