Network‐based characterization of the synaptic proteome reveals that removal of epigenetic regulator Prmt8 restricts proteins associated with synaptic maturation

The brain adapts to dynamic environmental conditions by altering its epigenetic state, thereby influencing neuronal transcriptional programs. An example of an epigenetic modification is protein methylation, catalyzed by protein arginine methyltransferases (PRMT). One member, Prmt8, is selectively expressed in the central nervous system during a crucial phase of early development, but little else is known regarding its function. We hypothesize Prmt8 plays a role in synaptic maturation during development. To evaluate this, we used a proteome‐wide approach to characterize the synaptic proteome of Prmt8 knockout versus wild‐type mice. Through comparative network‐based analyses, proteins and functional clusters related to neurite development were identified to be differentially regulated between the two genotypes. One interesting protein that was differentially regulated was tenascin‐R (TNR). Chromatin immunoprecipitation demonstrated binding of PRMT8 to the tenascin‐r (Tnr) promoter. TNR, a component of perineuronal nets, preserves structural integrity of synaptic connections within neuronal networks during the development of visual‐somatosensory cortices. On closer inspection, Prmt8 removal increased net formation and decreased inhibitory parvalbumin‐positive (PV+) puncta on pyramidal neurons, thereby hindering the maturation of circuits. Consequently, visual acuity of the knockout mice was reduced. Our results demonstrated Prmt8′s involvement in synaptic maturation and its prospect as an epigenetic modulator of developmental neuroplasticity by regulating structural elements such as the perineuronal nets. We propose that PRMT8 is an epigenetic regulator of proteins associated with synaptic plasticity in the visual cortex. Characterization of the synaptic proteome of Prmt8 knockout mice revealed that perineuronal nets are up‐regulated. These nets perturb normal circuit development of the visual cortex, leading to poorer visual acuity. These results provide further insight to epigenetic regulation of plasticity in the visual cortex.