CHARACTERISATION OF STRUCTURAL PLASTICITY OF THE VISUAL CORTEX IN PRMT8 NULL MICE?

Abstract

Epigenetics is the study of molecular switches that affect gene expression rather than the genetic sequences. The post-mitotic brain can, therefore, adapt to dynamic environmental conditions by altering its epigenetic state, thereby influencing neuronal transcriptional programs. One such epigenetic modification is protein methylation, catalysed by protein arginine methyltransferases (PRMT). One member, <i>Prmt8</i>, is selectively expressed in the central nervous system during a crucial phase of early development, but little is known regarding function. Using the dark-rearing deprivation paradigm, expression of <i>Prmt8</i> was discovered to be experience-dependent and highly regulated during a plasticity period in the visual cortex. Based in this expression pattern and its localization, I hypothesize <i>Prmt8</i> plays a role in synaptic maturation during development. To evaluate this, I used a proteome-wide approach (iTRAQ) to compare and characterize the synaptic proteome of <i>Prmt8</i> knockout versus wild type mice. Through 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). TNR, component of structures called perineuronal nets (PNNs), maintain structural integrity of synaptic connections within neuronal networks during the development of visual-somatosensory cortices. Chromatin immunoprecipitation confirmed PRMT8 binds to <i>tenascin-r</i> (<i>Tnr</i>) promoter. Upon closer inspection using various histology examination methods, removal of <i>Prmt8</i> increases 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 is reduced. Our results demonstrate <i>Prmt8</i>’s involvement in synaptic maturation and its prospect as an epigenetic modulator of developmental neuroplasticity by regulating elements such as the extracellular matrix.