EPIGENETIC REGULATION OF MICROGLIAL PHOSPHATIDYLINOSITOL 3-KINASE PATHWAY INVOLVED IN SYNAPTIC PLASTICITY IN RODENTS

Abstract

Microglia are the main form of immune defence in the central nervous system (CNS). Microglia express phosphatidylinositol 3-kinase (PI3K), shown to play a significant role in synaptic plasticity in neurons. This study shows that the microglial PI3K/AKT pathway is epigenetically regulated through miRNA targeting by miR-21-5p and histone modifications via HDAC3 resulting in changes in PI3K expression, the phosphorylation of AKT and the cAMP response element binding protein (CREB) and ultimately brain-derived neurotrophic factor (BDNF) expression, shown to be involved in neuronal LTP. Microglial PI3K was also found to be post-translationally regulated through sumoylation. Electrophysiological recordings in rat hippocampal slices show the involvement of this pathway in long-term potentiation (LTP) in neurons after PI3K and BDNF were able to rescue LTP following microglial ablation. Understanding the mechanisms by which microglial PI3K influences synapses provides insights into the ways it can modulate synaptic transmission and plasticity in learning and memory.