Molecular Mechanisms of Homeostatic Synaptic Plasticity

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Neurons are able to restore their activity when challenged by external or internal perturbations. This type of homeostatic plasticity is important for the maintenance of neuronal or network stability during development and normal brain function. During homeostatic synaptic plasticity, chronic suppression of neuronal activity leads to a compensatory increase in synaptically distributed AMPA receptors (AMPARs) and the intensity of synaptic currents. AMPARs are heterotetrameric channels composed of GluA1-4 subunits. Compared to regular GluA2-containing AMPARs that permit only sodium, GluA2-lacking receptors are permeable to both sodium and calcium. GluA2-lacking, calcium-permeable AMPARs (Cp-AMPARs) are formed during neuronal inhibition and are required for the expression of homeostatic plasticity. However, the molecular mechanisms underlying Cp-AMPAR biogenesis during homeostatic regulation remain largely unknown. We have discovered that miR124, a brain-enriched microRNA (miRNA), suppresses GluA2 translation by targeting the 3'-UTR of GluA2 mRNA, leading to the formation of Cp-AMPARs. Importantly, we found that inhibition of miR124 function abolished inactivity-induced homeostatic regulation. Therefore, we hypothesize that inactivity up-regulates miR124 expression via epigenetic modification, resulting in GluA2 translational suppression and formation of Cp-AMPARs, thus leading to the expression of homeostatic synaptic plasticity. In this proposed study, we will investigate the molecular details in the regulation of miR124 expression and the role of miR124 in GluA2 expression and Cp-AMPAR biogenesis. Furthermore, we will investigate the epigenetic control of miR124 expression by the inhibitory transcription factor EVI and its co-factor, the deacetylase HDAC1. More importantly, we will investigate the involvement of miRNA and the EVI transcriptional complex in the expression of homeostatic plasticity in vitro and in vivo. These studies will shed new light on our understanding of neural functional homeostasis and network stability. Elucidation of Cp-AMPAR biogenesis will also have an impact on clinical studies, as Cp-AMPARs have been implicated in disorders such as stroke, ALS and drug addiction.