Activity-dependent regulation of AMPA receptor calcium permeability and acetylation in homeostatic synaptic plasticity
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Abstract
The ability for neurons to alter their activity in response to stimuli is necessary for brain function, but restraining activities within a physiological range is also critical for neural stability. This challenge of balancing stability with adaptability is overcome by a negative feedback mechanism known as homeostatic plasticity. Homeostatic plasticity is a collection of processes by which neurons sense their own activity levels and adjust to regain functional homeostasis. While multiple cellular mechanisms underly homeostatic plasticity, activity of individual neurons is maintained by regulating the strength of synaptic inputs in a process known as homeostatic synaptic plasticity (HSP). HSP is mediated mainly by alterations to the abundance of AMPA receptors (AMPARs) on the postsynaptic membrane. After chronic activity deprivation, levels of synaptic AMPARs are increased to strengthen the synaptic drive. HSP is dysregulated in many neurological disorders, and is emerging as a therapeutic target for diseases such as Alzheimer’s disease and major depressive disorder. Previous work has shown that the formation of calcium permeable AMPARs (Cp-AMPARs) is a necessary precursor to HSP induction, but the molecular mechanisms underlying Cp-AMPAR formation after activity deprivation are unclear. The goals of this research are to identify the mechanisms underlying biogenesis of Cp-AMPARs after activity deprivation and identify downstream effects of increased calcium that contribute to HSP expression. We found that Cp-AMPARs are generated due to an activity-dependent change in mRNA editing of the AMPAR subunit GluA2, which confers AMPAR calcium permeability in primary murine neurons and in the mouse visual cortex. This editing change is mediated by decreased expression and enzymatic activity of the editing enzyme adenosine acting on RNA 2 (ADAR2). Regulation of ADAR2 and GluA2 editing are necessary for Cp-AMPAR generation and HSP induction. Secondly, increased AMPAR-derived calcium induces acetylation of the AMPAR subunit GluA1 which leads to synaptic retention of the GluA1-containing AMPARs that is necessary for HSP expression. Together, this study uncovers molecular mechanisms underlying the induction and maintenance of HSP expression.
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2025