Project Summary
Neurons are able to restore their activity when challenged by external or internal perturbations. This form of
homeostatic response is crucial for the maintenance of neuronal or network stability during development and
normal brain function. During homeostatic synaptic plasticity (HSP), chronic suppression of neuronal activity
leads to a compensatory increase in synaptically localized AMPA receptors (AMPARs) and the intensity of
synaptic currents. Under basal conditions, AMPARs exist as GluA2-containing heterotetramers, mostly in the
form of GluA1/GluA2 or GluA2/GluA3. The GluA2-containing AMPARs are permeable to sodium but
impermeable to calcium. The resistance to calcium derives from a unique posttranscriptional modification of
GluA2 mRNA. Editing of adenosine to inosine by the adenosine deaminase enzyme ADAR2 switches a
glutamine (Q) to arginine (R) in GluA2, which confers calcium impermeability in AMPARs. Thus, inefficient
editing of GluA2 mRNA, or a lack of incorporation of GluA2 in an AMPAR channel complex, will lead to
calcium-permeable AMPARs (Cp-AMPARs). While the role for the Cp-AMPAR has been well recognized as
a key signaling molecule in HSP, the molecular nature and mechanisms regarding the biogenesis of the Cp-
AMPAR in HSP remains largely unknown. We hypothesize that during HSP, neuronal inactivity triggers
cellular responses in the location and activity of the ADAR2 enzyme, leading to unedited GluA2 and the
formation of GluA2(Q)-containing Cp-AMPARs. Also, the molecular substrates of the Cp-AMPAR calcium
cascade that are involved in homeostatic responses remain unknown. We hypothesize that Cp-AMPAR
activity leads to GluA1 acetylation which enables AMPAR synaptic accumulation, leading to the expression
of homeostatic plasticity. In this proposal, we aim to examine the molecular details underlying the regulation
of GluA2 editing for the biogenesis of Cp-AMPARs, as well as the subsequent modification of AMPARs by
acetylation and their contribution to the expression of homeostatic synaptic plasticity in vitro in primary
neurons and in vivo in the mouse visual cortex.