ADAR2-mediated Q/R editing of GluA2 in homeostatic synaptic plasticity

Homeostatic synaptic plasticity is a negative feedback mechanism through which neurons modify their synaptic strength to counteract chronic increases or decreases in activity. In response to activity deprivation, synaptic strength is enhanced by increasing the number of AMPA receptors (AMPARs), particularly Ca²⁺-permeable AMPARs, at the synapse. Here, we found that this increase in Ca²⁺-permeable AMPARs during homeostatic upscaling was mediated by decreased posttranscriptional editing of GRIA2 mRNA encoding the AMPAR subunit GluA2. In cultured neurons, activity deprivation resulted in increases in the amount of unedited GluA2, such that its ion channel pore contains a glutamine (Q) codon instead of arginine (R), and in the number of Ca²⁺-permeable AMPARs at the synapse. These effects were mediated by a splicing factor-dependent decrease in ADAR2 abundance and activity in the nucleus. Overexpression of ADAR2 or CRISPR-Cas13-directed editing of GluA2 transcripts blocked homeostatic upscaling in activity-deprived primary neurons. In mice, dark rearing resulted in decreased Q-to-R editing of GluA2-encoding transcripts in the primary visual cortex (V1), and viral overexpression of ADAR2 in the V1 blocked the induction of homeostatic synaptic plasticity. The findings indicate that activity-dependent regulation of GluA2 editing contributes to homeostatic synaptic plasticity.