Ocular hypertension drives remodeling of AMPA receptors in select populations of retinal ganglion cells

Abstract

AMPA receptors in the CNS are normally impermeable to Ca2+ but aberrant expression of Ca2+-permeable AMPA receptors (CP-AMPARs) occurs in pathological conditions such as ischemia or epilepsy, or in degenerative diseases such as ALS. Here we show that select populations of retinal ganglion cells (RGCs) similarly express high levels of CP-AMPARs in a mouse model of glaucoma. CP-AMPAR expression increased dramatically in both On and transient Off RGCs, and this increase was prevented by genomic editing of the GluA2 Q/R site. On RGCs with elevated CP-AMPAR levels displayed profound synaptic depression, which was reduced by selectively blocking CP-AMPARs, buffering Ca2+ with BAPTA, or with the CB1 antagonist AM251, suggesting that depression was mediated by a retrograde transmitter which might be triggered by influx of Ca2+ through CP-AMPARs. Thus OHT alters the composition of AMPARs and modulates patterns of synaptic activity in select populations of RGCs.