Ocular Hypertension Drives Remodeling of AMPA Receptors in Select Populations of Retinal Ganglion Cells.

Asia L Sladek,Scott Nawy

doi:10.3389/fnsyn.2020.00030

Abstract

AMPA-type glutamate receptors in the CNS are normally impermeable to Ca2+, but the aberrant expression of Ca2+-permeable AMPA receptors (CP-AMPARs) occurs in pathological conditions such as ischemia or epilepsy, or 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 sustained alpha and Off transient alpha RGCs, and this increase was prevented by genomic editing of the GluA2 subunit. On sustained alpha 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 the influx of Ca2+ through CP-AMPARs. Thus, glaucoma may alter the composition of AMPARs and depress excitatory synaptic input in select populations of RGCs.

Highlights

Glaucoma is a neurodegenerative disease of retinal ganglion cells (RGCs) often associated with elevated intraocular pressure (IOP)
While early studies focused on the contribution of highly Ca2+-permeable NMDA receptors, ocular hypertension (OHT)-Induced Plasticity of Ca2+-Permeable AMPA Receptors recent studies have focused on the role of Ca2+-permeable AMPA receptors (CP-AMPAR; Wang et al, 2014; Cueva Vargas et al, 2015; Wen et al, 2018)
We show that elevation of IOP via injection of microbeads into the anterior chamber, a widely used experimental model for glaucoma (Sappington et al, 2010; ElDanaf and Huberman, 2015; Pang et al, 2015; Risner et al, 2018), FIGURE 5 | Genomic editing of the GluA2 Q/R site prevents remodeling of α On and transient Off RGCs by OHT. (A) Recordings from two α Off transient RGC from the ADAR2−/−:GluA2R/R mouse line, one showing responses to light and the other showing responses to puffs of AMPA at three holding potentials

Summary

INTRODUCTION

Glaucoma is a neurodegenerative disease of retinal ganglion cells (RGCs) often associated with elevated intraocular pressure (IOP). Within 1 week following the elevation of IOP, there are several morphological and functional changes in RGCs including deficits in axonal transport (Buckingham et al, 2008; Crish et al, 2010; Calkins, 2012; Ward et al, 2014), loss of dendrites and sites of synaptic contacts (Della Santina et al, 2013; El-Danaf and Huberman, 2015), spontaneous and light-evoked responses (Holcombe et al, 2008; Frankfort et al, 2013; Chen et al, 2015; Pang et al, 2015; Tao et al, 2019) and membrane excitability (Risner et al, 2018) It is currently unclear whether these previously described changes contribute directly to RGC death, or whether other yet to be described changes are critical.

MATERIALS AND METHODS

RESULTS

DISCUSSION

Findings

A Decrease in Synaptic Gain Is Associated With Elevated CP-AMPAR Expression