Mouse retinal ganglion cell signalling is dynamically modulated through parallel anterograde activation of cannabinoid and vanilloid pathways

Abstract

How retinal ganglion cells (RGCs) process and integrate synaptic, mechanical, swelling stimuli with light inputs is an area of intense debate. The nociceptive cation channel TRPV1 (transient receptor potential vanilloid type 1) modulates RGC Ca²⁺ signals and excitability yet the proportion of RGCs that express it remains unclear. Further, TRPV1's response to endocannabinoids (eCBs), the putative endogenous retinal activators unknown, as is the potential modulation by cannabinoid receptors (CBRs). The expression of TRPV1 in RGCs from the Ai9:Trpv1 reporter mouse was nonuniform with peak density in the early- and mid-peripheral retina. TRPV1 agonists including capsaicin (CAP) and the endocannabinoids (eCBs) anandamide and N-arachidonoyl-dopamine, elevated [Ca²⁺]_i in 30–40% of wild type RGCs, with effects suppressed by TRPV1 antagonists capsazepine (CPZ) and BCTC, and lacking in Trpv1^−/− cells. The cannabinoid receptor type 1 (CBR1) colocalized with TRPV1:tdTomato expression. Its agonists 2-arachidonoylglycerol (2-AG) and WIN55,122 inhibited CAP-induced [Ca²⁺]_i signals in adult, but not early postnatal, RGCs. The suppressive effect of 2-AG on TRPV1 activation was emulated by positive modulators of the protein kinase A pathway, inhibited by the CB1R antagonist rimonabant and G_i uncoupler pertussis toxin (PTX), and absent in Cnr1^−/− RGCs. We conclude that TRPV1 is a modulator of Ca²⁺ homeostasis in a subset of mouse RGCs that show peak expression in the mid-peripheral retina. Nonretrograde eCB-mediated modulation of RGC signalling involves a dynamic push-pull between direct TRPV1 activation and PKA-dependent regulation of channel inactivation, with potential functions in setting the bandwidth of postsynaptic responses, sensitivity to mechanical/excitotoxic stress and neuroprotection.

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