Short-Term Increases in Transient Receptor Potential Vanilloid-1 Mediate Stress-Induced Enhancement of Neuronal Excitation

Abstract

Progression of neurodegeneration in disease and injury is influenced by the response of individual neurons to stressful stimuli and whether this response includes mechanisms to counter declining function. Transient receptor potential (TRP) cation channels transduce a variety of disease-relevant stimuli and can mediate diverse stress-dependent changes in physiology, both presynaptic and postsynaptic. Recently, we demonstrated that knock-out or pharmacological inhibition of the TRP vanilloid-1 (TRPV1) capsaicin-sensitive subunit accelerates degeneration of retinal ganglion cell neurons and their axons with elevated ocular pressure, the critical stressor in the most common optic neuropathy, glaucoma. Here we probed the mechanism of the influence of TRPV1 on ganglion cell survival in mouse models of glaucoma. We found that induced elevations of ocular pressure increased TRPV1 in ganglion cells and its colocalization at excitatory synapses to their dendrites, whereas chronic elevation progressively increased ganglion cell Trpv1 mRNA. Enhanced TRPV1 expression in ganglion cells was transient and supported a reversal of the effect of TRPV1 on ganglion cells from hyperpolarizing to depolarizing, which was also transient. Short-term enhancement of TRPV1-mediated activity led to a delayed increase in axonal spontaneous excitation that was absent in ganglion cells from Trpv1 Ϫ/Ϫ retina. In isolated ganglion cells, pharmacologically activated TRPV1 mobilized to discrete nodes along ganglion cell dendrites that corresponded to sites of elevated Ca 2ϩ . These results suggest that TRPV1 may promote retinal ganglion cell survival through transient enhancement of local excitation and axonal activity in response to ocular stress.

Activation of transient receptor potential vanilloid-1 (TRPV1) influences how retinal ganglion cell neurons respond to pressure-related stress

“…34 In support of this hypothesis, additional results from our laboratory indicate that TRPV1 expression and localization in RGCs increases with short-term exposure to elevated ocular pressure and supports an enhanced excitatory influence on RGC activity. 35 Here we supplement our recent investigations by further characterizing the pattern of TRPV1 expression in RGCs and its influence on their survival. We report that like their rodent counterparts, RGCs in non-human primate and human retina express TRPV1 abundantly.…”

Nanosponge-Mediated Drug Delivery Lowers Intraocular Pressure

“…This increase in IOP is similar to other studies using this model in C57 mice. [41][42][43] Brimonidine Ocular pressure in C57 mice before microbead injection averaged 14.44 6 0.10 mm Hg (Fig. 2).…”

“…41,42 Injection of 1.5 lL of microbeads in C57 mice has produced ocular pressure elevations of 31% to 34% for up to 7 weeks. 43 The IOP was measured in anesthetized mice using a Tono-Pen (Reichert, Inc., Depew, NY) as described.…”

Selective Vulnerability of Specific Retinal Ganglion Cell Types and Synapses after Transient Ocular Hypertension

“…The differences from our study may be due to the fact that our MEA recordings were performed under light adapting background, thus identifying cone-driven light responses. Using the microbead occlusion model, Weitlauf et al (2014) showed that spontaneous activity actually increased at 4 weeks, but this analysis included a mixed population of ON, OFF, and ON-OFF RGCs and excluded RGCs with very low spontaneous firing rates (Ward et al, 2014). Indeed, the differences across studies to date underscore the importance of strain, model, IOP level, stage of degeneration, and the type of measurement when investigating patterns of RGC type-specific degeneration.…”