1. Short-term increases in transient receptor potential vanilloid-1 mediate stress-induced enhancement of neuronal excitation.
- Author
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Weitlauf C, Ward NJ, Lambert WS, Sidorova TN, Ho KW, Sappington RM, and Calkins DJ
- Subjects
- Action Potentials drug effects, Action Potentials physiology, Animals, Calcium metabolism, Capsaicin pharmacology, Cell Survival drug effects, Cell Survival physiology, Disease Models, Animal, Diterpenes pharmacology, Dopamine analogs & derivatives, Dopamine pharmacology, Glaucoma metabolism, Glaucoma physiopathology, Intraocular Pressure physiology, Mice, Mice, Knockout, Primary Cell Culture, Retinal Ganglion Cells drug effects, Retinal Ganglion Cells metabolism, TRPV Cation Channels agonists, TRPV Cation Channels antagonists & inhibitors, TRPV Cation Channels genetics, TRPV Cation Channels metabolism, Retinal Ganglion Cells physiology, Stress, Physiological physiology, TRPV Cation Channels physiology
- 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(-/-) retina. In isolated ganglion cells, pharmacologically activated TRPV1 mobilized to discrete nodes along ganglion cell dendrites that corresponded to sites of elevated Ca(2+). 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., (Copyright © 2014 the authors 0270-6474/14/3415369-13$15.00/0.)
- Published
- 2014
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