Short-term increases in transient receptor potential vanilloid-1 mediate stress-induced enhancement of neuronal excitation.

Weitlauf C, Ward NJ, Lambert WS, Sidorova TN, Ho KW, Sappington RM, Calkins DJ
J Neurosci. 2014 34 (46): 15369-81

PMID: 25392504 · PMCID: PMC4228139 · DOI:10.1523/JNEUROSCI.3424-14.2014

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.

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MeSH Terms (16)

Action Potentials Animals Calcium Capsaicin Cell Survival Disease Models, Animal Diterpenes Dopamine Glaucoma Intraocular Pressure Mice Mice, Knockout Primary Cell Culture Retinal Ganglion Cells Stress, Physiological TRPV Cation Channels

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