The Transient Receptor Potential Vanilloid-1 Channel and Neuronal Survival in Degenerative Disease
Ward, Nicholas John
Neuronal responses to stress are an important component of neurodegenerative disease and may represent targets for therapeutic intervention. In normal and pathogenic physiological conditions, members of the transient receptor potential (TRP) family of cation channels have been implicated in transducing stress-related stimuli. Studies detailed in this document characterize the response of the vanilloid-1 TRP channel (TRPV1) to stress from elevated intraocular pressure (IOP) in a mouse model of glaucomatous optic neuropathy. Knockout of TRPV1 (<i>Trpv1</i>-/-) resulted in accelerated degeneration of retinal ganglion cells (RGCs) with elevated IOP. Compared to C57 controls, <i>Trpv1</i>-/- mice exhibited more extensive pathology in terms of axonal transport deficits, loss of RGC axons within the optic nerve, and loss of RGC somas in the retina. This accelerated pathology indicates that TRPV1 may mediate important survival mechanisms in response to IOP-induced stress of RGCs. Soon after IOP elevation, TRPV1 protein levels transiently increase within a layer of the retina associated with RGC dendrites and synapses. Likewise, TRPV1 localization near RGC synaptic active zones increases with IOP-induced stress, indicating a potential influence of TRPV1 on synaptic activity. Morphological studies of RGC dendrites demonstrated that TRPV1 does influence dendritic complexity, indicating a potential role for TRPV1 at synaptic sites in dendrites. The data indicate that TRPV1 may help RGCs survive in response to stress by influencing activity at RGC synapses.