TRPV1 Tunes Optic Nerve Axon Excitability in Glaucoma

摘要

The transient receptor potential vanilloid member 1 (TRPV1) in the central nervous system may contribute to homeostatic plasticity by regulating intracellular Ca ~(2+), which becomes unbalanced in age-related neurodegenerative diseases, including Alzheimer’s and Huntington’s. Glaucomatous optic neuropathy – the world’s leading cause of irreversible blindness – involves progressive degeneration of retinal ganglion cell (RGC) axons in the optic nerve through sensitivity to stress related to intraocular pressure (IOP). In models of glaucoma, genetic deletion of TRPV1 ( Trpv1 ~(–/–) ) accelerates RGC axonopathy in the optic projection, whereas TRPV1 activation modulates RGC membrane polarization. In continuation of these studies, here, we found that Trpv1 ~(–/–) increases the compound action potential (CAP) of optic nerves subjected to short-term elevations in IOP. This IOP-induced increase in CAP was not directly due to TRPV1 channels in the optic nerve, because the TRPV1-selective antagonist iodoresiniferatoxin had no effect on the CAP for wild-type optic nerve. Rather, the enhanced CAP in Trpv1 ~(–/–) optic nerve was associated with increased expression of the voltage-gated sodium channel subunit 1.6 (NaV1.6) in longer nodes of Ranvier within RGC axons, rendering Trpv1 ~(–/–) optic nerve relatively insensitive to NaV1.6 antagonism via 4,9-anhydrotetrodotoxin. These results indicate that with short-term elevations in IOP, Trpv1 ~(–/–) increases axon excitability through greater NaV1.6 localization within longer nodes. In neurodegenerative disease, native TRPV1 may tune NaV expression in neurons under stress to match excitability to available metabolic resources.