Abstract
The transient receptor potential vanilloid member 1 (TRPV1) in the central nervous system may contribute to homeostatic plasticity by regulating intracellular Ca2+, 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.
Highlights
Transient receptor potential vanilloid member 1 (TRPV1) channels are activated by both physiologically relevant and pathological stimuli, conducting large Ca2+ currents that initiate downstream signaling cascades (Caterina et al, 1997; Hui et al, 2003; Patapoutian et al, 2009; Weitlauf et al, 2014)
We found that Trpv1−/− accelerates optic nerve axonopathy with elevated intraocular pressure (IOP), reducing nerve area, axon density, and axon transport to the brain (Ward et al, 2014)
We sought to determine the impact of Trpv1−/− with short-term IOP elevation on optic nerve signaling to the brain, using the evoked compound action potential (CAP)
Summary
Transient receptor potential vanilloid member 1 (TRPV1) channels are activated by both physiologically relevant and pathological stimuli, conducting large Ca2+ currents that initiate downstream signaling cascades (Caterina et al, 1997; Hui et al, 2003; Patapoutian et al, 2009; Weitlauf et al, 2014). We found that enhanced excitability in Trpv1−/− optic nerve was associated with longer axonal nodes of Ranvier with greater levels of the voltage-gated sodium channel, NaV1.6. These results suggest a role for TRPV1 in native tissue to regulate NaV in response to disease-relevant stressors. The absence of this tuning in Trpv1−/− mice suggests that accelerated axonopathy could arise from excessive excitation even as elevated IOP stresses match available metabolic resources in the optic projection to the brain (Baltan et al, 2010; Calkins, 2012)
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