Abstract
Early progression in neurodegenerative disease involves challenges to homeostatic processes, including those controlling axonal excitability and dendritic organization. In glaucoma, the leading cause of irreversible blindness, stress from intraocular pressure (IOP) causes degeneration of retinal ganglion cells (RGC) and their axons which comprise the optic nerve. Previously, we discovered that early progression induces axogenic, voltage-gated enhanced excitability of RGCs, even as dendritic complexity in the retina reduces. Here, we investigate a possible contribution of the transient receptor potential vanilloid type 1 (TRPV1) channel to enhanced excitability, given its role in modulating excitation in other neural systems. We find that genetic deletion of Trpv1 (Trpv1−/−) influences excitability differently for RGCs firing continuously to light onset (αON-Sustained) vs. light offset (αOFF-Sustained). Deletion drives excitability in opposing directions so that Trpv1−/− RGC responses with elevated IOP equalize to that of wild-type (WT) RGCs without elevated IOP. Depolarizing current injections in the absence of light-driven presynaptic excitation to directly modulate voltage-gated channels mirrored these changes, while inhibiting voltage-gated sodium channels and isolating retinal excitatory postsynaptic currents abolished both the differences in light-driven activity between WT and Trpv1−/− RGCs and changes in response due to IOP elevation. Together, these results support a voltage-dependent, axogenic influence of Trpv1−/− with elevated IOP. Finally, Trpv1−/− slowed the loss of dendritic complexity with elevated IOP, opposite its effect on axon degeneration, supporting the idea that axonal and dendritic degeneration follows distinctive programs even at the level of membrane excitability.
Highlights
Age-related neurodegenerative diseases involve diverse etiologies and phenotypes but share similar patterns of progression (Coleman, 2005; Morfini et al, 2009)
Our results demonstrate that while elevated intraocular pressure (IOP) enhances excitability in WT αON-S and αOFF-S retinal ganglion cell (RGC), it has an opposing influence on the same cell types in Trpv1−/− retina: decreasing excitability for αON-S RGCs while increasing it for αOFF-S cells
Our fundamental finding is that in the absence of induced stress, Trpv1−/− increases the light-driven excitability of αON-S RGCs while decreasing the excitability of αOFF-S RGCs (Figures 2, 4)
Summary
Age-related neurodegenerative diseases involve diverse etiologies and phenotypes but share similar patterns of progression (Coleman, 2005; Morfini et al, 2009). The disease involves sensitivity to intraocular pressure (IOP), which stresses retinal ganglion cell (RGC) axons where they exit the eye to form the optic nerve (Calkins, 2012). Short-term elevations in IOP transiently enhance RGC excitability, including their light response, even as dendritic arbors lose complexity (Weitlauf et al, 2014; Risner et al, 2018). Genetic ablation of the transient receptor potential vanilloid type 1 (TRPV1) channel (Trpv1−/−) increased NaV1.6 and excitability of RGC axons in the optic nerve following elevations in IOP (McGrady et al, 2020), while accelerating axon degeneration (Ward et al, 2014). Elevated IOP changes TRPV1’s net influence on RGC physiology from reducing to promoting excitation (Ward et al, 2014; Weitlauf et al, 2014)
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