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TRPV1 Supports Axogenic Enhanced Excitability in Response to Neurodegenerative Stress.
Front Cell Neurosci. 2020; 14:603419.FC

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.

Authors+Show Affiliations

Department of Ophthalmology and Visual Sciences, Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN, United States.Department of Ophthalmology and Visual Sciences, Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN, United States.Department of Ophthalmology and Visual Sciences, Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN, United States.Department of Ophthalmology and Visual Sciences, Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN, United States.Department of Ophthalmology and Visual Sciences, Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN, United States.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

33505248

Citation

Risner, Michael L., et al. "TRPV1 Supports Axogenic Enhanced Excitability in Response to Neurodegenerative Stress." Frontiers in Cellular Neuroscience, vol. 14, 2020, p. 603419.
Risner ML, McGrady NR, Boal AM, et al. TRPV1 Supports Axogenic Enhanced Excitability in Response to Neurodegenerative Stress. Front Cell Neurosci. 2020;14:603419.
Risner, M. L., McGrady, N. R., Boal, A. M., Pasini, S., & Calkins, D. J. (2020). TRPV1 Supports Axogenic Enhanced Excitability in Response to Neurodegenerative Stress. Frontiers in Cellular Neuroscience, 14, 603419. https://doi.org/10.3389/fncel.2020.603419
Risner ML, et al. TRPV1 Supports Axogenic Enhanced Excitability in Response to Neurodegenerative Stress. Front Cell Neurosci. 2020;14:603419. PubMed PMID: 33505248.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - TRPV1 Supports Axogenic Enhanced Excitability in Response to Neurodegenerative Stress. AU - Risner,Michael L, AU - McGrady,Nolan R, AU - Boal,Andrew M, AU - Pasini,Silvia, AU - Calkins,David J, Y1 - 2021/01/11/ PY - 2020/09/06/received PY - 2020/12/15/accepted PY - 2021/1/28/entrez PY - 2021/1/29/pubmed PY - 2021/1/29/medline KW - TRPV1 KW - axon KW - dendritic pruning KW - glaucoma KW - neurodegeneration KW - retinal ganglion cells SP - 603419 EP - 603419 JF - Frontiers in cellular neuroscience JO - Front Cell Neurosci VL - 14 N2 - 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. SN - 1662-5102 UR - https://www.unboundmedicine.com/medline/citation/33505248/TRPV1_Supports_Axogenic_Enhanced_Excitability_in_Response_to_Neurodegenerative_Stress_ L2 - https://doi.org/10.3389/fncel.2020.603419 DB - PRIME DP - Unbound Medicine ER -
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