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Absence of transient receptor potential vanilloid-1 accelerates stress-induced axonopathy in the optic projection
Nicholas J Ward1, Karen W Ho, Wendi S Lambert
1Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, Tennessee 37232-0654.
Abstract:
How neurons respond to stress in degenerative disease is of fundamental importance for identifying mechanisms of progression and new therapeutic targets. Members of the transient receptor potential (TRP) family of cation-selective ion channels are candidates for mediating stress signals, since different subunits transduce a variety of stimuli relevant in both normal and pathogenic physiology. We addressed this possibility for the TRP vanilloid-1 (TRPV1) subunit by comparing how the optic projection of Trpv1(-/-) mice and age-matched C57 controls responds to stress from elevated ocular pressure, the critical stressor in the most common optic neuropathy, glaucoma. Over a 5 week period of elevated pressure induced by microbead occlusion of ocular fluid, Trpv1(-/-) accelerated both degradation of axonal transport from retinal ganglion cells to the superior colliculus and degeneration of the axons themselves in the optic nerve. Ganglion cell body loss, which is normally later in progression, occurred in nasal sectors of Trpv1(-/-) but not C57 retina. Pharmacological antagonism of TRPV1 in rats similarly accelerated ganglion cell axonopathy. Elevated ocular pressure resulted in differences in spontaneous firing rate and action potential threshold current in Trpv1(-/-) ganglion cells compared with C57. In the absence of elevated pressure, ganglion cells in the two strains had similar firing patterns. Based on these data, we propose that TRPV1 may help neurons respond to disease-relevant stressors by enhancing activity necessary for axonal signaling.
Insights
Transient Receptor Potential Vanilloid-1 (TRPV1) channels may protect neurons from stress in optic neuropathies like glaucoma. Deleting TRPV1 in mice accelerated vision loss and nerve damage from elevated eye pressure.
Area of Science:
- Neuroscience
- Ophthalmology
- Ion Channel Physiology
Background:
- Neuronal stress responses are critical for understanding degenerative diseases and developing therapies.
- Transient Receptor Potential (TRP) ion channels are implicated in mediating stress signals in physiological and pathological contexts.
Purpose of the Study:
- To investigate the role of the TRP Vanilloid-1 (TRPV1) subunit in neuronal stress response within the optic projection.
- To determine if TRPV1 influences the progression of optic neuropathy under elevated ocular pressure.
Main Methods:
- Comparison of optic nerve stress response in Trpv1(-/-) mice and wild-type controls under induced elevated ocular pressure.
- Assessment of axonal transport, nerve degeneration, and retinal ganglion cell survival.
- Pharmacological antagonism of TRPV1 in rats subjected to elevated ocular pressure.
- Electrophysiological recordings of retinal ganglion cells.
Main Results:
- Trpv1(-/-) mice exhibited accelerated axonal transport degradation and optic nerve degeneration under elevated ocular pressure.
- Retinal ganglion cell body loss occurred earlier in Trpv1(-/-) mice, specifically in nasal sectors.
- Pharmacological TRPV1 blockade in rats also hastened axonopathy.
- Elevated ocular pressure altered ganglion cell firing rates and action potential thresholds differently in Trpv1(-/-) versus control mice.
Conclusions:
- TRPV1 may play a protective role in neuronal stress responses relevant to optic neuropathies.
- TRPV1 activity appears necessary for maintaining axonal signaling under disease-relevant stress.
- Targeting TRPV1 could offer a therapeutic strategy for conditions like glaucoma.
