TRPV1 Tunes Optic Nerve Axon Excitability in Glaucoma.

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.

Towards A Microbead Occlusion Model of Glaucoma for a Non-Human Primate.

Glaucoma is a group of optic neuropathies associated with aging and sensitivity to intraocular pressure (IOP). The disease causes vision loss through the degeneration of retinal ganglion cell neurons and their axons in the optic nerve. Using an inducible model of glaucoma, we elevated IOP in the squirrel monkey (Saimiri boliviensis) using intracameral injection of 35 µm polystyrene microbeads and measured common pathogenic outcomes in the optic projection. A 42% elevation in IOP over 28 weeks reduced anterograde transport of fluorescently-labeled cholera toxin beta from retina to the lateral geniculate nucleus (60% decrease), and to the superior colliculus (49% decrease). Pressure also reduced survival of ganglion cellaxons in the optic nerve by 22%. The same elevation caused upregulation of proteins associated with glaucomatous neurodegeneration in the retina and optic nerve, including complement 1q, interleukin 6, and brain-derived neurotrophic factor. That axon degeneration in the nerve lagged deficits in anterograde transport is consistent with progression in rodent models, while the observed protein changes also occur in tissue from human glaucoma patients. Thus, microbead occlusion in a non-human primate with a visual system similar to our own represents an attractive model to investigate neurodegenerative mechanisms and therapeutic interventions for glaucoma.

Progression and Pathology of Traumatic Optic Neuropathy From Repeated Primary Blast Exposure.

Indirect traumatic optic neuropathy (ITON) is a condition that is often associated with traumatic brain injury and can result in significant vision loss due to degeneration of retinal ganglion cell (RGC) axons at the time of injury or within the ensuing weeks. We used a mouse model of eye-directed air-blast exposure to characterize the histopathology of blast-induced ITON. This injury caused a transient elevation of intraocular pressure with subsequent RGC death and axon degeneration that was similar throughout the length of the optic nerve (ON). Deficits in active anterograde axon transport to the superior colliculus accompanied axon degeneration and first appeared in peripheral representations of the retina. Glial area in the ON increased early after injury and involved a later period of additional expansion. The increase in area involved a transient change in astrocyte organization independent of axon degeneration. While levels of many cytokines and chemokines did not change, IL-1α and IL-1ß increased in both the ON and retina. In contrast, glaucoma shows distal to proximal axon degeneration with astrocyte remodeling and increases in many cytokines and chemokines. Further, direct traumatic optic neuropathies have a clear site of injury with rapid, progressive axon degeneration and cell death. These data show that blast-induced ITON is a distinct neuropathology from other optic neuropathies.

Rapid Repeat Exposure to Subthreshold Trauma Causes Synergistic Axonal Damage and Functional Deficits in the Visual Pathway in a Mouse Model.

We examined the effect of repeat exposure to a non-damaging insult on central nervous system axons using the optic projection as a model. The optic projection is attractive because its axons are spatially separated from the cell bodies, it is easily accessible, it is composed of long axons, and its function can be measured. We performed closed-system ocular neurotrauma in C57Bl/6 mice using bursts of 15 or 26-psi (pounds per square inch) overpressure air that caused no gross damage. We quantified the visual evoked potential (VEP) and total and degenerative axons in the optic nerve. Repeat exposure to a 15-psi air blast caused more axon damage and vision loss than a single exposure to a 26-psi air blast. However, an increased VEP latency was detected in both groups. Exposure to three 15-psi air blasts separated by 0.5 sec caused 15% axon degeneration at 2 weeks. In contrast, no axon degeneration above sham levels was detected when the interinjury interval was increased to 10 min. Exposure to 15-psi air blasts once a day for 6 consecutive days caused 3% axon degeneration. Therefore, repeat mild trauma within an interinjury interval of 1 min or less causes synergistic axon damage, whereas mild trauma repeated at a longer interinjury interval causes additive, cumulative damage. The synergistic damage may underlie the high incidence of traumatic brain injury and traumatic optic neuropathy in blast-injured service members given that explosive blasts are multiple injury events that occur in a very short time span. This study also supports the use of the VEP as a biomarker for traumatic optic neuropathy.

Antioxidants prevent inflammation and preserve the optic projection and visual function in experimental neurotrauma.

We investigated the role of oxidative stress and the inflammasome in trauma-induced axon degeneration and vision loss using a mouse model. The left eyes of male mice were exposed to over-pressure air waves. Wild-type C57Bl/6 mice were fed normal, high-vitamin-E (VitE), ketogenic or ketogenic-control diets. Mice lacking the ability to produce vitamin C (VitC) were maintained on a low-VitC diet. Visual evoked potentials (VEPs) and retinal superoxide levels were measured in vivo. Tissue was collected for biochemical and histological analysis. Injury increased retinal superoxide, decreased SOD2, and increased cleaved caspase-1, IL-1α, IL-1ß, and IL-18 levels. Low-VitC exacerbated the changes and the high-VitE diet mitigated them, suggesting that oxidative stress led to the increase in IL-1α and activation of the inflammasome. The injury caused loss of nearly 50% of optic nerve axons at 2 weeks and astrocyte hypertrophy in mice on normal diet, both of which were prevented by the high-VitE diet. The VEP amplitude was decreased after injury in both control-diet and low-VitC mice, but not in the high-VitE-diet mice. The ketogenic diet also prevented the increase in superoxide levels and IL-1α, but had no effect on IL-1ß. Despite this, the ketogenic diet preserved optic nerve axons, prevented astrocyte hypertrophy, and preserved the VEP amplitude. These data suggest that oxidative stress induces priming and activation of the inflammasome pathway after neurotrauma of the visual system. Further, blocking the activation of the inflammasome pathway may be an effective post-injury intervention.

Reduced frequency prenatal visits in midwifery practice: attitudes and use.

Recent research supports the use of reduced frequency prenatal visit schedules (RFVS) for women of low obstetric risk. However, for the RFVS to be widely adopted for use in practice, health care providers must implement and support its use. The purpose of this study was to explore midwives' attitudes toward and use of reduced frequency prenatal care visit schedules for the care of low-risk women. A descriptive, correlational study was conducted at the 1999 Annual Meeting of the American College of Nurse-Midwives with completed surveys received from 234 midwives. Seventy-two percent (n = 170) responded that they were familiar with the reduced frequency visit schedule. Of those, 71% agreed that they could give effective prenatal care by using reduced frequency scheduling, although few (17%) reported using it in practice. Significant differences were found between the midwives who were familiar versus those who were unfamiliar with the visit schedule in their perceptions for five central themes: 1) quality of care of the RFVS, 2) women's empowerment or self-care with the RFVS, 3) ability to manage practice, 4) patient satisfaction, and 5) barriers to the use of RFVS. Providers' responses to the use of RFVS have been mixed. Successful integration of this schedule into prenatal care services may require more than knowledge of its safety for low-risk women. Careful selection of women for whom the schedule is appropriate and a commitment from midwives to tailor prenatal care to the individual women's needs is indicated. Further research is also needed to evaluate the barriers that prevent midwives from using a reduced frequency visit schedule for the prenatal care of low-risk clients.