VRC: Reduction of Vision Loss with Early Interventions After Optic Nerve Injury

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Abstract Ocular injury due to blast, blunt-force trauma and penetrating injuries have dramatic consequences on the clinical management of injured soldiers, Veterans and community members, and their quality of life after injury. Visual dysfunctions caused by traumatic brain injury, combat ocular trauma and glaucoma include blurred vision, photophobia, visual field defects, loss of acuity and blindness. These clinical signs are often due to ocular injury that leads to retinal ganglion cell and optic nerve degeneration, and retinal cell death. Molecular and cellular changes concomitant with ocular injury include the early dysregulation of voltage-gated calcium (Ca2+) channels and AMPA glutamate receptors, which in turn contributes to excessive intracellular Ca2+ flux into ganglion cells. Excessive Ca2+ has deleterious effects on cellular metabolism and signaling leading to cell death. These findings suggest the enhancement of ganglion cell survival can be increased by blocking the early influx of Ca2+ into ganglion cells after injury. Proposed investigations are focused on testing two pharmacological compounds, a L/T-type Ca2+ channel antagonist, lomerizine and a highly selective AMPA glutamate receptor antagonist, perampanel. We will test the action of these drugs on 1) short- and long-term ganglion cell survival, dendritic morphology, synaptic connectivity and visual function after optic nerve injury, and 2) maintaining visual behaviors. Investigations will focus on the well understood interplexiform retinal ganglion cell (ipRGCs) as a model ganglion cell model and test if these drugs preserve their morphological properties and behavioral functions following optic nerve injury. Specific Aim 1 will test if perampanel and lomerizine enhance ipRGC survival after optic nerve injury and preserve their dendritic morphology and synaptic connectivity. Specifically, investigations will determine if these drugs A) enhance ganglion cell survival, B) preserve ipRGC morphology and C) preserve ipRGC synaptic connectivity. Specific Aim 2 will test if perampanel and lomerizine restore ipRGC mediated behavioral function after optic nerve injury. Investigations will test visual behaviors mediated by ipRGCs including A) circadian rhythms, B) pupillary light reflex and C) light perception/aversion. These novel pharmacological approaches will lead to better understanding of fundamental processes mediating intracellular Ca2+ flux and the impact of excessive Ca2+ flux on ganglion cell degeneration. These studies will set the stage for the development of therapeutic approaches and diagnostic tools essential for the treatment and prevention of ocular damage, consistent with the health-related goals of the NEI to prevent impaired vision and blindness.