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.