Abstract Severe reductions of vision and blindness due to ocular disease and trauma are major clinical problems that have serious consequences on the Veteran's quality of life. Optic neuropathies from injury to the retina and optic nerve are characterized by a loss of ganglion cells and their axons. Ganglion cell death is initiated by excessive intracellular Ca2+ levels followed by a cascade of deleterious cellular processes that result in apoptosis. Consistent with this observation is the enhancement of ganglion cell survival when reducing intracellular Ca2+ levels with Ca2+ channel and calcium permeable AMPA receptor (CP-AMPAR) selective blockers. The rationale underlying the proposed studies is that the reduction of ganglion cell intracellular Ca2+ levels is an important component of protective strategies for the treatment of ocular injury. Suppression of elevated intracellular Ca2+ levels would provide a window for initiating ganglion cell survival and axonal recovery therapies following injury. Proposed studies will test the hypothesis that suppression of elevated intracellular Ca2+ after optic nerve trauma enhances ganglion cell survival. Specific Aim 1 will determine the contributions of L-type Ca2+ channels and CP-AMPARs to ganglion cell Ca2+ levels following optic nerve injury. Investigations will determine A) the transcriptional and translational regulation of L-type Ca2+ channels, CP-AMPARs and the RNA-specific editing enzyme, ADAR2, and B) characterize the physiological and biophysical properties of the L-type Ca2+ channels and CP-AMPARs. Specific Aim 2 will test the hypothesis that pharmacological antagonism or genetic suppression by siRNA of L-type Ca2+ channels stabilizes ganglion cell Ca2+ levels and enhances ganglion cell survival after optic nerve injury. Investigations will test A) the action of the Ca2+ channel antagonist lomerizine on the expression and function of L-type Ca2+ channels, B) if siRNA-mediated reduction of L-type Ca2+ channel subunit expression decreases ganglion cell intracellular Ca2+ levels and C) whether these treatments enhance ganglion cell survival following optic nerve injury. Specific Aim 3 will test the hypothesis that pharmacological antagonism of AMPARs or genetic regulation of the AMPAR subunit, GluA2, the auxiliary subunit, GSG1L, or the editing enzyme, ADAR2, stabilizes ganglion cell intracellular Ca2+ levels, and enhances ganglion cell survival after optic nerve injury. Investigations will test if A) the CP-AMPAR blockers, philanthotoxin-433 and 1-naphthyl acetyl spermine and B) the siRNA-mediated reduction of GSG1L, which regulates GluA2 (edited and unedited) subunits and CP-AMPA expression, reduces ganglion cell Ca2+ permeability and intracellular Ca2+ levels; C) if GluA2(R) (edited) subunit or ADAR2 gene expression reduces ganglion cell Ca2+ permeability and intracellular Ca2+ levels and D) these pharmacological and genetic approaches enhance ganglion cell survival following optic nerve injury...