Optic nerve injury impairs intrinsic mechanisms underlying electrical activity in a resilient retinal ganglion cell

Retinal ganglion cells (RGCs) are the sole output neurons of the retina and convey visual information to the brain via their axons in the optic nerve. Following injury to the optic nerve, RGC axons degenerate and many cells die. For example, a model of axon injury, the optic nerve crush (ONC), kills ∼80% of RGCs after 2 weeks. Surviving cells are biased towards 'resilient' types, including several with sustained firing to light stimulation. RGC survival may depend on activity, and there is limited understanding of how or why activity changes following optic nerve injury. Here we quantified the electrophysiological properties of a highly resilient RGC type, the sustained ON-Alpha (AlphaONS) RGC, 7 days after ONC with extracellular and whole-cell patch clamp recording. Both light- and current-driven firing were reduced after ONC, but synaptic inputs were largely intact. Resting membrane potential and input resistance were relatively unchanged, while voltage-gated currents were impaired, including a reduction in voltage-gated sodium channel current and channel density in the axon initial segment. Hyperpolarization or chelation of intracellular calcium partially rescued firing rates. Extracellular recordings at 3 days following ONC showed normal light-evoked firing from AlphaONS RGCs and other Alpha RGCs, including susceptible types. These data suggest that an injured resilient RGC reduces its activity by 1 week after injury as a consequence of reduced voltage-gated current and downregulation of intrinsic excitability via a Ca(2+)-dependent mechanism. Reduced excitability may be due to degradation of the axon but could also be energetically beneficial, preserving energy for survival and regeneration. KEY POINTS: Retinal ganglion cell (RGC) types show diverse rates of survival after axon injury. A resilient RGC type (sustained ON-Alpha RGC) maintains its synaptic inputs 1 week after injury. The resilient RGC type shows diminished firing and reduced expression of axon initial segment genes 1 week after injury Activity deficits reflect dysfunction of intrinsic properties (Na(+) channels, intracellular Ca(2+)), not changes to synaptic input. Both resilient and susceptible Alpha RGC types show intact firing at 3 days after injury, suggesting that activity at this time point does not predict resilience.