Axon hyperexcitability in the contralateral projection following unilateral optic nerve crush in mice

Optic neuropathies are characterized by degeneration of retinal ganglion cell axonal projections to the brain, including acute conditions like optic nerve trauma and progressive conditions such as glaucoma. Despite different aetiologies, retinal ganglion cell axon degeneration in traumatic optic neuropathy and glaucoma share common pathological signatures. We compared how early pathogenesis of optic nerve trauma and glaucoma influence axon function in the mouse optic projection. We assessed pathology by measuring anterograde axonal transport from retina to superior colliculus, current-evoked optic nerve compound action potential and retinal ganglion cell density 1 week following unilateral optic nerve crush or intraocular pressure elevation. Nerve crush reduced axon transport, compound axon potential and retinal ganglion cell density, which were unaffected by intraocular pressure elevation. Surprisingly, optic nerves contralateral to crush demonstrated 5-fold enhanced excitability in compound action potential compared with naive nerves. Enhanced excitability in contralateral sham nerves is not due to increased accumulation of voltage-gated sodium channel 1.6, or ectopic voltage-gated sodium channel 1.2 expression within nodes of Ranvier. Our results indicate hyperexcitability is driven by intrinsic responses of alpha ON-sustained retinal ganglion cells. We found alpha ON-sustained retinal ganglion cells in contralateral, sham and eyes demonstrated increased responses to depolarizing currents compared with those from naive eyes, while light-driven responses remained intact. Dendritic arbours of alpha ON-sustained retinal ganglion cells of the sham eye were like naive, but soma area and non-phosphorylated neurofilament H increased. Current- and light-evoked responses of sham alpha OFF-sustained retinal ganglion cells remained stable along with somato-dendritic morphologies. In retinas directly affected by crush, light responses of alpha ON- and alpha OFF-sustained retinal ganglion cells diminished compared with naive cells along with decreased dendritic field area or branch points. Like light responses, alpha OFF-sustained retinal ganglion cell current-evoked responses diminished, but surprisingly, alpha ON-sustained retinal ganglion cell responses were similar to those from naive retinas. Optic nerve crush reduced dendritic length and area in alpha ON-sustained retinal ganglion cells in eyes ipsilateral to injury, while crush significantly reduced dendritic branching in alpha OFF-sustained retinal ganglion cells. Interestingly, 1 week of intraocular pressure elevation only affected alpha OFF-sustained retinal ganglion cell physiology, depolarizing resting membrane potential in cells of affected eyes and blunting current-evoked responses in cells of saline-injected eyes. Collectively, our results suggest that neither saline nor sham surgery provide a true control, chronic versus acute optic neuropathies differentially affect retinal ganglion cells composing the ON and OFF pathways, and acute stress can have near-term effects on the contralateral projection. Acute and progressive neurodegeneration can impact tissues unaffected by the initial insult or locus of disease. McGrady et al. find that axons of alpha ON-sustained retinal ganglion cells initiate hyperexcitability in the optic nerve after crush injury in the opposing nerve. Thus, contralateral hyperexcitability could be an early indicator of neurodegeneration in the visual pathways to the brain.