Voltage-gated sodium channel-dependent retroaxonal modulation of photoreceptor function during post-natal development in mice

Juvenile (postnatal day 16) mice lacking Na_v1.6 channels (null-mutant Scn8a^dmu) have reduced photoreceptor function, which is unexpected given that Na_v channels have not been detected in mouse photoreceptors and do not contribute appreciably to photoreceptor function in adults. We demonstrate that acute block of Na_v channels with intravitreal TTX in juvenile (P16) wild-type mice has no effect on photoreceptor function. However, reduced light activity by prolonged dark adaptation from P8 caused significant reduction in photoreceptor function at P16. Injecting TTX into the retrobulbar space at P16 to specifically block Na_v channels in the optic nerve also caused a reduction in photoreceptor function comparable to that seen at P16 in null-mutant Scn8a mice. In both P16 null-mutant Scn8a^dmu and retrobulbar TTX-injected wild-type mice, photoreceptor function was restored following intravitreal injection of the TrkB receptor agonist 7,8-dihydroxyflavone, linking Na_v-dependent retrograde transport to TrkB-dependent neurotrophic factor production pathways as a modulatory influence of photoreceptor function at P16. We also found that in Scn8a^dmu mice, photoreceptor function recovers by P22-25 despite more precarious general health of the animal. Retrobulbar injection of TTX in the wild type still reduced the photoreceptor response at this age but to a lesser extent, suggesting that Na_v-dependent modulation of photoreceptor function is largely transient, peaking soon after eye opening. Together, these results suggest that the general photosensitivity of the retina is modulated following eye opening by retrograde transport through activity-dependent retinal ganglion cell axonal signaling targeting TrkB receptors.