Contribution of Na(v) channels to the development and function of the retina

Abstract

Voltage gated (Nav) channel isoforms are precisely located in the nervous system and expressed sequentially during development. Because Nav channels control the rising phase of action potentials isoform differences may play a fundamental role in neural encoding of information. However perinatal mortality, developmental compensation, and a lack of isoform specific small molecule blockers has limited the investigation into specific roles filled by Nav channels. Using the macroscopic light response of the whole retina I first investigated into the contribution of TTX-sensitive Nav channels as a function of light adaptation and in response to daily rhythms in ambient light. Further work using a Nav1.6 knockout mouse revealed a surprising role of Nav1.6 in retrograde signaling in the optic nerve following eye opening. This retroaxonal feedback mechanism operating while the retina is still developing after eye opening controls photoreceptor light sensitivity via TrkB receptors and appears to require Nav1.6 in the optic nerve.

Finally two projects focused specifically on the role of individual Nav channel isoforms in retinal signaling. First using a newly developed subtype specific blocker A803467 I investigated the function of Nav1.8 in the retina finding, in particular, a selective reduction in the oscillatory potentials (OPs) as well as a reduction in the light responses of sustained ON retinal ganglion cells. Secondly I developed a method using membrane permeablized antibodies to common Nav channel isoforms to identify unique contributions of each to retinal processing. In combination with small molecule blockers and a knockout mouse to Nav1.6 this method identified Nav1.6 as a key component of light responses in ON cone bipolar cells, as well as supporting the majority of spiking activity in retinal ganglion cells. Interestingly Nav1.1 appears to be predominately involved in sustaining spiking in response to longer duration stimuli rather than contributing to the amplitude of the spiking response. Together these results define new roles for Nav channel isoforms in the retina and optic nerve and contribute both to our understanding of how the retina uses the unique properties of Nav channel isoforms to adapt to visual input.