Â鶹´«Ã½

developmental neurobiology, retina, sodium channel, Na(v)1.6, optic nerve, multiple sclerosis.

am interested in several aspects of the development and function of the nervous system in both health and disease. My group uses the mammalian retina to study neuronal biology because of its extensive postnatal development, layered cellular architecture, relatively simple circuitry, and accessibility. Indeed, because of these features, the retina is probably the best characterized part of the central nervous system. Here are two projects that are ongoing in my laboratory.

Role of a voltage gated sodium channel in retina development

Mice that have a mutation inÌýScn8a, the gene that encodes the voltage-gated sodium channel Na(v)1.6, have dramatically reduced retinal function according to electroretinogram (ERG) recordings (CôtéÌýet al, 2005; Smith and Côté, 2012). Interestingly, the visual defect originates at the level of the photoreceptors, the cells of the retina that initially capture light.


This observation is puzzling for two reasons:

1. photoreceptors are known to use graded ‘analog’-type signals to convey information to other cells while Na(v)1.6 is involved in the production and propagation of action potentials (all-or-nothing ‘binary’-type signals)


2. the expression of Na(v)1.6 in photoreceptors is very weak. For these reasons, it is perhaps more likely that other cell types in the retina that strongly express Na(v)1.6 need to communicate directly or indirectly with the photoreceptors during a critical period of development.

We are currently using cell biological and electrophysiological techniques to uncover the cellular pathways that link Na(v)1.6 and photoreceptor function.

Role of the voltage-gated sodium channel Nav1.6 in neuronal death following
demyelination

Voltage gated sodium channels (VGSCs) allow sodium to enter a cell in response to a reduction of the voltage across the cell membrane and are essential for the generation of the nerve impulse. In multiple sclerosis the usually tightly regulated placement and concentration of VGSCs along the axon is profoundly altered following demyelination. It is believed that an increase in Na(v)1.6, a type of VGSC that has a strong ability to allow persistent sodium entry, is an important factor in eventual neuron death.

This neuron death, in turn, is thought to cause many of the non-remitting aspects of multiple sclerosis and as such is of central importance. We wish to determine if eliminating or blocking Na(v)1.6 leads to reduced neuronal death and to assess whether other sodium channels with less propensity for persistent sodium conductance can preserve some ability of the nerve to conduct signals. We are currently using a combination of genetic and pharmacological approaches to address this issue. This research will allow us to determine the extent to which Na(v)1.6 is responsible for neuron death in an animal model of MS and may help validate Na(v)1.6 as a molecular target for the treatment of multiple sclerosis.

Selected Publications

Alrashdi, B., Dawod, B., Tacke, S., Kuerten, S., Côté, P. D., Marshall, J. S.Ìý(2021)ÌýMice Heterozygous for the Sodium Channel Scn8a (Nav1.6)ÌýHave Reduced Inflammatory Responses During EAE and Following LPSÌýChallenge.ÌýFrontiers in Immunology, 12, 533423

Smith, B. J., Côté, P. D., Tremblay, F. (2020) Voltage-gated sodiumÌýchannel-dependent retroaxonal modulation of photoreceptor functionÌýduring post-natal development in mice. Developmental Neurobiology, 2020 Nov 28. EpubÌýahead of print.

Alrashdi, B., Dawod, B., Schampel, A., Tacke, S., Kuerten, S., Marshall, J. S., & Côté, P. D. (2019). Nav1.6 promotes inflammation and neuronal degeneration in a mouse model of multiple sclerosis. Journal of neuroinflammation, 16(1), 215.

Smith BJ, Côté PD, Tremblay F. (2017)ÌýContribution of Nav1.8 sodium channels toÌýretinal function.ÌýNeuroscienceÌý340: 279–90.

Smith BJ, Côté PD, Tremblay F. (2015)ÌýDopamine modulation of rod pathwayÌýsignalingÌýbyÌýsuppression of GABAC feedback to rod-driven depolarizing bipolar cells. Eur J Neurosci. 42(6):2258-70.

Sato T, Fujita M, Shimizu Y, Kanetaka H, Chu LW, Côté PD, Ichikawa H. (2015) Glial reaction in the spinal cord of the degenerating muscle mouse (Scn8a (dmu)). Neurochem Res. 40(1):124-9.

Smith BJ, Côté PD, Tremblay F. (2015)ÌýD1 dopamine receptors modulate cone ON bipolar cell Nav channels to control daily rhythms in photopic vision. Chronobiol Int. 32(1):48-58.

Smith BJ, Wang X, Chauhan BC, Côté PD, Tremblay F. (2014) Contribution of retinal ganglion cells to the mouse electroretinogram. Doc Ophthalmol. 128(3):155-68.

Smith BJ, Tremblay F, Côté PD.Ìý(2013)ÌýVoltage-gated sodium channels contribute to the b-wave of the rodent electroretinogram by mediating input to rod bipolar cell
GABA(c) receptors.ÌýExp Eye Res. 116: 279-290.

Murphy JP, Côté PD, Pinto D. (2012)ÌýMonitoring the Switch: The Warburg Effect and Targeted Proteomic Analysis of Cancer Metabolism.ÌýCurr Proteomics.Ìý9 (1): 26-39.

Smith BJ , Côté PD (2012) Reduced Retinal Function in the Absence of Nav1.6. PLoS ONE 7(2): e31476. doi:10.1371/journal.pone.0031476

Sato T, Shimizu Y, Kano M, Suzuki T, Kanetaka H, Chu LW, Côté PD, Shimauchi H, Ichikawa H. (2011) Increase of CGRP expression in motor endplates within fore and hind limb muscles of the degenerating muscl. mouse (Scn8a(dmu)). Cell Mol Neurobiol. 31(1):155-61.

Ichikawa H, Kano M, Shimizu Y, Suzuki T, Sawada E, Ono W, Chu LW, Côté PD. (2010) Increase of c-Fos and c-Jun expression in spinal and cranial motoneurons of the degenerating muscle mouse (Scn8a(dmu)). Cell Mol Neurobiol. 30(5): 737-42.

Shafey D, Côté PD, De Repentigny Y, Kothary R. (2005) siRNA mediated knockdown of the Survival of Motor Neuron (Smn) protein in cell culture and in transgenic mice. Exp Cell Res 311(1): 49-61.

Côté PD, De Repentigny Y, Coupland SG, Schwab Y, Roux M, Levinson SR, Kothary R. (2005) Physiological maturation of photoreceptors depends on the voltage-gated sodium channel NaV1.6 (Scn8a). J Neurosci. 25 (20): 5046-50.

Côté PD, Moukhles H, Carbonetto S. (2002) Dystroglycan is not required for localization of dystrophin, syntrophin, and neuronal nitric-oxide synthase at the sarcolemma but regulates integrin alpha 7B expression and caveolin-3 distribution. J Biol Chem. 277 (7): 4672-9.

De Repentigny Y, Côté PD, Pool M, Bernier G, Girard S, Vidal SM, Kothary R.
(2001) Pathological and genetic analysis of the degenerating muscle (dmu) mouse: a new allele of Scn8a. Hum Mol Genet. 10 (17): 1819-27.

Jacobson C, Côté PD, Rossi SG, Rotundo RL, Carbonetto S. (2001) The dystroglycan complex is necessary for stabilization of acetylcholine receptor clusters at neuromuscular junctions and formation of the synaptic basement membrane. J Cell Biol. 152 (3): 435-50.

Côté PD, Moukhles H, Lindenbaum M, Carbonetto S. (1999) Chimaeric mice deficient in dystroglycans develop muscular dystrophy and have disrupted myoneural synapses. Nat Genet. 23 (3): 338-42. SEE ALSO NEWS AND VIEWS ARTICLE: Chamberlain J (1999) The dynamics of dystroglycan Nat Genet. 23 (3): 256-8.

Links