Côté, Patrice
Permanent URI for this collectionhttps://hdl.handle.net/10222/22294
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Item Open Access The dystroglycan complex is necessary for stabilization of acetylcholine receptor clusters at neuromuscular junctions and formation of the synaptic basement membrane(2001-02) Jacobson, C.; Cote, Patrice D.; Rossi, SG; Rotundo, RL; Carbonetto, S.The dystrophin-associated protein (DAP) complex spans the sarcolemmal membrane linking the cytoskeleton to the basement membrane surrounding each myofiber. Defects in the DAP complex have been linked previously to a variety of muscular dystrophies, Other evidence points to a role for the DAP complex in formation of nerve-muscle synapses. We show that myotubes differentiated from dystroglycan(-/-) embryonic stem cells are responsive to agrin, but produce acetyl choline receptor (AChR) clusters which are two to three times larger in area, about half as dense, and significantly less stable than those on dystroglycan+/+ myotubes, AChRs at neuromuscular junctions are similarly affected in dystroglycan-deficient chimeric mice and there is a coordinate increase in nerve terminal size at these junctions. In culture and in vivo the absence of dystroglycan disrupts the localization to AChR clusters of laminin, perlecan, and acetylcholinesterase (AChE), but not rapsyn or agrin. Treatment of myotubes in culture with laminin induces AChR clusters on dystroglycan+/+, but not -/- myotubes, These results suggest that dystroglycan is essential for the assembly of a synaptic basement membrane, most notably by localizing AChE through its binding to perlecan, In addition. they suggest that dystroglycan functions in the organization and stabilization of AChR clusters, which appear to be mediated through its binding of laminin.Item Open Access Reduced Retinal Function in the Absence of Na(v)1.6(2012-02) Smith, Benjamin J.; Cote, Patrice D.Background: Mice with a function-blocking mutation in the Scn8a gene that encodes Na(v)1.6, a voltage-gated sodium channel (VGSC) isoform normally found in several types of retinal neurons, have previously been found to display a profoundly abnormal dark adapted flash electroretinogram. However the retinal function of these mice in light adapted conditions has not been studied. Methodology/Principal Findings: In the present report we reveal that during light adaptation these animals are shown to have electroretinograms with significant decreases in the amplitude of the a-and b-waves. The percent decrease in the a-and b-waves substantially exceeds the acute effect of VGSC block by tetrodotoxin in control littermates. Intravitreal injection of CoCl2 or CNQX to isolate the a-wave contributions of the photoreceptors in littermates revealed that at high background luminance the cone-isolated component of the a-wave is of the same amplitude as the a-wave of mutants. Conclusions/Significance: Our results indicate that Scn8a mutant mice have reduced function in both rod and the cone retinal pathways. The extent of the reduction in the cone pathway, as quantified using the ERG b-wave, exceeds the reduction seen in control littermates after application of TTX, suggesting that a defect in cone photoreceptors contributes to the reduction. Unless the postreceptoral component of the a-wave is increased in Scn8a mutant mice, the reduction in the b-wave is larger than can be accounted for by reduced photoreceptor function alone. Our data suggests that the reduction in the light adapted ERG of Scn8a mutant mice is caused by a combination of reduced cone photoreceptor function and reduced depolarization of cone ON bipolar cells. This raises the possibility that Na(v)1.6 augments signaling in cone bipolar cells.