Expression of Nav1.8 sodium channels perturbs the firing patterns of cerebellar Purkinje cells.
The sensory neuron specific sodium channel Na(v)1.8/SNS exhibits depolarized voltage-dependence of inactivation, slow inactivation and rapid repriming, which differentiate it from other voltage-gated sodium channels. Na(v)1.8 is normally selectively expressed at high levels in sensory ganglion neurons, but not within the CNS. However, expression of Na(v)1.8 mRNA and protein are upregulated within cerebellar Purkinje cells in animal models of multiple sclerosis (MS), and in human MS. To examine the effect of expression of Na(v)1.8 on the activity pattern of Purkinje cells, we biolistically introduced Na(v)1.8 cDNA into these cells in vitro. We report here that Na(v)1.8 can be functionally expressed at physiological levels (similar to the levels in DRG neurons where Na(v)1.8 is normally expressed) within Purkinje cells, and that its expression alters the activity of these neurons in three ways: first, by increasing the amplitude and duration of action potentials; second, by decreasing the proportion of action potentials that are conglomerate and the number of spikes per conglomerate action potential; and third, by contributing to the production of sustained, pacemaker-like impulse trains in response to depolarization. These results provide support for the hypothesis that the expression of Na(v)1.8 channels within Purkinje cells, which occurs in MS, may perturb their function.
Renganathan
M
M
Department of Neurology LCI-707and PVA/EPVA Neuroscience Research Center, Yale Medical School, P O Box 208018, New Haven, CT 06510, USA.
Gelderblom
M
M
Black
J A
JA
Waxman
S G
SG
D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D002531:Cerebellum / Q000502:physiology; D005727:Ganglia, Spinal / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009479:Neuropeptides / Q000096:biosynthesis* / Q000502:physiology; D011689:Purkinje Cells / Q000378:metabolism* / Q000502:physiology; D015222:Sodium Channels / Q000096:biosynthesis* / Q000502:physiology
D062559:NAV1.8 Voltage-Gated Sodium Channel; D009479:Neuropeptides; C568317:SCN10A protein, human; C568318:Scn10a protein, mouse; D015222:Sodium Channels