Sensory neuron-specific sodium channel SNS is abnormally expressed in the brains of mice with experimental allergic encephalomyelitis and humans with multiple sclerosis

Abstract

Clinical abnormalities in multiple sclerosis (MS) have classically been considered to be caused by demyelination and͞or axonal degeneration; the possibility of molecular changes in neurons, such as the deployment of abnormal repertoires of ion channels that would alter neuronal electrogenic properties, has not been considered. Sensory Neuron-Specific sodium channel SNS displays a depolarized voltage dependence, slower activation and inactivation kinetics, and more rapid recovery from inactivation than classical ''fast'' sodium channels. SNS is selectively expressed in spinal sensory and trigeminal ganglion neurons within the peripheral nervous system and is not expressed within the normal brain. Here we show that sodium channel SNS mRNA and protein, which are not present within the cerebellum of control mice, are expressed within cerebellar Purkinje cells in a mouse model of MS, chronic relapsing experimental allergic encephalomyelitis. We also demonstrate SNS mRNA and protein expression within Purkinje cells from tissue obtained postmortem from patients with MS, but not in control subjects with no neurological disease. These results demonstrate a change in sodium channel expression in neurons within the brain in an animal model of MS and in humans with MS and suggest that abnormal patterns of neuronal ion channel expression may contribute to clinical abnormalities such as ataxia in these disorders.demyelinating diseases ͉ gene transcription ͉ ion channels M ultiple sclerosis (MS) has classically been considered to be a demyelinating disease in which clinical abnormalities are the result of damage to the insulating myelin sheath, which causes axonal conduction block (1, 2). Recently, increased attention has been focused on axonal degeneration in MS, and it has been suggested that axonal loss can produce persistent clinical deficits in MS (3, 4). Demyelination and axonal degeneration, however, do not necessarily underlie all of the clinical abnormalities that are observed in MS. The question of whether there are any changes in neurons that might affect their function in this disorder remains unanswered. In this regard, the possibility of molecular changes within neurons, such as deployment of abnormal repertoires of ion channels that would alter neuronal electrical signaling capability, has not received attention.The generation and transmission of electrical impulse activity in neurons depend on ion f luxes through voltage-gated sodium channels, which consist of large (230 -260 kDa) poreforming ␣-subunits and smaller modulatory ␤-subunits. At least 10 different genes encode distinct sodium channel ␣-subunits with a common overall motif (5) but with different amino acid sequences that underlie different voltage dependences and kinetic properties. The expression of different sodium channel isotypes in different types of neurons endows them with distinct patterns of electroresponsiveness and impulse generation (6 -11).Sensory neuron-specific sodium channel SNS (alternatively termed PN3, SCN1OA, and Nav 1.8) is a tet...

Functional reciprocity between Na + channel Na v 1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth

“…Although cerebellar neurons express TTX-sensitive VGSCs, TTX-resistant (TTX-R) Na v 1.8 is up-regulated under pathophysiological conditions (40)(41)(42). TTX-R Na v 1.5 channels also are upregulated in Scn1b null ventricular myocytes (12).…”

Roles of Voltage-Dependent Sodium Channels in Neuronal Development, Pain, and Neurodegeneration

“…In post-mortem analysis of human cerebellar Purkinje cells from multiple sclerosis patients, Na v 1.8 mRNA and protein levels were up-regulated, presumably being related to cerebellar ataxia seen in multiple sclerosis patients (37,48).…”

Channelopathy-related SCN10A gene variants predict cerebellar dysfunction in multiple sclerosis

“…It has been shown that Na V 1.8 channels are expressed ectopically in the cerebellar Purkinje neurons of patients with MS and mice with experimental autoimmune encephalomyelitis (EAE). 6,7 This channelopathy causes abnormal firing patterns in the cerebellar Purkinje cells 8,9 and motor coordination deficits in the absence of obvious signs of ataxia in mice models. 5 In this study, we aimed to examine the effects of potentially functional SCN10A genetic variations on clinical and imaging outcomes in patients with MS. We hypothesized that consistent with results from animal studies SCN10A genotype would affect performance in motor coordination tasks in MS, irrespective of gross clinical ataxia.…”