Reduced Sodium Current in Purkinje Neurons from Na_V1.1 Mutant Mice: Implications for Ataxia in Severe Myoclonic Epilepsy in Infancy

Abstract

Loss-of-function mutations of Na V 1.1 channels cause severe myoclonic epilepsy in infancy (SMEI), which is accompanied by severe ataxia that contributes substantially to functional impairment and premature deaths. Mutant mice lacking Na V 1.1 channels provide a genetic model for SMEI, exhibiting severe seizures and premature death on postnatal day 15. Behavioral assessment indicated severe motor deficits in mutant mice, including irregularity of stride length during locomotion, impaired motor reflexes in grasping, and mild tremor in limbs when immobile, consistent with cerebellar dysfunction. Immunohistochemical studies showed that Na V 1.1 and Na V 1.6 channels are the primary sodium channel isoforms expressed in cerebellar Purkinje neurons. The amplitudes of whole-cell peak, persistent, and resurgent sodium currents in Purkinje neurons were reduced by 58 -69%, without detectable changes in the kinetics or voltage dependence of channel activation or inactivation. Nonlinear loss of sodium current in Purkinje neurons from heterozygous and homozygous mutant animals suggested partial compensatory upregulation of Na V 1.6 channel activity. Current-clamp recordings revealed that the firing rates of Purkinje neurons from mutant mice were substantially reduced, with no effect on threshold for action potential generation. Our results show that Na V 1.1 channels play a crucial role in the excitability of cerebellar Purkinje neurons, with major contributions to peak, persistent, and resurgent forms of sodium current and to sustained action potential firing. Loss of these channels in Purkinje neurons of mutant mice and SMEI patients may be sufficient to cause their ataxia and related functional deficits.

Specific deletion of Na V 1.1 sodium channels in inhibitory interneurons causes seizures and premature death in a mouse model of Dravet syndrome

“…Moreover, GABAergic interneurons in the hippocampus have a profound and selective loss of sodium current and electrical excitability in global loss-of-function mouse models of DS (14,17). However, studies of other GABAergic inhibitory neurons in the cerebellum, reticular nucleus of the thalamus, and cerebral cortex have revealed smaller losses of sodium currents and lesser impairments of excitability in our mouse model of DS (16,18,19). Therefore, these previous observations did not establish a causal relationship between the loss of sodium current and action potential firing in GABAergic interneurons and the hyperexcitability, seizure, and premature death in DS.…”

“…These global heterozygous mice exhibit temperature-induced and spontaneous seizures, mild ataxia, and premature death (14)(15)(16). Na V 1.1 channels are expressed in both excitatory and inhibitory neurons (3,6), yet electrophysiological studies in dissociated hippocampal neurons from DS mice showed selective loss of sodium current and excitability in GABAergic interneurons (14,17).…”

“…These results led to the hypothesis that the epilepsy and comorbidities of DS are caused by selective impairment of inhibitory interneuron function. However, subsequent studies have revealed lesser impairments of sodium current and excitability in GABAergic inhibitory neurons in the cerebellum, reticular nucleus of the thalamus, and cerebral cortex (16,18,19), so this hypothesis requires further validation.…”

Na V 1.1 channels are critical for intercellular communication in the suprachiasmatic nucleus and for normal circadian rhythms

“…Scn1a +/− mice are a genetic model for a devastating form of epilepsy, severe myoclonic epilepsy of infancy (SMEI) (15-17). Loss of firing of GABAergic neurons and the resulting disinhibition of neural circuits are hypothesized to be the underlying cause of epilepsy and comorbid ataxia in this disease (13,14,18). Homozygous Scn1a −/− mice are more severely impaired and die on postnatal day 15 (P15) (13).…”

Novel Animal Models of Pediatric Epilepsy

“…Recordings of cerebellar Purkinje neurons from mutant mice showed a reduction of sodium currents without any change in the kinetics or voltage dependence of channel activation or inactivation. These changes were responsible for a reduction of the firing rates [141].…”