[PS4] Parallel Session 4: Neurogenetics 1

[PS4-1D-K] Sodium Channel Gene Mutations and Epilepsy, Intellectual Disability and Autism

^○Kazuhiro YAMAKAWA (Laboratory for Neurogenetics, RIKEN Brain Science Institute, Saitama, Japan)

Mutations of Voltage-gated sodium channel genes have been described in patients with epilepsy and autism. Dravet syndrome, a highly intractable epileptic encephalopathy associated intellectual disability and autism, is caused by mutations of SCN1A encoding voltage-gated sodium channel alpha-1 subunit Nav1.1. In neocortex and hippocampus, Nav1.1 is dominantly expressed in parvalbumin-positive (PV+) and a minor amount in somatostatin-positive (Som+) inhibitory interneurons. Nav1.1 is also expressed in a distinct subpopulation of pyramidal cells in neocortex but hippocampal excitatory neurons are completely negative for Nav1.1. GABAergic neurons of reticular thalamic nucleus and thalamo-cortical projection neurons are positive for Nav1.1. Scn1a-knock-in mouse with a disease-relevant nonsense mutation caused epileptic seizures and sudden death. Selective Scn1a deletion in PV+ cells was sufficient to cause spontaneous epileptic seizures and sudden death, and that of Som+ cells was slightly contributes. Notably, selective Scn1a deletion in global inhibitory neurons caused severer epileptic seizures and premature death than those of constitutive Scn1a-deficient mice and it was rescued by additional Scn1a deletion in excitatory neurons in the mice. These results indicate that functional impairment of PV+ inhibitory neurons with Nav1.1 haploinsufficiency is the major cause for the epileptic pathology of Dravet syndrome, and that Nav1.1 haploinsufficiency in excitatory neurons has an ameliorating effect on it.
Mutations of SCN2A encoding Nav1.2 have also been described in patients with epilepsy and autism with a highest frequency but the expression sites of Nav1.1 and Nav1.2 are largely different to each other, suggesting highly distinct pathomechanisms.