Severe deficiency of the voltage-gated sodium channel NaV1.2 elevates neuronal excitability in adult mice.

Scn2a encodes the voltage-gated sodium channel NaV1.2, a main mediator of neuronal action potential firing. The current paradigm suggests that NaV1.2 gain-of-function variants enhance neuronal excitability, resulting in epilepsy, whereas NaV1.2 deficiency impairs neuronal excitability, contributing to autism. However, this paradigm does not explain why ∼20%-30% of individuals with NaV1.2 deficiency still develop seizures. Here, we report the counterintuitive finding that severe NaV1.2 deficiency results in increased neuronal excitability. Using a NaV1.2-deficient mouse model, we show enhanced intrinsic excitability of principal neurons in the prefrontal cortex and striatum, brain regions known to be involved in Scn2a-related seizures. This increased excitability is autonomous and reversible by genetic restoration of Scn2a expression in adult mice. RNA sequencing reveals downregulation of multiple potassium channels, including KV1.1. Correspondingly, KV channel openers alleviate the hyperexcitability of NaV1.2-deficient neurons. This unexpected neuronal hyperexcitability may serve as a cellular basis underlying NaV1.2 deficiency-related seizures.

NaV1.2 haploinsufficiency in Scn2a knock-out mice causes an autistic-like phenotype attenuated with age.

Mutations of the SCN2A gene, encoding the voltage gated sodium channel NaV1.2, have been associated to a wide spectrum of epileptic disorders ranging from benign familial neonatal-infantile seizures to early onset epileptic encephalopathies such as Ohtahara syndrome. These phenotypes may be caused by either gain-of-function or loss-of-function mutations. More recently, loss-of-function SCN2A mutations have also been identified in patients with autism spectrum disorder (ASD) without overt epileptic phenotypes. Heterozygous Scn2a knock-out mice (Scn2a+/-) may be a model of this phenotype. Because ASD develops in childhood, we performed a detailed behavioral characterization of Scn2a+/- mice comparing the juvenile/adolescent period of development and adulthood. We used tasks relevant to ASD and the different comorbidities frequently found in this disorder, such as anxiety or intellectual disability. Our data demonstrate that young Scn2a+/- mice display autistic-like phenotype associated to impaired memory and reduced reactivity to stressful stimuli. Interestingly, these dysfunctions are attenuated with age since adult mice show only communicative deficits. Considering the clinical data available on patients with loss-of-function SCN2A mutations, our results indicate that Scn2a+/- mice constitute an ASD model with construct and face validity during the juvenile/adolescent period of development. However, more information about the clinical features of adult carriers of SCN2A mutations is needed to evaluate comparatively the phenotype of adult Scn2a+/- mice.

Impaired cortico-striatal excitatory transmission triggers epilepsy.

STXBP1 and SCN2A gene mutations are observed in patients with epilepsies, although the circuit basis remains elusive. Here, we show that mice with haplodeficiency for these genes exhibit absence seizures with spike-and-wave discharges (SWDs) initiated by reduced cortical excitatory transmission into the striatum. Mice deficient for Stxbp1 or Scn2a in cortico-striatal but not cortico-thalamic neurons reproduce SWDs. In Stxbp1 haplodeficient mice, there is a reduction in excitatory transmission from the neocortex to striatal fast-spiking interneurons (FSIs). FSI activity transiently decreases at SWD onset, and pharmacological potentiation of AMPA receptors in the striatum but not in the thalamus suppresses SWDs. Furthermore, in wild-type mice, pharmacological inhibition of cortico-striatal FSI excitatory transmission triggers absence and convulsive seizures in a dose-dependent manner. These findings suggest that impaired cortico-striatal excitatory transmission is a plausible mechanism that triggers epilepsy in Stxbp1 and Scn2a haplodeficient mice.