Abstract
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.
Highlights
Mutations of the SCN2A gene, which encodes the voltage-gated sodium channel Nav1.2, have been associated to a wide spectrum of epileptic disorders ranging from mild forms, as benign familial neonatal-infantile seizures (BFNIS), to very severe ones, as early-infantile epileptic encephalopathies, Ohtahara syndrome or West syndrome[1,2,3,4,5,6]
Because SCN2A haploinsufficiency has been proposed to be linked to autism spectrum disorder (ASD), in the present study we undertook a detailed behavioral characterization of Scn2a+/− mice focused on behavioral tasks relevant to ASD and the different comorbidities frequently found in this disorder, such as anxiety or intellectual disability
Our study demonstrates that Nav1.2 haploinsufficiency in mice -modeling heterozygous Nav1.2 complete loss-of-function associated with mutations identified in humans- causes a self-limited autistic-like phenotype, which is attenuated with age
Summary
Mutations of the SCN2A gene, which encodes the voltage-gated sodium channel Nav1.2, have been associated to a wide spectrum of epileptic disorders ranging from mild forms, as benign familial neonatal-infantile seizures (BFNIS), to very severe ones, as early-infantile epileptic encephalopathies, Ohtahara syndrome or West syndrome[1,2,3,4,5,6]. Expression of Nav1.2 channels in axon initial segments of glutamatergic neurons shows a developmental pattern: Nav1.2 is the only subtype present in the first post-natal days, and is partially replaced by Nav1.6 during maturation, at around the third week of age in mice[13,22]. These spatial and temporal patterns of expression add to the complexity of genotype-phenotype relationships associated with SCN2A mutations. Since ASD appears during early childhood, we have analyzed the behavioral phenotype of these mice at two developmental stages, the juvenile/adolescent period and the adulthood
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