Scn2a haploinsufficient mice display a spectrum of phenotypes affecting anxiety, sociability, memory flexibility and ampakine CX516 rescues their hyperactivity

Abstract

Background Mutations of the SCN2A gene encoding a voltage-gated sodium channel alpha-II subunit Nav1.2 are associated with neurological disorders such as epilepsy, autism spectrum disorders, intellectual disability, and schizophrenia. However, causal relationships and pathogenic mechanisms underlying these neurological defects, especially social and psychiatric features, remain to be elucidated. Methods We investigated the behavior of mice with a conventional or conditional deletion of Scn2a in a comprehensive test battery including open field, elevated plus maze, light-dark box, three chambers, social dominance tube, resident-intruder, ultrasonic vocalization, and fear conditioning tests. We further monitored the effects of the positive allosteric modulator of AMPA receptors CX516 on these model mice. Results Conventional heterozygous Scn2a knockout mice ( Scn2a KO/+ ) displayed novelty-induced exploratory hyperactivity and increased rearing. The increased vertical activity was reproduced by heterozygous inactivation of Scn2a in dorsal-telencephalic excitatory neurons but not in inhibitory neurons. Moreover, these phenotypes were rescued by treating Scn2a KO/+ mice with CX516. Additionally, Scn2a KO/+ mice displayed mild social behavior impairment, enhanced fear conditioning, and deficient fear extinction. Neuronal activity was intensified in the medial prefrontal cortex of Scn2a KO/+ mice, with an increase in the gamma band. Conclusions Scn2a KO/+ mice exhibit a spectrum of phenotypes commonly observed in models of schizophrenia and autism spectrum disorder. Treatment with the CX516 ampakine, which ameliorates hyperactivity in these mice, could be a potential therapeutic strategy to rescue some of the disease phenotypes. Electronic supplementary material The online version of this article (10.1186/s13229-019-0265-5) contains supplementary material, which is available to authorized users.

Characterization of a gene-trap knockout mouse model ofScn2aencoding voltage-gated sodium channel Nav1.2

“…Juvenile behavior of Scn2a gtKO/gtKO mice remains to be tested. Also, Dr. Yasakawa's team at RIKEN Center in Japan has conducted extensive behavioral analysis in which most of the assays reveal no difference between WT and Scn2a +/− (males only) in body weight, hot plate, and auditory startle [13]. Similarly, our study of Scn2a WT/gtKO males show no statistically significant differences for these tests.…”

“…Canonical knock-out (null) of Scn2a in mice is perinatal lethal, therefore current studies focus on heterozygous Scn2a knockout mice (Scn2a +/− ) as the main model for study, which display only mild behavioral abnormalities. Scn2a +/− mice show little differences from wild-type (WT) mice in body weight, olfactory, auditory startle, thermal sensitivity, nesting, and marble burying [10] [11] [12] [13]. We reasoned that if we can substantially reduce the Scn2a expression level without eliminating it completely, the residual Scn2a protein may allow the mice to survive and to exhibit more severe phenotypes in adulthood than is observed in heterozygous knockout mice, thereby providing a novel model for the study of Scn2a deficiencyrelated biological processes.…”

SCN2A channelopathies in the autism spectrum of neuropsychiatric disorders: a role for pluripotent stem cells?

“…Nevertheless, Scn2a haploinsufficient mouse models (Scn2a +/− ) show significant phenotypes linked to human disease and have been used to further elucidate the role of Na V 1.2 in both normal neurodevelopment and disease. Scn2a +/− mice display mild absence-like seizures, delayed spatial learning, increased contextual fear learning, impaired fear extinction, and hyperactivity [42,46,75,76], all of which may be related to ASD symptoms in humans. Cortical neurons from these mice display impaired excitability and impaired excitatory synapse function [61].…”

“…To date, the Simons Foundation for Autism Research has listed 174 genes as "high confidence" for association with autism spectrum disorders [41]. SCN2A, which encodes the voltage-gated sodium channel Na V 1.2, is of particular interest as an in vitro model for several reasons, including the following: (1) It is among the most common monogenic sources of autism-causing mutations [19]; (2) Gain-of-function and loss-of-function mutations have both been identified in humans but with markedly different phenotypes (epilepsy vs autism/intellectual disability, respectively) [17], allowing for a compare-and-contrast opportunity between variants; (3) Several mouse models already exist which may complement iPSC models [42][43][44][45][46]; (4) Sodium channels are "druggable" targets [47][48][49][50]; and (5) Elucidation of the role of SCN2A in neural development and function may also contribute to the development of therapies to treat SCN2A-related diseases such as epilepsy, which is often intractable [51].…”

Home-cage Monitoring Ascertains Signatures of Ictal and Interictal Behavior In Mouse Models of Generalized Seizures

“…Aside from measurements of learning and memory, assessments of interictal emotional behavior in rodents have relied heavily on phenotyping batteries (23)(24)(25) to identify features of "depression-related" or "anxiety-related" behavior extrapolated from assessments of behavioral despair (e.g., forced swim test) or exploration (e.g., open field / elevated plus maze tests). While these tests are certainly convenient and offer a reasonably high throughput, they are short in duration (5-10 minutes long) and are often measured during the biological night (when lights are on).…”