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Scn2a haploinsufficient mice display a spectrum of phenotypes affecting anxiety, sociability, memory flexibility and ampakine CX516 rescues their hyperactivity
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Scn2a haploinsufficient mice display a spectrum of phenotypes affecting anxiety, sociability, memory flexibility and ampakine CX516 rescues their hyperactivity
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Journal Article
Scn2a haploinsufficient mice display a spectrum of phenotypes affecting anxiety, sociability, memory flexibility and ampakine CX516 rescues their hyperactivity
2019
Overview
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.
Publisher
BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
Subject
/ Animals
/ Anxiety
/ Attention deficit hyperactivity disorder
/ Autism
/ Autism Spectrum Disorder - drug therapy
/ Autism Spectrum Disorder - genetics
/ Behavior
/ Dopamine
/ Epilepsy
/ Genes
/ Light
/ Male
/ Medicine
/ Membrane Transport Modulators - therapeutic use
/ Memory
/ Mice
/ Mutation
/ NAV1.2 Voltage-Gated Sodium Channel - genetics
/ Neurons
/ Patients
/ Piperidines - therapeutic use
/ Prefrontal Cortex - drug effects
/ Prefrontal Cortex - physiopathology
/ Psychomotor Agitation - drug therapy
/ Psychomotor Agitation - genetics
/ Rodents
/ Scn2a
/ Software
