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 (Scn2aKO/+) 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 Scn2aKO/+ mice with CX516. Additionally, Scn2aKO/+ mice displayed mild social behavior impairment, enhanced fear conditioning, and deficient fear extinction. Neuronal activity was intensified in the medial prefrontal cortex of Scn2aKO/+ mice, with an increase in the gamma band.

Conclusions:

Scn2aKO/+ 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.

• Authors: Tetsuya Tatsukawa, Matthieu Raveau, Ikuo Ogiwara, Satoko Hattori, Hiroyuki Miyamoto, Emi Mazaki, Shigeyoshi Itohara, Tsuyoshi Miyakawa, Mauricio Montal, Kazuhiro Yamakawa
• Journal: Molecular autism (Mol Autism) Vol. 10 Pg. 15 ( 2019) ISSN: 2040-2392 [Electronic] England
• PMID: 30962870 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 1-(quinoxalin-6-ylcarbonyl)piperidine
• Dioxoles
• Membrane Transport Modulators
• NAV1.2 Voltage-Gated Sodium Channel
• Piperidines

Topics

• Animals
• Anxiety (drug therapy, genetics)
• Autism Spectrum Disorder (drug therapy, genetics)
• Dioxoles (therapeutic use)
• Gamma Rhythm
• Haploinsufficiency
• Male
• Membrane Transport Modulators (therapeutic use)
• Memory
• Mice
• Mice, Inbred C57BL
• NAV1.2 Voltage-Gated Sodium Channel (genetics)
• Phenotype
• Piperidines (therapeutic use)
• Prefrontal Cortex (drug effects, physiopathology)
• Psychomotor Agitation (drug therapy, genetics)
• Social Behavior