Monday, March 21, 2022

Hyperexcitability in adult mice with severe deficiency in NaV1.2 channels

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Int J Physiol Pathophysiol Pharmacol. 2022 Feb 15;14(1):55-59. eCollection 2022.

ABSTRACT

Epilepsy is one of the most common neurological diseases. Epileptic individuals are faced with seizures, which are largely caused by enhanced neuronal excitability and/or decreased neuronal inhibitory activity. SCN2A encodes a neuronal voltage-gated sodium channel, NaV1.2 that is primarily found in excitatory neurons throughout the brain. NaV1.2 is most concentrated within the principal neurons of the corticostriatal circuit, which includes pyramidal neurons in the medial prefrontal cortex and medium spiny neurons in the striatum. In the early stage of adult development, the NaV1.2 channel plays critical roles in generation and propagation of action potentials in these neurons. Gain of Function variants of SCN2A results in unprovoked seizures and epilepsy, while loss-of-function variants of SCN2A is a leading cause for autism spectrum disorder as well as intellectual disability. Previous studies have shown that full deletion of Scn2a gene in mice is lethal and partial disruption of Scn2a gene (less than 50%) leads to inhibition of neuronal excitability. A recent study from Dr. Yang's laboratory revealed an unexpected result from mice with severe NaV1.2 deficiency and they demonstrated that severe deletion of Scn2a gene (around 68% gene disruption) in NaV1.2 triggers neuronal hyperexcitability in adult mice. Their findings may explain the puzzling clinical observation that certain individuals with NaV1.2 deficiency still develop unprovoked seizure. With the knowledge that using sodium-channel blockers simply exacerbates the seizure, the need for understanding the intrinsic nature of the NaV1.2 channel provides an important research topic in the future.

PMID:35310859 | PMC:PMC8918607

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