Cellular and behavioral effects of altered NaV1.2 sodium channel ion permeability in Scn2aK1422E mice.

Autor:	Echevarria-Cooper DM; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.; Northwestern University Interdepartmental Neuroscience Program, Northwestern University, Chicago, IL 60611, USA., Hawkins NA; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA., Misra SN; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.; Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA., Huffman AM; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA., Thaxton T; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA., Thompson CH; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA., Ben-Shalom R; Mind Institute and Department of Neurology, University of California, Davis, Sacramento, CA 95817, USA., Nelson AD; Department of Neurology, Kavli Institute for Fundamental Neuroscience, Weill Institute for Neurosciences, University of California, San Francisco, CA 94158, USA., Lipkin AM; Department of Neurology, Kavli Institute for Fundamental Neuroscience, Weill Institute for Neurosciences, University of California, San Francisco, CA 94158, USA.; Neuroscience Graduate Program, University of California, San Francisco, CA 94158, USA., George AL Jr; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.; Northwestern University Interdepartmental Neuroscience Program, Northwestern University, Chicago, IL 60611, USA., Bender KJ; Department of Neurology, Kavli Institute for Fundamental Neuroscience, Weill Institute for Neurosciences, University of California, San Francisco, CA 94158, USA., Kearney JA; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.; Northwestern University Interdepartmental Neuroscience Program, Northwestern University, Chicago, IL 60611, USA.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2022 Aug 25; Vol. 31 (17), pp. 2964-2988.
DOI:	10.1093/hmg/ddac087
Abstrakt:	Genetic variants in SCN2A, encoding the NaV1.2 voltage-gated sodium channel, are associated with a range of neurodevelopmental disorders with overlapping phenotypes. Some variants fit into a framework wherein gain-of-function missense variants that increase neuronal excitability lead to developmental and epileptic encephalopathy, while loss-of-function variants that reduce neuronal excitability lead to intellectual disability and/or autism spectrum disorder (ASD) with or without co-morbid seizures. One unique case less easily classified using this framework is the de novo missense variant SCN2A-p.K1422E, associated with infant-onset developmental delay, infantile spasms and features of ASD. Prior structure-function studies demonstrated that K1422E substitution alters ion selectivity of NaV1.2, conferring Ca2+ permeability, lowering overall conductance and conferring resistance to tetrodotoxin (TTX). Based on heterologous expression of K1422E, we developed a compartmental neuron model incorporating variant channels that predicted reductions in peak action potential (AP) speed. We generated Scn2aK1422E mice and characterized effects on neurons and neurological/neurobehavioral phenotypes. Cultured cortical neurons from heterozygous Scn2aK1422E/+ mice exhibited lower current density with a TTX-resistant component and reversal potential consistent with mixed ion permeation. Recordings from Scn2aK1442E/+ cortical slices demonstrated impaired AP initiation and larger Ca2+ transients at the axon initial segment during the rising phase of the AP, suggesting complex effects on channel function. Scn2aK1422E/+ mice exhibited rare spontaneous seizures, interictal electroencephalogram abnormalities, altered induced seizure thresholds, reduced anxiety-like behavior and alterations in olfactory-guided social behavior. Overall, Scn2aK1422E/+ mice present with phenotypes similar yet distinct from other Scn2a models, consistent with complex effects of K1422E on NaV1.2 channel function. (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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