Abstract
Mutations in the voltage-gated sodium channel SCN1A are responsible for a number of seizure disorders including Generalized Epilepsy with Febrile Seizures Plus (GEFS+) and Severe Myoclonic Epilepsy of Infancy (SMEI). To determine the effects of SCN1A mutations on channel function in vivo, we generated a bacterial artificial chromosome (BAC) transgenic mouse model that expresses the human SCN1A GEFS+ mutation, R1648H. Mice with the R1648H mutation exhibit a more severe response to the proconvulsant kainic acid compared with mice expressing a control Scn1a transgene. Electrophysiological analysis of dissociated neurons from mice with the R1648H mutation reveal delayed recovery from inactivation and increased use-dependent inactivation only in inhibitory bipolar neurons, as well as a hyperpolarizing shift in the voltage dependence of inactivation only in excitatory pyramidal neurons. These results demonstrate that the effects of SCN1A mutations are cell type-dependent and that the R1648H mutation specifically leads to a reduction in interneuron excitability.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Newborn
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Arginine / genetics
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Biophysical Phenomena
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Cells, Cultured
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Chromosomes, Artificial, Bacterial / physiology*
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Disease Models, Animal*
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Dose-Response Relationship, Drug
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Electroencephalography / methods
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Electromyography / methods
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Epilepsy, Generalized / chemically induced
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Epilepsy, Generalized / complications
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Epilepsy, Generalized / genetics*
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Epilepsy, Generalized / pathology
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Histidine / genetics
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Kainic Acid
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Membrane Potentials / drug effects
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Membrane Potentials / genetics
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Membrane Potentials / physiology
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Mutation / genetics*
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NAV1.1 Voltage-Gated Sodium Channel
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Nerve Tissue Proteins / genetics*
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Neurons / physiology
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Patch-Clamp Techniques
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RNA, Messenger / metabolism
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Seizures, Febrile / chemically induced
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Seizures, Febrile / complications
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Seizures, Febrile / genetics*
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Seizures, Febrile / pathology
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Sodium Channel Blockers / pharmacology
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Sodium Channels / genetics*
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Tetrodotoxin / pharmacology
Substances
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NAV1.1 Voltage-Gated Sodium Channel
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Nerve Tissue Proteins
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RNA, Messenger
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SCN1A protein, human
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Scn1a protein, mouse
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Sodium Channel Blockers
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Sodium Channels
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Tetrodotoxin
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Histidine
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Arginine
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Kainic Acid