title: Molecular correlates of age-dependent seizures in an inherited neonatal-infantile epilepsy.
abstract: Many idiopathic epilepsy syndromes have a characteristic age dependence, the underlying molecular mechanisms of which are largely unknown. Here we propose a mechanism that can explain that epileptic spells in benign familial neonatal-infantile seizures occur almost exclusively during the first days to months of life. Benign familial neonatal-infantile seizures are caused by mutations in the gene SCN2A encoding the voltage-gated Na(+) channel Na(V)1.2. We identified two novel SCN2A mutations causing benign familial neonatal-infantile seizures and analysed the functional consequences of these mutations in a neonatal and an adult splice variant of the human Na(+) channel Na(V)1.2 expressed heterologously in tsA201 cells together with beta1 and beta2 subunits. We found significant gating changes leading to a gain-of-function, such as an increased persistent Na(+) current, accelerated recovery from fast inactivation or altered voltage-dependence of steady-state activation. Those were restricted to the neonatal splice variant for one mutation, but more pronounced for the adult form for the other, suggesting that a differential developmental splicing does not provide a general explanation for seizure remission. We therefore analysed the developmental expression of Na(V)1.2 and of another voltage-gated Na(+) channel, Na(V)1.6, using immunohistochemistry and real-time reverse transcription-polymerase chain reaction in mouse brain slices. We found that Na(V)1.2 channels are expressed early in development at axon initial segments of principal neurons in the hippocampus and cortex, but their expression is diminished and they are gradually replaced as the dominant channel type by Na(V)1.6 during maturation. This finding provides a plausible explanation for the transient expression of seizures that occur due to a gain-of-function of mutant Na(V)1.2 channels.
authors.affiliation: Neurological Clinic and Institute of Applied Physiology, University of Ulm, Ulm, 89081, Germany.
authors.forename: Yunxiang
authors.initials: Y
authors.lastname: Liao
authors.forename: Liesbet
authors.initials: L
authors.lastname: Deprez
authors.forename: Snezana
authors.initials: S
authors.lastname: Maljevic
authors.forename: Julika
authors.initials: J
authors.lastname: Pitsch
authors.forename: Lieve
authors.initials: L
authors.lastname: Claes
authors.forename: Dimitrina
authors.initials: D
authors.lastname: Hristova
authors.forename: Albena
authors.initials: A
authors.lastname: Jordanova
authors.forename: Sirpa
authors.initials: S
authors.lastname: Ala-Mello
authors.forename: Astrid
authors.initials: A
authors.lastname: Bellan-Koch
authors.forename: Dragica
authors.initials: D
authors.lastname: Blazevic
authors.forename: Simone
authors.initials: S
authors.lastname: Schubert
authors.forename: Evan A
authors.initials: EA
authors.lastname: Thomas
authors.forename: Steven
authors.initials: S
authors.lastname: Petrou
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Becker
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.forename: Holger
authors.initials: H
authors.lastname: Lerche
mesh_terms: D000328:Adult; D000375:Aging / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000378:metabolism; D001483:Base Sequence; D002460:Cell Line; D004594:Electrophysiology; D020936:Epilepsy, Benign Neonatal / Q000235:genetics* / Q000503:physiopathology; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D062551:NAV1.2 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism
chemical_list: D062551:NAV1.2 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; C568251:SCN2A protein, human; C000654500:Scn2a protein, mouse; C491046:Scn8a protein, mouse; D015222:Sodium Channels