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ERIC Number: EJ882333
Record Type: Journal
Publication Date: 2010-May
Pages: 12
Abstractor: As Provided
Reference Count: 0
ISSN: ISSN-0006-8950
Molecular Correlates of Age-Dependent Seizures in an Inherited Neonatal-Infantile Epilepsy
Liao, Yunxiang; Deprez, Liesbet; Maljevic, Snezana; Pitsch, Julika; Claes, Lieve; Hristova, Dimitrina; Jordanova, Albena; Ala-Mello, Sirpa; Bellan-Koch, Astrid; Blazevic, Dragica; Schubert, Simone; Thomas, Evan A.; Petrou, Steven; Becker, Albert J.; De Jonghe, Peter; Lerche, Holger
Brain, v133 n5 p1403-1414 May 2010
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[superscript +] channel Na[subscript 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[superscript +] channel Na[subscript 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[superscript +] 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[subscript V]1.2 and of another voltage-gated Na[superscript +] channel, Na[subscript V]1.6, using immunohistochemistry and real-time reverse transcription-polymerase chain reaction in mouse brain slices. We found that Na[subscript 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[subscript 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[subscript V]1.2 channels.
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Publication Type: Journal Articles; Reports - Research
Education Level: N/A
Audience: N/A
Language: English
Sponsor: N/A
Authoring Institution: N/A