Sodium channel gene expression and epilepsy.
Na+ channelopathies that prolong membrane depolarization lead to neuronal bursting, abnormal network synchronization, and various patterns of episodic neurological disorders, including epilepsy. Two distinct pathways exist for generating epileptic phenotypes based on inherited disorders of voltage-gated Na+ ion channels. The first pathway is direct, involving mutations in genes encoding the pore-forming alpha1 and regulatory beta subunits of the channel that directly alter current amplitude or kinetics. These mutations favour repetitive firing and network hyperexcitability, although often the circuits most vulnerable to functional alterations are not easy to identify and the emergent clinical phenotypes are difficult to predict. The second pathway involves mutation of other genes that lead to downstream modifications in Na+ channel expression. Two clinically relevant examples of localization-related vulnerability in brain are described that illustrate how specific phenotypes arise from both direct and secondary pathways. Selective expression of the cardiac SCN5A channel within limbic regions of brain may explain why mutation of the gene for this tetrodotoxin-insensitive current may be associated with seizures. Ectopic expression of type II Na+ channels along axonal internodes in hypomyelinated brain may reveal why deletion of the myelin basic protein gene leads to subcortical seizure patterns. Analysis of these models offers insight into developmental processes that control the cellular expression and plasticity of Na+ channel genes, and will help to clarify mechanisms of hereditary Na+ channel-based epileptogenesis.
Noebels
Jeffrey L
JL
Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA.
D000818:Animals; D001921:Brain / Q000502:physiology; D004827:Epilepsy / Q000235:genetics*; D006801:Humans; D008032:Limbic System / Q000502:physiology; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D021122:Protein Subunits; D015222:Sodium Channels / Q000235:genetics*
D062554:NAV1.5 Voltage-Gated Sodium Channel; D021122:Protein Subunits; C568320:SCN5A protein, human; D015222:Sodium Channels