Aberrant sodium channel activity in the complex seizure disorder of Celf4 mutant mice

• DOI: 10.1113/jphysiol.2012.240168
• Publication Date: 2012-10-23T04:56:22Z
• Authors: Wenzhi Sun; Jacy L. Wagnon; Connie L. Mahaffey; Michael Briese; Jernej Ule; Wayne N. Frankel
• Keywords: Nap; NAV1; Wild type; Heterozygote advantage

Mice deficient for CELF4, a neuronal RNA-binding protein, have complex seizure disorder that includes both convulsive and non-convulsive seizures, is dependent upon Celf4 gene dosage mouse strain background. It was previously shown expressed predominantly in excitatory neurons, deficiency results abnormal synaptic neurotransmission. To examine the physiological molecular basis of this, we studied Celf4-deficient neurons brain slices. Assessment intrinsic properties layer V cortical pyramidal showed from mutant heterozygotes homozygotes lower action potential (AP) initiation threshold larger AP gain when compared with wild-type neurons. also demonstrate an increase persistent sodium current (I(NaP)) hyperpolarizing shift voltage dependence activation. As part related study, find CELF4 directly binds Scn8a mRNA, encoding channel Na(v)1.6, primary instigator at axon initial segment (AIS) main carrier I(NaP). In present study dramatic elevation expression Na(v)1.6 protein AIS null heterozygous Together these suggest activation plays crucial role generation this model neurological disease.