title: Aberrant sodium channel activity in the complex seizure disorder of Celf4 mutant mice.
abstract: Mice deficient for CELF4, a neuronal RNA-binding protein, have a complex seizure disorder that includes both convulsive and non-convulsive seizures, and is dependent upon Celf4 gene dosage and mouse strain background. It was previously shown that Celf4 is expressed predominantly in excitatory neurons, and that deficiency results in abnormal excitatory synaptic neurotransmission. To examine the physiological and molecular basis of this, we studied Celf4-deficient neurons in brain slices. Assessment of intrinsic properties of layer V cortical pyramidal neurons showed that neurons from mutant heterozygotes and homozygotes have a lower action potential (AP) initiation threshold and a larger AP gain when compared with wild-type neurons. Celf4 mutant neurons also demonstrate an increase in persistent sodium current (I(NaP)) and a hyperpolarizing shift in the voltage dependence of activation. As part of a related study, we find that CELF4 directly binds Scn8a mRNA, encoding sodium channel Na(v)1.6, the primary instigator of AP at the axon initial segment (AIS) and the main carrier of I(NaP). In the present study we find that CELF4 deficiency results in a dramatic elevation in the expression of Na(v)1.6 protein at the AIS in both null and heterozygous neurons. Together these results suggest that activation of Na(v)1.6 plays a crucial role in seizure generation in this complex model of neurological disease.
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609-1500, USA.
authors.forename: Wenzhi
authors.initials: W
authors.lastname: Sun
authors.forename: Jacy L
authors.initials: JL
authors.lastname: Wagnon
authors.forename: Connie L
authors.initials: CL
authors.lastname: Mahaffey
authors.forename: Michael
authors.initials: M
authors.lastname: Briese
authors.forename: Jernej
authors.initials: J
authors.lastname: Ule
authors.forename: Wayne N
authors.initials: WN
authors.lastname: Frankel
mesh_terms: D000818:Animals; D001921:Brain / Q000502:physiology; D000067878:CELF Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D062557:NAV1.6 Voltage-Gated Sodium Channel / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D016601:RNA-Binding Proteins / Q000502:physiology*; D012640:Seizures / Q000503:physiopathology*; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D000067878:CELF Proteins; C470022:Celf4 protein, mouse; D062557:NAV1.6 Voltage-Gated Sodium Channel; D016601:RNA-Binding Proteins; C491046:Scn8a protein, mouse; D013629:Tamoxifen