A spontaneous mutation involving Kcnq2 (Kv7.2) reduces M-current density and spike frequency adaptation in mouse CA1 neurons.
The M-type K+ current [IK(M)] activates in response to membrane depolarization and regulates neuronal excitability. Mutations in two subunits (KCNQ2 and KCNQ3; Kv7.2 and Kv7.3) that underlie the M-channel cause the human seizure disorder benign familial neonatal convulsions (BFNC), presumably by reducing IK(M) function. In mice, the Szt1 mutation, which deletes the genomic DNA encoding the KCNQ2 C terminus and all of CHRNA4 (nicotinic acetylcholine receptor alpha4 subunit) and ARFGAP-1 (GTPase-activating protein that inactivates ADP-ribosylation factor 1), reduces seizure threshold, and alters M-channel pharmacosensitivity. Genomic deletions affecting the C terminus of KCNQ2 have been identified in human families with BFNC, and truncation of the C terminus prevents proper KCNQ2/KCNQ3 channel assembly in Xenopus oocytes. We showed previously that Szt1 mice have a reduced baseline seizure threshold and altered sensitivity to drugs that act at the M-channel. Specifically, the proconvulsant M-channel blocker linopirdine and anticonvulsant enhancer retigabine display increased and decreased potency, respectively, in Szt1 mice. To investigate the effects of the Szt1 mutation on IK(M) function explicitly, perforated-patch electrophysiology was performed in CA1 pyramidal neurons of the hippocampus in brain slices prepared from C57BL/6J-Szt1/+ and control C57BL/6J+/+ mice. Our results show that Szt1 reduces both IK(M) amplitude and current density, inhibits spike frequency adaptation, and alters many aspects of M-channel pharmacology. This is the first evidence that a naturally occurring Kcnq2 mutation diminishes the amplitude and function of the native neuronal IK(M), resulting in significantly increased neuronal excitability. Finally, the changes in single-cell biophysical properties likely underlie the altered seizure threshold and pharmacosensitivity reported previously in Szt1 mice.
Otto
James F
JF
Anticonvulsant Drug Development Program, Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah 84112, USA.
Yang
Yan
Y
Frankel
Wayne N
WN
White
H Steve
HS
Wilcox
Karen S
KS
D000818:Animals; D005260:Female; D006624:Hippocampus / Q000502:physiology*; D066298:In Vitro Techniques; D051658:KCNQ2 Potassium Channel / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009474:Neurons / Q000502:physiology*; D009865:Oocytes / Q000502:physiology; D017966:Pyramidal Cells / Q000502:physiology*; D012640:Seizures / Q000503:physiopathology; D014162:Transfection; D014981:Xenopus / Q000502:physiology
D051658:KCNQ2 Potassium Channel