Conditional transgenic suppression of M channels in mouse brain reveals functions in neuronal excitability, resonance and behavior.
In humans, mutations in the KCNQ2 or KCNQ3 potassium-channel genes are associated with an inherited epilepsy syndrome. We have studied the contribution of KCNQ/M-channels to the control of neuronal excitability by using transgenic mice that conditionally express dominant-negative KCNQ2 subunits in brain. We show that suppression of the neuronal M current in mice is associated with spontaneous seizures, behavioral hyperactivity and morphological changes in the hippocampus. Restriction of transgene expression to defined developmental periods revealed that M-channel activity is critical to the development of normal hippocampal morphology during the first postnatal weeks. Suppression of the M current after this critical period resulted in mice with signs of increased neuronal excitability and deficits in hippocampus-dependent spatial memory. M-current-deficient hippocampal CA1 pyramidal neurons showed increased excitability, reduced spike-frequency adaptation, attenuated medium afterhyperpolarization and reduced intrinsic subthreshold theta resonance. M channels are thus critical determinants of cellular and neuronal network excitability, postnatal brain development and cognitive performance.
Peters
H Christian
HC
Institut für Neurale Signalverarbeitung, Zentrum für Molekulare Neurobiologie Hamburg, Martinistrasse 52, 20246 Hamburg, Germany.
Hu
Hua
H
Pongs
Olaf
O
Storm
Johan F
JF
Isbrandt
Dirk
D
D000818:Animals; D001522:Behavior, Animal; D055592:Biophysical Phenomena; D001703:Biophysics; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004594:Electrophysiology; D004827:Epilepsy / Q000235:genetics / Q000473:pathology / Q000503:physiopathology* / Q000523:psychology; D005260:Female; D005799:Genes, Dominant; D006948:Hyperkinesis / Q000235:genetics; D051658:KCNQ2 Potassium Channel; D008297:Male; D018782:Maze Learning; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009474:Neurons; D009865:Oocytes; D010641:Phenotype; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017966:Pyramidal Cells; D013550:Swimming; D014982:Xenopus laevis
D051658:KCNQ2 Potassium Channel; C114401:Kcnq2 protein, mouse; D009419:Nerve Tissue Proteins; D024642:Potassium Channels, Voltage-Gated