Conditional deletions of epilepsy-associated KCNQ2 and KCNQ3 channels from cerebral cortex cause differential effects on neuronal excitability.
KCNQ2 and KCNQ3 potassium channels have emerged as central regulators of pyramidal neuron excitability and spiking behavior. However, despite an abundance of evidence demonstrating that KCNQ2/3 heteromers underlie critical potassium conductances, it is unknown whether KCNQ2, KCNQ3, or both are obligatory for maintaining normal pyramidal neuron excitability. Here, we demonstrate that conditional deletion of Kcnq2 from cerebral cortical pyramidal neurons in mice results in abnormal electrocorticogram activity and early death, whereas similar deletion of Kcnq3 does not. At the cellular level, Kcnq2-null, but not Kcnq3-null, CA1 pyramidal neurons show increased excitability manifested as a decreased medium afterhyperpolarization and a longer-lasting afterdepolarization. As a result, these Kcnq2-deficient neurons are hyperexcitable, responding to current injections with an increased number and frequency of action potentials. Biochemically, the Kcnq2 deficiency secondarily results in a substantial loss of KCNQ3 and KCNQ5 protein levels, whereas loss of Kcnq3 only leads to a modest reduction of other KCNQ channels. Consistent with this finding, KCNQ allosteric activators can still markedly dampen neuronal excitability in Kcnq3-null pyramidal neurons, but have only weak effects in Kcnq2-null pyramidal neurons. Together, our data reveal the indispensable function of KCNQ2 channels at both the cellular and systems levels, and demonstrate that pyramidal neurons have near normal excitability in the absence of KCNQ3 channels.
Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut 06269.
Heun
H
Soh
Rima
R
Pant
Joseph J
JJ
LoTurco
Anastasios V
AV
Tzingounis
D000200:Action Potentials; D000818:Animals; D004827:Epilepsy / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D017353:Gene Deletion; D051658:KCNQ2 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D051659:KCNQ3 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D017966:Pyramidal Cells / Q000378:metabolism / Q000502:physiology*
D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; C114401:Kcnq2 protein, mouse; C496917:Kcnq3 protein, mouse; D009419:Nerve Tissue Proteins
BFNC; KCNQ2; KCNQ3; M current; epilepsy