Mouse models of human KCNQ2 and KCNQ3 mutations for benign familial neonatal convulsions show seizures and neuronal plasticity without synaptic reorganization.
The childhood epilepsy syndrome of benign familial neonatal convulsions (BFNC) exhibits the remarkable feature of clinical remission within a few weeks of onset and a favourable prognosis, sparing cognitive abilities despite persistent expression of the mutant KCNQ2 or KCNQ3 potassium channels throughout adulthood. To better understand such dynamic neuroprotective plasticity within the developing brain, we introduced missense mutations that underlie human BFNC into the orthologous murine Kcnq2 (Kv7.2) and Kcnq3 (Kv7.3) genes. Mutant mice were examined for altered thresholds to induced seizures, spontaneous seizure characteristics, hippocampal histology, and M-current properties of CA1 hippocampal pyramidal neurons. Adult Kcnq2(A306T/+) and Kcnq3(G311V/+) heterozygous knock-in mice exhibited reduced thresholds to electrically induced seizures compared to wild-type littermate mice. Both Kcnq2(A306T/A306T) and Kcnq3(G311V/G311V) homozygous mutant mice exhibited early onset spontaneous generalized tonic-clonic seizures concurrent with a significant reduction in amplitude and increased deactivation kinetics of the neuronal M-current. Mice had recurrent seizures into adulthood that triggered molecular plasticity including ectopic neuropeptide Y (NPY) expression in granule cells, but without hippocampal mossy fibre sprouting or neuronal loss. These novel knocking mice recapitulate proconvulsant features of the human disorder yet show that inherited M-current defects spare granule cells from reactive changes in adult hippocampal networks. The absence of seizure-induced pathology found in these epileptic mouse models parallels the benign neurodevelopmental cognitive profile exhibited by the majority of BFNC patients.
Singh
Nanda A
NA
Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA. nsingh@genetics.utah.edu
Otto
James F
JF
Dahle
E Jill
EJ
Pappas
Chris
C
Leslie
Jonathan D
JD
Vilaythong
Alex
A
Noebels
Jeffrey L
JL
White
H Steve
HS
Wilcox
Karen S
KS
Leppert
Mark F
MF
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D004195:Disease Models, Animal; D004562:Electrocardiography; D020936:Epilepsy, Benign Neonatal / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D051658:KCNQ2 Potassium Channel / Q000235:genetics* / Q000378:metabolism; D051659:KCNQ3 Potassium Channel / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009473:Neuronal Plasticity / Q000235:genetics*; D009474:Neurons / Q000502:physiology; D012640:Seizures / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000502:physiology*
D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; C114401:Kcnq2 protein, mouse; C496917:Kcnq3 protein, mouse; D009419:Nerve Tissue Proteins