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J Physiol Volume 586, Number 14, 3405-3423, July 15, 2008 DOI: 10.1113/jphysiol.2008.154971
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NEUROSCIENCE

Mouse models of human KCNQ2 and KCNQ3 mutations for benign familial neonatal convulsions show seizures and neuronal plasticity without synaptic reorganization

 Nanda A. Singh1, James F. Otto2, E. Jill Dahle1, Chris Pappas1, Jonathan D. Leslie3, Alex Vilaythong4, Jeffrey L. Noebels4, H. Steve White2, Karen S. Wilcox2 and Mark F. Leppert1

1 Department of Human Genetics
2 Anticonvulsant Drug Development Program, Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112, USA
3 Vertebrate Development Laboratory, Cancer Research UK, London, WC2A 3PX, UK
4 Department of Neurology, Baylor College of Medicine, Houston, TX, 77030, USA

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 Kcnq2A306T/+ and Kcnq3G311V/+ heterozygous knock-in mice exhibited reduced thresholds to electrically induced seizures compared to wild-type littermate mice. Both Kcnq2A306T/A306T and Kcnq3G311V/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 knockin 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.

(Received 8 April 2008; accepted after revision 13 May 2008; first published online 15 May 2008)
Corresponding author N. A. Singh: Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA. Email: nsingh{at}genetics.utah.edu

This paper has online supplemental material.






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