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

Abstract

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 Kcnq3 G311V/+ heterozygous knock-in mice exhibited reduced thresholds to electrically induced seizures compared to wild-type littermate mice. Both Kcnq2 A306T/A306Tand 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 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. Benign familial neonatal convulsions (BFNC [MIM 121200,121201]) is an autosomal dominantly inherited epileptic disorder in which newborns experience several daily partial or generalized seizures during wakefulness and sleep (Rett & Teubel, 1964;Ryan et al. 1991;Ronen et al. 1993). In the majority of cases, seizures spontaneously remit by 3-4 months yet 16% of BFNC individuals continue to experience one or more seizures during adulthood (Ronen et al. 1993;Singh et al. 2003). Mutations in either of two homologous potassium channel genes, This paper has online supplemental material.KCNQ2 and KCNQ3, have been found in patients with BFNC (Biervert et al. 1998;Charlier et al. 1998;Singh et al. 1998;Lucarini et al. 2007). The protein products of these genes colocalize and generate the M-current, a critical regulator of action potential firing and neuronal excitability (Wang et al. 1998).An intriguing phenotypic trait of BFNC is that the frequent spontaneous seizures exhibited by the neonates are not generally associated with any developmental sequelae (Ryan et al. 1991;Ronen et al. 1993). This is in stark contrast to malignant early childhood onset convulsive seizure disorders that can produce neuronal death and synaptic reorganization with subsequent (Ben-Ari & Holmes, 2006;Blume, 2006). A biological mechanism that exp...

Validation criteria for genetic animal models of epilepsy

“…They include autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) [7][8][9], benign familial neonatal convulsion (BFNC) [10,11], childhood absence epilepsy (CAE) [12,13], severe myoclonic epilepsy in infancy (SMEI) [14] and febrile seizures (FS) [15]. However, their phenotypic features have not been determined fully.…”

Cortical KCNQ2/3 channels; insights from knockout mice

“…5 Soh et al extended these findings by showing that deletion of Kcnq2-but not Kcnq3-from cortical pyramidal neurons is sufficient for the development of aberrant EEG activity and leads to death by the third week of life. Electrophysiological recordings from pyramidal neurons in the CA1 subregion of the hippocampus showed that in the absence of KCNQ2 channels the M-current was reduced by »85%, whereas the mAHP was reduced by »50-60%.…”

Genetic Epilepsy Syndromes Without Structural Brain Abnormalities: Clinical Features and Experimental Models

“…Transgenic mice expressing a dominant negative KCNQ2 mutant [59] show spontaneous partial and generalized tonicclonic seizures, but also pronounced hyperactivity and cell loss in the hippocampus, with impaired hippocampus-related memory, which are not consistent with the typical BNFS human phenotype. Knockin mice of KCNQ2 A306T and KV7.3 G311V mutations [60] show spontaneous tonic-clonic seizures and, consistent with BNFS, no hippocampal neurodegeneration; however, only homozygous mice manifest epilepsy, and they also tend to have seizures in adulthood.…”