[P3-66] Abnormal GABA neurotransmission in a Kcnq2 model of early-onset epilepsy
[Introduction] Mutations of the KCNQ2 gene, which encodes the Kv7.2 subunit of voltage-gated M-type potassium channels (M-channels), have been associated with epilepsy in the neonatal period. This developmental stage is unique in that the neurotransmitter GABA, which is inhibitory in adults, triggers excitatory action due to a reversed chloride gradient.
[Methodology] To examine whether KCNQ2-related neuronal hyper-excitability involves neonatally excitatory GABA, we examined one-week-old knock-in mice expressing the Kv7.2 variant p.Tyr284Cys (Y284C).
[Results] Brain slice electrophysiology revealed elevated CA1 hippocampal GABAergic interneuron activity with respect to presynaptic firing and postsynaptic current frequency. Blockade with the GABAA receptor antagonist bicuculline decreased ictal bursting in divalent ion-challenged brain slices, which is consistent with GABA mediating an excitatory function that contributes to the hyper-excitability observed in mutant animals.
[Conclusions] We conclude that excitatory GABA contributes to the phenotype in these animals, which raises the question of whether this special type of neurotransmission has broader importance in neonatal epilepsy than is currently recognized.
[Methodology] To examine whether KCNQ2-related neuronal hyper-excitability involves neonatally excitatory GABA, we examined one-week-old knock-in mice expressing the Kv7.2 variant p.Tyr284Cys (Y284C).
[Results] Brain slice electrophysiology revealed elevated CA1 hippocampal GABAergic interneuron activity with respect to presynaptic firing and postsynaptic current frequency. Blockade with the GABAA receptor antagonist bicuculline decreased ictal bursting in divalent ion-challenged brain slices, which is consistent with GABA mediating an excitatory function that contributes to the hyper-excitability observed in mutant animals.
[Conclusions] We conclude that excitatory GABA contributes to the phenotype in these animals, which raises the question of whether this special type of neurotransmission has broader importance in neonatal epilepsy than is currently recognized.