Abstracts

Rationale: Targeted disruption of the Kcna1 gene encoding the voltage-gated potassium channel alpha-subunit Kv1.1 in mice leads to frequent spontaneous recurrent seizures early in postnatal development. Kcna1-null (KO) mice exhibit many of the hallmark features of human temporal lobe epilepsy and represent a clinically relevant model of early-onset epilepsies, as well as a model of SUDEP. Although there is evidence of increased excitability in both hippocampal and neocortical pyramidal cells in KO mice, far less is known about the function of interneurons, especially in hippocampus. We hypothesized that deletion of Kv1.1 increases CA1 interneuron function, leading to the generation and/or maintenance of the epileptic state. This is in line with a growing body of evidence suggesting that enhanced GABAergic signaling might promote seizure activity. Methods: Whole-cell patch-clamp and multi-electrode array (MEA) recordings were used to assess electrophysiological properties of hippocampal interneurons in brain slices from KO and wild-type (WT) C3H control mice. The interneuron identity in the hippocampal layers was assessed using immunohistochemistry and confocal microscopy. Results: Analysis of over 200 whole-cell patch clamp recordings in KO and WT animals revealed that CA1 interneurons in stratum oriens (SO) and radiatum (SR) were more excitable in KO mice than their WT counterparts. The number of action potentials elicited by suprathreshold pulses increased from 11 to 17 in SR and from 17 to 30 in SO interneurons (p Conclusions: The Kv1.1 potassium channel likely plays an important role in CA1 interneuron excitability by limiting spontaneous action potential firing. We have identified selective interneuron dysfunction in Kcna1-null mice and provide new insights into the role of specific interneuron subtypes in the pathogenesis of seizures and epilepsy. The aberrant interneuron output might in part be responsible for the disruption of oscillatory activities in the CA1, thereby contributing to the generation and/or maintenance of the epileptic phenotype seen in this model. Funding: CIHR, Alberta Children's Hospital Research Institute (JMR), NIH NS085389 (TAS)