Abstracts

Rationale: Mice lacking the Kcna1 gene, which encodes the voltage-gated potassium channel Kv1.1 (i.e., Kcna1-null or KO mice), exhibit all the hallmark features of human temporal lobe epilepsy, and represent a clinically relevant model of early-onset epilepsy. Despite previous studies reporting alterations in electrophysiological properties of both hippocampal and neocortical pyramidal cells in KO mice, far less is known about interneuron function, especially in the hippocampus. We hypothesized that deletion of Kv1.1 induces a paradoxical increase in the CA1 hippocampal interneuron function. While increases in GABAergic inhibition might in part represent a compensatory response to increased network excitability, a growing body of evidence suggests that enhanced GABA signaling might promote seizure activity. Here we investigated the electrophysiological properties of CA1 interneurons from KO and wild-type (WT) C3H mice, to assess whether lack of the Kv1.1 subunit is associated with altered interneuron function.Methods: Whole-cell patch-clamp and multi-electrode array (MEA) recordings were made in brain slices from CA1 hippocampus of KO mice. Immunohistochemical and confocal microscopy techniques were used to identify specific interneuron subtypes, and full interneuron arborisations were constructed using Imaris software.Results: All major types of interneurons were identified in stratum oriens (bistratified interneurons, oriens lacunosum moleculare, horizontal-basket cells, and axo-axonic cells) as well as in stratum radiatum (basket cells, Schaffer collateral-associated interneurons, perforant path-associated cells and neurogliaform interneurons). Most CA1 interneuron populations (with the exception of oriens basket cells) in KO mice had altered membrane properties and were more excitable than their counterparts. We found that stratum oriens interneurons (n = 113, KO) had a lower threshold current amplitude (~28%, p < 0.05) and increased number of action potentials (~75%, p < 0.001) elicited by suprathreshold pulses (100 pA, 500 ms) as compared to control interneurons (n = 83). Stratum radiatum interneurons exhibited similar alterations: the number of action potentials increased from 12 in control (n = 23) to 17 in KO interneurons (n = 21, p < 0.05) while the threshold current amplitude decreased from 49 to 32 pA (p < 0.05). Finally, MEA recordings in stratum oriens revealed that the spontaneous firing was significantly increased from 1Hz in control interneurons (n = 17) to 1.9Hz in KO cells (n = 21, p < 0.05).Conclusions: Kv1.1 channel modulates the excitability of most CA1 interneuron subpopulations by limiting the action potential firing. Deletion of Kv1.1 induces an enhanced neuronal output in specific CA1 interneurons. This aberrant interneuron firing might in part disrupt the timing and the oscillatory activities in the hippocampal network, thereby contributing to the generation, propagation and/or maintenance of the epileptic phenotype seen in this model.