Abstracts

Rationale: The Kcna1 gene encodes the delayed-rectifier voltage-gated potassium channel α subunit protein, Kv1.1. Kcna1-null mice exhibit frequent recurrent spontaneous seizures by P21-28. A previous study found increased CA3 hippocampal excitability only in response to provocation; however, no clear electrophysiological alterations were identified to explain the frequent epileptic seizures and interictal epileptiform activity observed in vivo.Methods: To determine whether acute hippocampal slices exhibit evidence of hyperexcitability, we employed a novel planar 64-electrode array (Panasonic MED64) to record network activity. Spontaneous population events, as well as single units, were recorded. A paired pulse paradigm (50 ms interstimulus interval) was used to investigate possible abnormalities of synaptic transmission in the Kcna1-null slices. Results: Spontaneous interictal epileptiform-like activity [i.e., sharp wave discharges (SWDs) with high frequency oscillations (HFOs)] was evident in each slice from null mice. The interictal events were generated in CA3 stratum pyramidale, traveled between CA3 and CA1 at a speed of ~70-80 mm/s suggesting polysynaptic pathways and occurred at a frequency of ~1-2 Hz. HFOs occurred with SWDs with high fidelity in CA1 and CA3 and had frequencies of 208.2 ± 0.7 and 226.4 ± 0.7 Hz, respectively. HFOs also occurred in CA3 in the absence of SWDs. Single unit firing was correlated with both the SWDs and HFOs. In addition, occasional ictal-like events of longer duration were detected, but with only focal propagation to a limited number of surrounding electrodes. Paired-pulse facilitation in CA1 in response to Schaffer collateral stimulation appeared normal. Co-application of CNQX and D-AP5 eliminated all epileptiform activity except for rogue HFOs in CA3 (~0.2 Hz). Conclusions: Using a unique microelectrode array, we demonstrate for the first time that Kcna1-null hippocampal slices are intrinsically hyperexcitable and spontaneously generate interictal-like events. Future studies will address the mechanism of epileptiform generation and propagation in tissue slices from Kcna1-null mice and the effectiveness of clinical and investigational anticonvulsant agents. As a model of in vitro, unprovoked epileptiform activity, Kcna1-null mice bear great promise toward expanding our understanding of epileptic mechanisms.