Abstracts

Rationale: In human disease, functional reduction of the delayed rectifier potassium channel alpha-subunit Kv1.1 either by mutation or autoimmune inhibition results in temporal lobe epilepsy. Similarly, Kcna1-null mice exhibit severe partial and generalized tonic-clonic seizures, hippocampal cell loss, mossy fiber sprouting and sudden unexplained death. Kv1.1 is prominently expressed in the axons of the hippocampal tri-synaptic pathway. Thus, we hypothesized that the absence of Kv1.1 would alter synaptic plasticity and result in widespread effects on normal network oscillatory activity. Methods: Recordings of spontaneous and evoked extracellular field potentials were acquired using a 64 multi-electrode array. Acutely isolated hippocampal slices from wild-type (WT) and Kcna1-null mice were positioned with electrodes (interpolar spacing of 150 um) in the fields of CA1, CA3 and dentate gyrus. Larger arrays with 300 um spacing were used to simultaneously record from the entorhinal cortex, subiculum and hippocampus proper. Electrodes underlying axon fibers of the perforant path, mossy fibers and Schaffer-collaterals were used for stimulation.Results: Spontaneous network oscillations identified as sharp waves (SPWs) and high frequency oscillations (HFOs) were evident in hippocampal slices from both WT and Kcna1-null mice. Loss of Kv1.1 resulted in a 40-100% increase in the incidence of SPWs and ripples (HFOs in the bandwidth 80-200 Hz) and the emergence of pathologic HFOs in the fast ripple bandwidth (200-600 Hz) as well as a 44% increase in durations. Propagation analysis and micro-dissection of hippocampal regions indicates a CA3 origin of WT and Kcna1-null SPWs and HFOs. In addition, short-term plasticity was abnormal at several Kcna1- null synapses, indicating increased neurotransmitter release probabilities at medial perforant path and mossy fiber terminals and decreased release probabilities at CA3 terminals. Removal of the entorhinal cortex and dentate gyrus altered Kcna1-null SPW, ripple and fast ripple characteristics suggesting a primary role for mossy fiber synapses in shaping these network oscillations.Conclusions: These data indicate that loss of Kv1.1 alters individual synaptic coupling, which promotes the emergence of fast ripples in the CA3 region of Kcna1-null hippocampi and subsequent propagation throughout the hippocampal formation.