Abstracts

RATIONALE: Three mechanisms are believed to underlie highly synchronized discharges in large groups of neurons during seizures: 1) alterations of the intrinsic membrane properties of neurons that would make them pathologically hyperexcitable; 2) increase in glutamatergic excitation, and 3) decrease in GABAergic inhibition. Because dendrites play an active role in the processing and propagation of synaptic inputs via the activation of voltage-gated Na+, K+ and Ca2+ channels in control tissue, we have begun to investigate the fate of these dendritic channels in experimental temporal lobe epilepsy (TLE). K+ channels are ideally located to control pyramidal neuron excitability. Previous work has demonstrated that there is a very high density of transient, A-type K+ channels in CA1 pyramidal neuron dendrites in control tissue. These channels raise threshold for action potential initiation in the dendrites, limit the back-propagation of action potentials from the soma to the dendrites, and reduce the amplitude of excitatory synaptic events.
METHODS: We have used simultaneous somatic and dendritic recordings of CA1 pyramidal cells in pilocarpine-treated rats with spontaneous recurrent seizures.
RESULTS: We have found that all action potentials were first generated in the perisomatic region during evoked epileptiform discharges or with depolarizing steps. The perisomatic region is therefore still the normal site for spike initiation in experimental TLE. These backpropagating spikes, however, had a greater amplitude in TLE than in control, because of a downregulation of A type K+ channel function that could be partially reversed following their dephosphorylation. The increased dendritic excitability was due to a change in the ratio of available Na/K channels in favour of Na+ channels. Finally, preventing phosphorylation of K+ channels dramatically reduced evoked epileptiform discharges in the dendrites.
CONCLUSIONS: We propose that there is an increased endogenous phosphorylation in epileptic tissue which results in decreased K+ channel activity and increased dendritic excitability. Targeting the phosphorylation site of dendritic A type K+ channels to upregulate their activity may be a fruitful new drug strategy in TLE.
[Supported by: INSERM and NIH.]