When an epileptic seizure occurs in a neuronal circuit, the likelihood of subsequent seizures in that circuit is often increased. In some cases at least, this seems to be accomplished by the formation, through axon sprouting, of new excitatory connections between neurons that fired synchronously during the seizure. However, in Science, Bernard et al. now report on a 'wireless' mechanism for seizure facilitation, in which dendritic excitability is increased through the loss of an inhibitory potassium current.
When an action potential is generated in the cell body of a neuron, the signal is predominantly transmitted down the axon, but some of the activity can be reflected, or backpropagated, into the dendritic tree. Normally, these backpropagated action potentials (bAPs) are dissipated by an outward potassium current, which is known as the A current because it is generated by the opening of A-type potassium channels in the dendrites.
To investigate the effects of seizure activity on the A current, Bernard et al. generated a rat model of temporal lobe epilepsy. They treated the rats with the acetylcholine-receptor agonist pilocarpine to trigger a prolonged seizure, which led to the development of chronic spontaneous seizures several weeks later. The authors took recordings from the dendrites of CA1 pyramidal neurons in hippocampal slices from the epileptic rats, and they observed unusually high bAP amplitudes at a distance of more than 250 μm from the soma (the bAP amplitude usually diminishes markedly with distance from the soma). Although the authors did not measure the A current directly, the increased bAP amplitude was taken to indicate a reduction in this current.
The authors found that both the synthesis and function of A-type channels was affected by the seizures. In the epileptic animals, transcription of the KV4.2-channel gene was downregulated, and the activity of many of the remaining channels was decreased through protein kinase C-mediated phosphorylation.
Many studies have implicated inherited ion-channel defects in epilepsy, and this study illustrates that channelopathies can also be acquired as a result of seizure activity. If similar phenomena are shown to underlie seizure facilitation in humans, new anti-epileptic drug targets might be identified on the basis of the molecular mechanisms that modulate dendritic excitability.
References
ORIGINAL RESEARCH PAPER
Bernard, C. et al. Acquired dendritic channelopathy in temporal lobe epilepsy. Science 305, 532–535 (2004)
FURTHER READING
Staley, K. Epileptic neurons go wireless. Science 305, 482–483 (2004)
Steinlein, O. K. Genetic mechanisms that underlie epilepsy. Nature Rev. Neurosci. 5, 400–408 (2004)
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Wood, H. The current view of epilepsy. Nat Rev Neurosci 5, 672 (2004). https://doi.org/10.1038/nrn1504
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DOI: https://doi.org/10.1038/nrn1504