Abstracts & Commentary
Synopsis: Such acquired channelopathy is likely to amplify neuronal activity and may contribute to the initiation and/or propagation of seizures in TLE.
Sources: Bernard, C., et al. Acquired Dendritic Channelopathy in Temporal Lobe Epilepsy. Science. 2004;305:532-532.; Staley K. Epileptic Neurons Go Wireless [editorial]. Science. 2004;305 482-483.
Increases in neuronal excitability and/or decreases in inhibition are broadly thought to be the basis of epileptogensis. As Bernard and colleagues put it, there is "an augmented neuronal input-output relation" leading to hyperexcitability. Bernard et al have found mechanisms by which changes in the expression and post-translational modification of ion channels in the dendritic tree can affect neuronal excitability.
While dendrites serve as a main integrator for synaptic input, this function has previously been thought to be relatively passive. One effect that has not received much attention is back-propagating action potentials (b-APs). B-APs can produce an echo in the dendritic tree that could theoretically affect the magnitude, or other properties (such as burst firing), of the forward AP propagating down the axon. Normally, A-type potassium (K+) channels in the dendrite serve to modulate (ie decrease) the magnitude of b-APs.
Pilocarpine-treated rats have been used as a model of human temporal lobe epilepsy. Using whole-cell dendritic recording in hippocampal CA1 pyramidal cells from such rats, Bernard et al discovered that b-AP amplitudes were significantly larger in these rats vs sham-treated animals. They further found that the increase in b-AP amplitude was due to both 1) decreases in the transcriptional expression of A-type K+ channels and 2) phosphorylation of these channels. B-AP amplitude could be reduced in both pilocarpine and sham-treated rats by inhibiting phosphorylation.
Commentary
Animal models of epileptogenesis, in particular the kindling paradigm, have emphasized potential changes in neuronal network properties. Under this model, rodents begin to have spontaneous seizures after repetitive electrical stimulation of the brain; a major pathological feature of this model is new axonal sprouting in the hippocampus. On the other hand, less experimental data is available providing insight into intrinsic neuronal factors modifying excitability, including: ion channel type, number, and distribution; biochemical modification of receptors; activation of second-messenger systems (eg via metabotropic receptors); and modulation of gene expression (eg, for ion channels and receptor proteins).
Bernard et al have made a significant contribution to understanding the molecular and cellular pathophysiology of epileptogenesis by describing how changes in the expression and function of A-type K+ channels could lead to augmented b-APs and burst firing in the pilocarpine model of temporal lobe epilepsy. Some currently marketed antiepileptic drugs (eg, topirimate) do act in part via modulation of K+ channels, but it is not known whether these agents work specifically through A-type K+ channels on dendrites. Alert looks forward to clinical applications that exploit the fact that, as Bernard et al point out, "Dendrites contain a very high density of ion channels that can be targeted by antiepileptic drugs." — Andy Dean, MD
Dr. Dean, Assistant Professor of Neurology and Neuroscience; Director of the Epilepsy Monitoring Unit, Department of Neurology, New York Presbyterian Hospital Cornell Campus, is Assistant Editor of Neurology Alert.
Such acquired channelopathy is likely to amplify neuronal activity and may contribute to the initiation and/or propagation of seizures in TLE.
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