BioWorld International Correspondent
LONDON - A better understanding of how neurons in the brain become overexcited in epilepsy has opened up an entirely new field of research and might lead to new drugs to treat the disease.
The discovery by an international team of researchers focuses on a type of ion channel found on processes (dendrites) of neurons. Rats with experimentally induced epilepsy had fewer of those ion channels, and those that were present had been phosphorylated, which impaired function.
Heinz Beck, professor of epilepsy research at the department of epileptology at the University of Bonn in Germany, told BioWorld International, "This channel found on the dendrites of nerve cells is normally considered to be an inhibitory channel, so that its loss leads to a net increase in excitability."
That and other studies might make it possible, he speculated, to find the "magic bullet" that could interfere selectively with very specific targets in the epileptic brain, without affecting normal brain function.
He and his colleagues now want to investigate whether it is possible to pharmacologically reverse the phosphorylation-induced changes in the channels. "One way to reverse the changes in epilepsy might be to dephosphorylate the channel," he said. "This could be an interesting pharmacological target and we already have some ideas."
The Institute of Epileptology treats many patients with surgery, so Beck and his colleagues also plan to obtain human brain tissue to find out if a similar abnormality exists in people with epilepsy.
The team, which has members in Marseille, France; in Bonn; and in the U.S., reported their results in the July 23, 2004, issue of Science in a paper titled "Acquired Dendritic Channelopathy in Temporal Lobe Epilepsy."
In epilepsy, seizures are linked to increased excitability of neurons, with uncontrolled mass discharge by neurons causing many different symptoms, including loss of consciousness and convulsions. However, little is known about how that synchronized paroxysmal activity develops at the level of the nerve cells.
Until recently, much research had concentrated on studying how nerve impulses pass from one cell to another via the synapses, with the assumption that seizures are due to disturbed synaptic transmission. But Beck and his collaborators have shown that in epileptic rats the integration of synaptic signals in the neurons themselves also is affected.
During the passage of a nerve impulse, various ion channels in the membrane of the nerve cell allow specific ions to enter or leave. Some are permanently open, others let only certain ions through when needed, or use energy to "pump" them against a concentration gradient.
The study focused on the Kv4.2 channel, which is permeable to positively charged potassium ions. During excitatory synaptic input, those channels open and allow potassium ions to leak out. As a result, that type of channel has the important function of attenuating incoming excitatory synaptic input from other nerve cells.
Beck said: "In the rat model of temporal lobe epilepsy, which is the most common form of epilepsy in adults, we found that some dendrites have far fewer functioning Kv4.2 channels than healthy rats."
The results reported in Science show that there were two reasons for that. First, the genes for the Kv4.2 channel were transcribed less often than in normal neurons, with the result that the cells produced fewer Kv4.2 channels. In addition, an enzyme called extracellular signal-regulated kinase phosphorylates the channels that are available so that they no longer function as normal.
"Consequently," Beck added, "since the input signals at the dendrites reach the neuron largely unabsorbed, the epileptic rats probably react much more frequently than healthy rats by transmitting an impulse to their signal output, the axon of the nerve cell."
Commenting on the paper, Kevin Staley of the University of Colorado Health Sciences Center in Denver described in Science how a phenomenon called back-propagation of nerve impulses can "echo" the incoming nerve impulses and re-enter the dendrites.
In his article, titled "Epileptic Neurons Go Wireless," Staley wrote, "[This] study provides evidence for a new pathway that enables the re-entry of action potentials via the dendrites of the neurons that initiated the action potential in the first place."