Epilepsy: Signals 'brake' in brain impaired

July 28, 2004

To date epilepsy research has mainly concentrated on the transmission of the nerve cell signals to what are known as the synapses. However, recent observations by medical researchers from the US, France and the University of Bonn support the idea that in 'falling sickness' the signal processing in the nerve cells (neurons) is altered: normally specific ion channels absorb the neuronal activity. In rats suffering from epilepsy, however, this signals brake seems impaired: they have far fewer functioning ion channels than healthy rats. The results are published in the latest edition of the prestigious scientific journal 'Science' (23rd July, vol. 305, no. 5683). They offer hope of new therapeutic possibilities.

Epilepsy is a common disease: in Germany alone there are 600,000 people whose nerve cells in the brain occasionally switch from healthy chaos to common mode. The result of the uncontrolled mass discharge of neurons is loss of consciousness and spastic convulsions of the muscles, during which those affected can seriously injure themselves. Yet how this synchronised paroxysmic activity develops at the level of nerve cells is still largely a mystery.

Nerve cells are interlinked via a large number of branching networks through which they communicate with each other. Each neuron has a series of dendrites which receive signals from other neurons at what are known as synapses. The cell 'processes' these incoming signals like a kind of biological microprocessor and transmits as a result electrical pulses via a special projection, the axon, to the dendrites of other neurons. Many epilepsy researchers have up to now assumed that when epilepsy occurs this communication between the cells does not work properly because the transmission of the signals to the synapses is impaired. However, the Bonn researchers in conjunction with their US colleagues and a research team from Marseilles discovered in the case of epileptic rats that the signal processing is not only affected in the synapses but also in the neurons themselves.

The nerve cells are surrounded by a cell membrane. Yet this membrane is not impervious: different kinds of specialised pores ensure that specific charged particles, the ions, can pass through the membrane. Some of these ion channels are permanently open, others only let 'their' ions through when needed or use energy to 'pump' them against a concentration gradient. One important ion pore is the Kv4.2 channel, which is permeable for positively charged potassium ions. This channel is mainly located at the signal inputs of a neutron, the dendrites, and has an important function there: it absorbs incoming excitant signals from other nerve cells. They 'trickle away', so to speak, through the many little 'potassium leaks'; on their journey through the dendrites the pulses therefore level out more and more.

'In rats with what we call a temporal lobe epilepsy some dendrites have far fewer functioning Kv4.2 channels than healthy rats,' the Bonn epilepsy researcher Professor Heinz Beck explains. There are two reasons for this, the researchers were able to show: on the one hand the genes for the potassium sluice are read less often, with the result that the cells produce fewer Kv4.2 channels. On the other hand a particular enzyme, the ERK or Extra-Cellular Signal-Regulated Kinase, changes the channels present chemically in such a way that they no longer function. The consequence is, Professor Beck adds, that 'since the input signals at the dendrites reach the neuron largely unabsorbed, the rats probably react much more frequently than healthy rats by transmitting an impulse to their signal output, the axon.' The nerve impulses can therefore multiply more easily; the lack of signal absorbance may thus decisively contribute to the increased excitability of the neurons in chronic epilepsy.

When the teams impeded the ERK with specific substances, the signal response of the nerve cells largely normalised. The findings therefore make it appear possible to discover new therapeutic approaches. 'Admittedly, the ERK has so many tasks to do that there would probably be side-effects if it was impeded directly,' says Heinz Beck. 'However, the attempt could be made to protect the Kv4.2 channels from ERK attack, or reverse the chemical changes in the channels.'
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University of Bonn

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