A research update from the University of Manchester

Seizures fuel seizures. In other words, if people who experience small seizure episodes are not treated, they can go on to have larger more frequent seizures. Despite years of research, our understanding of the underlying biological mechanisms of seizure progression is incomplete. Research using the fruit fly, Drosophila melanogaster, in the laboratory of Professor Richard Baines at The University of Manchester, has uncovered some important clues.

That’s right – a small fly that buzzes around your fruit bowl in the summer can be used to study epilepsy. The fly and epilepsy have  a long history dating back to the early 1970’s, which includes, not only the identification of gene mutations that lower seizure threshold, but also detailed studies of its nervous system to understand how seizures begin and spread. For further proof of the suitability of this insect for epilepsy research you need look no further than the fact that anti-epileptic drugs used to treat humans are equally effective in flies. This reinforces what biologists already know – the nervous system evolved only once and animals differ only in the numbers of nerve cells they contain: from about 1 million in the fly to 10 billion in us.

The Baines group studies sodium channels, which form specialised holes in the membrane of nerve cells and are critical for the generation of electrical signals that we call action potentials1. During a seizure neurons often fire too many action potentials, and so a lot of focus has fallen on these channels.  The nervous system has numerous functions that require coordination by sodium channels. To produce the many different types of sodium channels required, a process called alternative splicing is used. By inclusion or exclusion of specific gene regions (i.e. splicing), a single gene can produce many closely related channel variants. A good analogy is making cocktails: a few common ingredients produce many different drinks. It turns out that sodium channels in flies can contain one of two possible gene regions; a K region or an L region.

Why is this important? Well, L-containing sodium channels allow nerve cells to fire more action potentials than K-containing channels. In addition, increased activity in the nervous system encourages more L regions to be included in sodium channels, which in turn leads to more activity. Thus, small seizures that increase activity can lead to the inclusion of even more L regions, which increases the likelihood of bigger seizures.

But is this relevant for human epilepsy? The Baines group thinks so. Human sodium channels are remarkably similar to fruit fly channels, in that the their ‘type’ is dictated by activity. The laboratory is able to manipulate a protein that controls the decision as to which region is incorporated into a sodium channel: K (resulting in less nervous activity) or L (more nervous activity, more seizures). Reducing the number of L-containing channels in this way is a very effective anti-epileptic treatment in flies. That same protein, called Nova, also regulates sodium channel formation in humans. Therefore, although it is still early days, the Baines group has identified a possible new target for the design of novel, and we hope better, anti-epileptic drugs.

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