Approximately one in 1000 babies under 12 months have epileptic seizures. Unfortunately, some of these babies have severe epilepsy that does not respond well to treatment, as well as delayed developmental milestones. In up to 50% of babies with seizures, tests show that there are changes or ‘spelling mistakes’ in their genetic code, which can lead to proteins not working properly in brain cells.
Genes are instructions for cells which allow them to make important proteins. These proteins have a number of different roles that are key to the function of brain cells. Some of these proteins act as gates or shuttles, letting the right amounts of potassium or chloride in and out of the cells. This is vital, as the wrong amount of potassium or chloride can drastically affect the excitability of cells, which is when a cell is sufficiently stimulated and reacts with a brief electrical discharge, called an action potential.
The excitability of brain cells is also affected by chemicals called neurotransmitters. One example is GABA, which opens chloride channels and allows the negatively charged chloride to flow into the brain cell, effectively calming it down. However, this calming effect does not happen if the chloride level in the cells is already too high. We know that a rare form of genetic epilepsy is caused by high chloride levels in brain cells, but we believe that chloride channels may also play a role in other kinds of epilepsies by contributing to over-excitable brain cells and epileptic seizures.
In our lab we have created a model that can closely mimic what is happening in the brains of people with epilepsy. We take skin samples donated from people with genetic epilepsy and convert them into brain cells. We can check the chloride levels and electrical activity in these “brain cells in a dish”, which gives us a window into the genetic changes that lead to epilepsy. We will also use this brain cell model to test new treatments.
We hope that understanding how chloride levels vary in different epilepsies will help us identify new targets for treatment, such as modifying chloride transport in and out of brain cells. This could have an impact for rare genetic epilepsies and more common types of epilepsy. The Endeavour Project Grant award will drive this work forward to improve our understanding of why seizures occur in babies and to develop new epilepsy treatments.
