MICA: The role of excitatory synaptic scaling in epileptogenesis in rodent and human brain networks

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Brain cells are electrically excitable, meaning that they communicate with each other through tiny voltage 'spikes'. How likely a brain cell is to spike is related to how easily excitable it is. However, excitability of brain cells is not a static thing, it changes in response to recent activity, and we call this homeostatic scaling (HS). HS keeps brain cell spiking activity in a kind of special zone where the amount of excitation in brain cells is kept at just the right rate for them to 'talk' to each other without everyone talking at once.Epilepsy is a neurological (brain) disease which is characterised by seizures. Seizures are periods of time when networks of brain cells are too active and are uncontrollably excited and spiking. If uncontrolled excitation spreads to brain regions that control movement, then too many brain cells are 'talking at the same time' and we can see seizures as changes in movement such as jerks and twitches. The problem with our current treatment of epilepsy is that we can't stop seizures in as many as a third of people, and of the ones that we do treat successfully, about a third will stop responding to the drugs. If you add these two groups together, then about half of people with epilepsy are not being helped enough by their medication. Most of the drugs that are used in epilepsy aim to stop seizures from happening, and for this reason, they often work in similar ways and aim at the same targets in the brain. What is needed is a new approach, looking at how epilepsy establishes itself in vulnerable brain areas, and how we might be abel to stop this process from happening.Like brain excitability, epilepsy itself is not static, rather, it is an ever-changing process, where the excitability of brain cells and networks is altered by the epileptic seizures themselves. This means that the high activity of a seizure might drive down the excitability of the brain cells, as a kind of compensation that helps to prevent seizures in the short term. This kind of compensatory change happens through HS, just like in non-epileptic brains. We think this HS process goes wrong in epilepsy, overcompensating for seizure activity and making networks so 'quiet' that a process of re-compensation happens which makes individual brain cells start to become super-excitable. This project aims to test this idea by looking at how different amounts of epileptic activity in the brain can alter its excitability. In rats with implanted brain electrodes that broadcast brain activity using a Wi-Fi system, we will map how brain cells alter their excitability in response to seizures and how this change in spiking is related to how cells communicate via their thousands of synapses. We predict that if there are a lot of seizures, synapses will decrease their activity and brain cells will become more likely to spike. We will test antiepileptic drugs, and new drugs designed to interfere with HS to see if they can prevent seizures from developing or reduce their intensity. Finally, we will test this all in human brain, using samples of living tissue taken from children with difficult to treat epilepsies who have had to have some brain tissue removed to stop the seizures. The people in our project team are epilepsy specialists, epilepsy surgeons, molecular biologists and scientists from GW Pharma, the company responsible for the newest successful antoepilepsy drug, Epidiolex (CBD). Together, we are going to be able to make animal models of epilepsy processes, test that they happen in human brain and explore how new antiepileptic drugs can interfere in how epilepsy is established in the brain. Answers to these questions will mean that we can focus on making drugs that target the processes undelying epilepsy, modifying the disease itself instead of just stopping the symptoms. Our project will help future patients, clinicians treating epilepsy and providing scientists with new knowledge from which to further other projects.