Research in a lab setting
Understanding how seizures develop in the lab to uncover new treatments for epilepsy

Dr Daniela Ivanova
Endeavour Project Researcher
University of Edinburgh

Researcher Dr Daniela Ivanova is unravelling the complexity of epilepsy in the lab. Dr Ivanova’s ERUK-funded project aims to understand how the structure of nerve cells in the brain influences how seizures develop. In this Research Blog, Daniela discusses the impact this work could have for people living with uncontrolled seizures.

Epilepsy is often referred to as the brain becoming “overexcited” or having “too much communication”. But how does brain communication occur and how can it result in epilepsy?

Brain cells (neurons) communicate with each other using a combination of rapid electrical impulses and chemical signals. At the contact sites between neurons, called synapses, electrical activity is converted into the release of chemical neurotransmitters. This release of neurotransmitters initiates an electrical response in the neighbouring neuron and the process is repeated, allowing the signal to travel from neuron to neuron. This process controls every aspect of our existence: our thoughts, movements, sensations, body functions, self-awareness, and perception of the world.

Seizures happen because of a sudden and excessive burst of electrical activity in a collection of neurons that might be located in different regions of the brain. The brain’s of people with epilepsy are hyperexcitable, meaning that neurons generate more intense electrical discharges than usual when stimulated. Because of this, one method to better understand epilepsy development is to explore the fundamental features that make the brain hyperexcitable.

But what creates a state of hyperexcitability in the brain? A number of factors can lead to neuronal hyperexcitability and result in epilepsy, including variations in our genes, problems with brain development in the womb, brain trauma and, importantly, simple seizures. Indeed, the old saying in epilepsy research that “seizures beget seizures” is based on the observation that a simple seizure may increase the likelihood of more seizures occurring in the future. However, little is known about how activity-induced changes in neuronal cells disrupt typical brain function and increase seizure susceptibility.

We discovered a new cellular pathway which occurs at synapses – the contact sites between neurons – and controls signal transmission between neurons during their highest activity by altering the properties of the cell outer membrane. The electrical force generated during neuronal communication deforms this membrane and induces synapse shape changes that are quickly transmitted inside the cell. This results in alterations in both the amount and location of neurotransmitter release. The latter may lead to activation of more distant neurons, in addition to neighbouring ones, resulting in more widespread propagation of brain activity. We believe that this might be the foundation for the excessive and rhythmic synaptic activity during seizures. Furthermore, these structural alterations at synapses can be sustained and expanded by repeated bursts of seizure activity, suggesting that they can result in changes to the wiring of the brain, making it permanently hyperexcitable.

With funding from Epilepsy Research UK’s generous supporters, we will investigate this new pathway and its potential contribution to the development of epilepsy at a synaptic, circuit and whole-body level.

Intriguingly, these changes in the synaptic outer membrane are highly reminiscent of the structural changes occurring in other biological membranes, such as those taking place during immune and cancer cells activation. This type of membrane deformation is used by immune cells to fight foreign intruders, such as viruses and bacteria, and by cancer cells to feed and sustain themselves. This means that due to the universality of this biological phenomenon, we already have at our disposal a number of fully approved drug candidates for human use which are potentially repurposable. Since there is comprehensive information available on the pharmacology, dose, and potential interactions of these drugs, we can easily assess their antiepileptic efficacy in our experimental systems, and if successful, in people with epilepsy. This should considerably accelerate the translation of our research into therapies that will hopefully help more people to live a seizure-free life. We believe that this research will have a significant impact on a broad range of epilepsies regardless of their underlying cause.

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