EPILEPSY RESEARCH UK
ENDEAVOUR PROJECT GRANT
£149,994 over 24 months
Awarded in 2022

SCIENTIFIC TITLE

Impact of seizure-induced changes in nerve cell structure on epileptogenesis

LEAD INVESTIGATOR

Dr Karen Smillie

CO-INVESTIGATORS

Dr Daniela Ivanova (University of Edinburgh), Prof Michael Cousin (University of Edinburgh)

INSTITUTION

University of Edinburgh

Almost a year ago, we made a completely serendipitous discovery that may change a central dogma in synapse biology and open up a new avenue of epilepsy research. Because of the fundamental nature of the biological phenomenon we are investigating, and its key role in synaptic transmission, we believe that this research will have a significant impact on a broad range of epilepsies regardless of their underlying cause.
Dr Daniela Ivanova

BACKGROUND

Epilepsy is a complex condition with diverse symptoms and underlying mechanisms. Some of these mechanisms can be understood and their potential for new therapies is determined only by investigating the basic aspects of nerve cell (neuron) function.

THE STUDY

With this project, the Edinburgh team are going back to basics. The aim of this project is to characterise a new molecular pathway that controls signals at synapses, the contact sites through which neurons communicate. Synapses act as fine-tuned filters, at which the signal can be either amplified or reduced. Therefore, structural and functional alterations of the synaptic terminals play a major role in the onset and progression of all neuronal disease processes, including epilepsy. We discovered that a new pathway that occurs at synaptic terminals and modulates signal transmission between neurons during their highest activity by altering the mechanical properties of the cell membrane. We propose to investigate this pathway and its potential contribution to the development of epilepsy (epileptogenesis) at a molecular, cellular and whole-body level.

SIGNIFICANCE

This study will provide a new theoretical and conceptual framework for studying brain communication and its seizure-induced plasticity. The team expect that this will generate important insights into epileptogenesis and provide leads for new therapeutic approaches in the immediate future.

Despite incredible advances in technology, the translation of new therapies for epilepsy is a relatively slow process. Drug repurposing offers the benefit of shorter developmental timelines at a relatively low cost by the use of already de-risked compounds. Interestingly, the synapse shape changes induced by epileptiform activity resemble and share molecular signatures with the process that constitutes the main weapon in the arsenal of the immune system against pathogenic particles. This means that there are several approved, potentially repurposable drug candidates whose antiepileptic efficacy can be immediately assessed in our model systems, and if successful in people with epilepsy.