Investigating a new model of genetic epilepsy
Epilepsy Research UK Grant Announcements 2016
Grant type: Project grant
Principal investigator: Professor David Wyllie
Institution: University of Edinburgh
Duration: 24 months
Scientific title: GluN2A haploinsufficiency: a novel pre-clinical model of epilepsy
“Individuals who carry mutations in genes that encode receptors activated by the excitatory neurotransmitter, glutamate, can suffer from a variety of disorders, many of which are associated with epilepsy. While our previous research has focused on studying glutamate receptors and their role in neuronal communication, the project funded by ERUK allows us to extend our work to a pre-clinical model that is a direct correlate of epileptic encephalopathy.” Professor David Wyllie (pictured)
Neurons communicate with each other using special chemicals known as neurotransmitters, which are classified as being either excitatory (meaning that they increase the likelihood that the neurons they act upon fire signals), or inhibitory (meaning that they decrease the likelihood of firing). The main excitatory and inhibitory neurotransmitters in the brain are called glutamate and GABA respectively, and they act via protein structures called receptors (which they ‘activate’). A fine balance between excitation and inhibition must exist in order for the brain to function properly. If for some reason there is too much excitation, signalling becomes uncontrolled and there is a risk of seizures.
Mutations in a gene called GRIN2A, which encodes a protein called GluN2A, can lead to a reduction in one type of receptor that is activated by glutamate. This reduction can make individuals more susceptible to epileptic seizures, but the mechanisms that underlie this are not clear.
Professor Wyllie and his colleagues have generated a genetically-engineered rodent to mimic the effects of the loss GluN2A. In the current project, they plan to record the small electrical signals generated when glutamate acts at its receptors to:
- investigate how signalling is altered when GluN2A expression is reduced
- determine what interventions can be used to correct this altered signalling and potentially reduced the incidence of seizures
This research will give detailed insights into neuronal communication in the hippocampus (an important memory structure in which seizures frequently originate), at both the single cell and neuronal circuit level. It is a knowledge-gaining project, but the findings could potentially pave the way for the development of new epilepsy treatments in the next 10-15 years.
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