Grant round winners 2013
The events leading up to a seizure are still not clear, and this makes it difficult for scientists to design the most effective anti-epileptic drugs. GABA, the main inhibitory neurotransmitter in the brain, is an important regulator of neuronal excitability; and its role in seizure initiation is the focus of much ongoing research.
Recent evidence suggests that when epileptic discharges (bursts of electrical activity in neurons) occur in the brain, some GABA signals from special connecting neurons called interneurons may actually stimulate these discharges rather than dampen them. Dr Ivan Pavlov and colleagues, at University College London, have been awarded £138,634, over 24 months, to carry out a project entitled Optogenetic control of GABAergic interneurons during epileptiform activity; in which they will try and find out whether manipulation of these interneurons can help to stop or reduce epileptic discharges once they have begun.
During the study, the team will trigger epileptic activity in brain slices using standard experimental methods. They will then use cutting edge optogenetic techniques to try and control GABA signalling mediated by different groups of interneurons at different time points. In optogenetics, weakened viruses are used to incorporate a gene into a particular population of cells. The gene in question encodes a special type of ion channel or pump that is activated by light of a certain wavelength. By shining the appropriate light on the cells, the researcher can control whether or not the cells are active or dormant.
In the current study, this technique will be used to incorporate one of two genes into different populations of interneurons. The light-sensitive molecules (opsins) encoded by one of these genes switch interneurons off when activated, whilst opsins encoded by the other gene switch interneurons on when activated.
By alternately activating and deactivating different groups of interneurons, and measuring the effect on the epileptic activity, the team hopes to gain a clearer understanding of how seizures begin and the role that GABA plays. This could potentially lead to new, more targeted, approaches to epilepsy treatment.
This work will build upon the Epilepsy Research UK Fellowship, entitled Cell type-specific modulation of tonic GABA(A) receptor-mediated conductances in epilepsy, that Dr Pavlov was awarded in 2009 and completed in 2012.