Grant winner 2017

Surprisingly little remains known about the contribution of different cell types in the generation of seizures. While the conventional view is that seizure onset and maintenance are associated with failed inhibitory control of network excitability, some studies point that hyperactivity of interneurons may paradoxically play a role in the generation of pathological epileptiform discharges. Since many antiepileptic drugs target GABAergic neurotransmission, it is important to resolve this controversy. Our experimental approach is beneficial for novel drug development and will help establish better targeted interventions based on gene therapy.Dr Ivan Pavlov (pictured)

Grant type: Project grant

Principal investigator: Dr Ivan Pavlov

Institution: University College London

Amount: £149,947

Duration: 24 months

Scientific title: The role of parvalbumin-positive interneurons in the generation of epileptiform discharges in vivo

Background
Epileptic seizures are caused by excessive activity of groups of neurons in the brain, and many treatments aim to suppress this by increasing inhibitory signalling. Studies in extracted brain tissue have now shown that certain inhibitory neurons that were supposed to stop pathological (disease-causing) ‘firing’ can actually promote seizure activity; however, it is not clear how this happens, or what its role in living organisms is.

The study
Here, Dr Pavlov and colleagues will explore the behaviour of selected inhibitory neurons during seizures, in awake rodents. They will investigate two theories about how inhibitory neurons might promote seizures: 1) that these neurons ‘fire’ so much to suppress excitation when a seizure begins that they become unable to do so, and 2) that during a seizure their inhibitory actions progressively weaken and may even convert to excitatory activity due to activity-dependent chloride accumulation in surrounding cells.

During the project the team will implant a window made from transparent film into the skulls of rodents to allow easy access to their brains. Seizures will be chemically induced and tiny electrodes will be used to record the electrical activity of individual inhibitory neurons in the rodents’ brains. The scientists will also probe the neurons’ behaviour using a cutting-edge technique called optogenetics, which allows researchers to control the activity of cells with light.

To explore whether chloride is a part of the seizure-promoting activity of inhibitory neurons, the group will genetically manipulate the neurons so that they are able to pump chloride out more efficiently. They will then assess the neurons’ behaviour during seizures to see if decreasing their chloride load changes their function.

The team will perform the investigations in both healthy rodents and those with chronic epilepsy. By comparing the results, they will be able to see whether inhibitory neurons change their functional role in epilepsy.

Significance
This important project will help us to better understand the mechanisms that underlie epilepsy. This is crucial for the identification of new drug targets and the development of novel therapies.

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