A new mechanism for absence seizures
ERUK Fellow Dr Murray Herd, from the University of Dundee, has discovered a new mode of signalling in neurons that may promote absence seizures.
Absence seizures can occur between 20 and several hundred times per day, and they usually last between five and 20 seconds. During a seizure the person usually loses consciousness briefly; stops whatever they are doing; and stares blankly into space.
On EEG, absence seizures are characterised by a particular pattern known as spike-wave discharges. Interestingly, these are produced by excessive, abnormal inhibition rather than too much excitation (as is usually reported); however it is still not clear how they come about. In 2010, Dr Murray Herd, at the University of Dundee, was awarded an Epilepsy Research UK fellowship to investigate this. His final report has now been submitted.
Fellowship background, aims and methodology
There are networks of neurons that exist between the thalamus in the centre of the brain, and the cortex – the folded brain surface. These pathways, known as thalamocortical circuits, play an important part in normal sleep production, but evidence shows that they are also vital in the generation of absence seizures. This led researchers to wonder whether absence seizures might arise from a distortion of electrical activity within thalamocortical circuits.
Pivotal to the function of thalamocortical circuits are cells in the thalamus that release the inhibitory messenger GABA. By acting on different types of receptor – found at the communication gateways between neurons (synaptic receptors) and just outside (extrasynaptic receptors) – GABA can produce short- and long-lived neuronal inhibition respectively. This fellowship aimed to find out just how these modes of inhibition respond to different levels of thalamic activity (higher levels being most associated with absence seizure brain patterns), and how they interact to produce absence seizures.
To carry out the study, Dr Herd acquired several strains of genetically engineered rodents and a ‘healthy’ control group. The former had been bred to lack a receptor component required for normal inhibition in the thalamus. He then measured the electrical activity in thalamocortical circuits in various conditions, to find out how a type of GABA receptor known as extrasynaptic GABAA responded to different levels of activity.
The project revealed some unexpected results. Dr Herd discovered that, instead of providing a constant but relatively static inhibitory ‘brake’ to neuronal excitability (as previously believed), extrasynaptic GABAA receptors are responsible for a highly dynamic inhibitory signal that varies in both and duration and intensity. He found that during bursts of GABA release (as are seen in absence seizures), these receptors were recruited in a ‘spillover’ mechanism to significantly increase inhibition. Importantly, this new inhibitory mode was amplified by abnormalities that are linked to absence seizure generation (e.g. a dysfunction in the processes that ‘mop up’ GABA after it has acted), but it was also highly sensitive to drugs that selectively target extrasynaptic GABAA receptors. This highlights a possible new treatment strategy for the future.
These findings suggest that abnormal enhancement of a spill-over mechanism involving extrasynaptic GABAA receptors might render thalamocortical networks more susceptible absence seizure generation. They also identify a potential drug target to counteract this excessive inhibition, and treat absence seizures more effectively.
Dr Herd commented, “The funding provided by ERUK was invaluable in allowing us to further explore the contribution of abnormal inhibitory mechanisms during absence seizure generation. Our study emphasises the likely importance of a specific aspect of inhibitory neuronal signalling requiring activation of extrasynaptic GABAA receptors. Encouragingly, we found that the newly identified signalling mechanism is highly sensitive to modification following drug treatments that selectively target extrasynaptic GABAA receptors. With this knowledge at hand, we now plan to use our close links with the pharmaceutical industry to identify and develop new molecules that, by selectively reducing the abnormally amplified inhibitory signal, may provide new drug strategies to improve the clinical outcome of patients who are resistant to, or poorly tolerate existing anti-absence medications.”