Role of the GABA transporter, GAT-3, in regulating network excitability in the hippocampus

The hippocampus is a part of the brain that plays a key role in memory and learning. Damage to or dysfunction of the hippocampus is important for the symptoms of a number neurological diseases including Alzheimer's disease and epilepsy. Indeed, damage to the hippocampus from prolonged convulsions in childhood is the commonest cause of drug-resistant epilepsy.
In order for the hippocampus to operate normally, there is a fine balance between excitation mediated by the neurotransmitter glutamate, and inhibition mediated by the neurotransmitter GABA. Understanding how these two processes work can help understand the manifestations of neurological disease and how to treat them.
Throughout the brain there are nerve cells and glia. Nerve cells communicate with one another and are crucial for brain activity. Glia were once considered "the glue" of the brain and to play purely a supportive role. However, one of the major recent advances in neuroscience is the realisation that glia also play a critical role in brain activity and can also "communicate" to one another and to neurons.
Glia can regulate GABA in the hippocampus by mean of a GABA transporter termed GAT3, but also we have recently discovered that activation of GAT3 can result in the release of other chemicals that modify hippocampal function. This research asks how do these different roles of GAT3 complement one another and how does GAT3 control inhibition in the hippocampus. In addition, we will be asking whether modifying GAT3 activity can be used to treat epilepsy.
Addressing these questions is critical as GAT3 is a druggable target that could be used to treat a range of neurological and neurodegenerative conditions from epilepsy to Alzheimer's disease.

GAT1 and GAT3, are the two main GABA transporters in the hippocampus. These play a critical role in regulating the concentration of the major inhibitory transmitter GABA in the extracellular space. This is crucial as extracellular GABA can act on extrasynaptic GABA(A) receptors on neurons to mediate a powerful form of tonic inhibition of neurons, regulating signal processing and memory.
These two transporters, however, serve different roles and have a distinct distribution, so that GAT1 is mainly expressed on neurons, whilst GAT3 is mainly expressed on glia. GAT1 is the main regulator of extracellular GABA in the hippocampus, whilst GAT3 only comes into play during excessive neuronal activity.
We have recently shown that GAT3 serves a secondary role in that it enables glia to detect extracellular GABA concentrations and consequently network activity and to respond to this by releasing gliatransmitters that have a marked influence on network excitability. This may serve as a powerful homeostatic mechanism regulating network excitability over long time periods. However, many questions on the role of GAT3 remain unanswered. Can it work in reverse to increase the concentration of GABA in the extracellular space and under what conditions? What is the range of inhibitory and excitatory gliatransmitters that are released with GAT3 activation and does this depend upon circumstances (eg the degree of GAT3 activation and the activation of other glia receptors)? What is the role of GAT-3 during excessive neuronal activity such as occurs with seizures? What is the impact of changes in GAT3 expression that occurs during the development of epilepsy and other neurological disease? Addressing these questions is critical as GAT3 is a druggable target that could be used to treat a range of neurological and neurodegenerative conditions from epilepsy to Alzheimer's disease.

This work will provide fundamental insights into mechanisms regulating interactions between astroglia and synaptic circuits, and how this impacts upon seizures and epilepsy. The work will have, however, wider applicability as dysregulation of glial-neuronal communication and GABA homeostasis have been proposed to play a part in a range of brain diseases including Alzheimer's disease, Schizophrenia, Down Syndrome and depression. In the longer term, we would expect our research to have a broad impact on neurological disease.

From the pharmacological perspective, in the commercial and private sector, companies interested in developing novel approaches to treating seizures will benefit from a currently unexploited target, GAT3, which is an obvious candidate for new drug development.

Patients and their clinicians are another potential beneficiary from our findings. Approximately 1% of the population is affected by epilepsy, of whom over 20% continue to have seizures despite optimal pharmacotherapy. Those who continue to have seizures experience major co-morbidities and social exclusion. The annual risk of sudden unexpected death in refractory epilepsy is around 0.5%. The annual cost of epilepsy to the European Union was estimated at Euro 15.5 billion (2004). The treatment gap is immense, and epilepsy research is underfunded in comparison to diseases of comparable impact. Per patient, Parkinson's disease and multiple sclerosis research receive 7 times more funding from the NIH (Meador, Neurology 2011). In the longer term we hope our work will provide options for drugs that evade current mechanisms of drug resistance.

Timescales: During the course of the project we will present data at symposia that will reach our academic and clinical beneficiaries. Our publications will fall towards the end of the project, and shortly thereafter. By the end of the project (3 years) we hope that our findings will be informing other studies of the role of GAT3 in epilepsy, and after our publication (6+ years) these data may lead to rationally targeted novel drugs.

Skills for staff on project: The staff will benefit from the development of advanced skills in electrophysiology, neuroimaging, models of epilepsy and computer modelling. We have found skilled electrophysiologists to be in high demand (both when we try to recruit, and when students graduate from the group), thus we anticipate that the skills developed in this project will place the researcher in high demand for future positions.