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

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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.