Nerve cells in the brain rely on tiny gateways called GABA-A receptors to keep their electrical activity in check, and this project will uncover how those gateways are moved into and out of position at the cell surface. When these receptors malfunction, the result can be uncontrolled brain activity—most visibly in epilepsy. The researchers have already identified where natural brain compounds called neurosteroids bind to the receptors, giving them a precise genetic tool to probe which receptor subtypes matter most. They will now track how receptors are trafficked to synapses, how their numbers change during synaptic plasticity, and what goes wrong in animal models of epilepsy. This is fundamental science. It will not produce a new drug tomorrow. But GABA-A receptors are already the targets of benzodiazepines, anaesthetics, and barbiturates. Understanding exactly how the brain regulates these receptors—and why regulation fails in disease—could eventually guide the design of more selective treatments for epilepsy and other conditions involving neural hyperexcitability, with fewer side effects than current drugs.
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For the brain to function coherently, it is vital that individual nerve cells exert some control over their innate excitability. The main mechanism by which this is achieved involves the process of synaptic inhibition. Principally, this requires nerve cells to express GABA-A receptors at selected locations on their cell surface which are located opposite presynaptic nerve terminals releasing the neurotransmitter GABA. These structures are known as synapses. It is the release of GABA that activates the receptors causing a rapid but brief flow of chloride ions across the cell membrane through ion channels contained within the receptor structure. This flow either causes the cell to hyperpolarize, or massively increases the membrane conductance of the cell membrane, thereby reducing neuronal excitation. These receptors are known targets for numerous drugs, including, benzodiazepines, barbiturates, general anaesthetics and neurosteroids. A malfunction in synaptic inhibition, which could occur as a result of, a receptor mutation; a reduction in receptor numbers near GABA-releasing terminals; or because of dysregulation by naturally-occurring agents in the brain, can easily result in uncontrolled excitability with devastating consequences for humans, e.g., epilepsy. This research programme will focus on understanding the molecular mechanisms by which GABA-A receptors are regulated at or near synapses, and specifically what controls their movement (trafficking) into and out of synapses in the cell surface membrane. We will also concentrate on identifying which endogenous regulatory processes are important in modulating GABA-A receptor function and how they influence receptor trafficking. To this end, we have recently solved where a group of endogenous compounds in the brain, known as neurosteroids, bind to and modulate GABA-A receptors. With this knowledge we can use a genetic approach to dissect the importance of particular GABA-A receptor subtypes in health and disease processes. We plan to integrate our new knowledge into achieving a better understanding of how GABA-A receptors are regulated at synapses by studying synaptic plasticity: a phenomenon whereby synaptic transmission between neurones can be manipulated over time; and also by using animal models of disease, principally epilepsy. These aims will be achieved using cellular, genetic, molecular and pharmacological approaches in conjunction with novel techniques to explain how the most important inhibitory receptor in the brain controls nerve cell excitability. This study will be performed at UCL which is a recognised centre of excellence in neuroscience. The results of this research will be disseminated to the public via lectures and open publications
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