Neurosteroids and GABA-A receptors and their roles in neuropsychiatric disorders

The brain receives and sorts information by individual nerve cells communicating with each other using a process known as chemical neurotransmission. This involves networks of cells becoming broadly excited or inhibited to control key aspects of mental function such as memory and the overall behaviour of individuals. The basis for this is the release of chemicals (neurotransmitters) from one nerve cell that binds to specific protein receptors on another, to cause excitation or inhibition. One major neurotransmitter in the brain is GABA. It is responsible for dampening nerve cell excitation by causing inhibition - it does this by interacting with a class of receptors known as GABA-A receptors (GABA-ARs). Most nerve cells in the brain will possess GABAARs underlining the pivotal role that they play in fundamental aspects of brain function including the following examples of - cognition, memory, sleep, sensation, control of muscle movement and response to stress. Indeed, so important are these receptors that their dysfunction is directly implicated in numerous and serious neurological and mental health disorders, such as anxiety and depression, epilepsy, schizophrenia, pain, substance addiction, autism, Down's and Fragile-X syndromes, to name only a few. As a consequence, GABAARs are widely recognised as molecular targets for therapeutic drug classes that include the benzodiazepines (BDZs) and general anaesthetics. Of equal significance, GABA-ARs are also subject to regulation by a number of endogenous agents in the brain. Prime amongst these are the neurosteroids, which are released from cells and can potentiate GABA-AR function at very low concentrations. Dysfunctional neurosteroid production is also implicated in neurological diseases, such as anxiety and depression, pain and catamenial epilepsy, and this is thought to involve altered GABA-AR function. It is therefore critical to understand how neurosteroids regulate GABA-ARs, what neural circuits are involved, how this contributes to disease, and how neurosteroids may be used as therapeutic agents. Our recent breakthrough in identifying the molecular basis for neurosteroid binding sites on GABA-ARs enables us to address these questions and determine precisely which types of GABA-ARs are involved in particular actions of the neurosteroids. Our aims are to use a combination of techniques, some involving genetic engineering, to determine how neurosteroids regulate selected GABA-ARs and to broaden our understanding of neuropsychiatric disease when neurosteroid regulation becomes dysfunctional. We will use the neurosteroid modulatory site on GABA-ARs to facilitate the development of novel therapeutics for the treatment of neurological disorders. Our aim is to improve understanding of mechanisms that may precipitate mental illness and to provide new approaches to its prevention and treatment. Specifically, we have four goals - (i) to examine what actions of the neurosteroids are mediated by a specific isoform of the GABA-AR that is involved in mediating anxiety and pain; (ii) to understand how modification of GABA-ARs by naturally-occurring enzymes in the brain affects neurosteroid modulation; (iii) to probe these interactions with neurosteroids at another important GABA-AR that is involved in dampening excitation and is implicated in substance addiction; and (iv) to examine how we can develop new neurosteroid agents for therapeutic benefit. The outcomes from our programme of work will have many implications. Chiefly, it will provide much needed information on the basis by which neurosteroids work in the brain, how they regulate GABA-ARs under physiological conditions and what happens during dysfunction to precipitate disease. By exploring the neurosteroid binding site, we now have for the first time, an opportunity to provide new impetus for the treatment of neurological diseases.