GABAA receptors sculpt activity of neurons and are important in neuropsychiatric illnesses including schizophrenia, epilepsy, and autism. Drugs acting at GABAA receptors are important for treating anxiety and likely depression. We are studying two major classes of receptors by genetically engineering mice. The mice carry a mutation in a key subunit of the GABAA receptor that renders the receptor insensitive to areceptor antagonist. In this way we pharmacologically isolate receptor populations to study their characteristics, including responses to drugs and roles insculpting activity.
We are studying a cellular model of a CNS autoimmune disorder to evaluate treatment strategies. NMDA receptor encephalitis is caused by CNS auto-antibodies directed against NMDARs, a major class of glutamate receptor. When receptors are bound by antibody, they are internalized, leading to symptoms including psychosis, movement disorders, and seizures. We are evaluating potential treatments that restore normal levels of function to NMDARs using compounds characterized by our group
We are studying cholesterol metabolites, notably 24S-hydroxycholesterol and 25-hydroxycholesterol, as signaling molecules. The brain synthesizes its own cholesterol, some of which turns over.The labile pool is converted mainly to 24S-hydroxycholesterol in neurons. Instead of simply being waste, we find that the molecule may in fact have a neuromodulatory role by interacting with NMDA receptors to increase their function. Compounds that mimic the effect of 24S-hydroxycholesterol may have benefit in Alzheimer’s disease or schizophrenia.
With collaborators Doug Covey, we are exploring chemical biology approaches to understanding the above neuromodulators. We have developed and characterized novel analogues that include the ability to visualize compounds in situ, thereby lending insight into additional targets and insights into cellular factors that may control access of the compounds to plasma-membrane receptors.