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Therapeutic Roles for Neurosteroids

We are investigating the mechanisms behind the therapeutic effects of the neurosteroid, allopregnanolone. Allopregnanolone acts as a positive allosteric modulator of GABAA receptors and has been shown to have rapid-acting and long-lasting anti-depressant effects as well as neuroprotective effects. We are studying the effects of allopregnanolone in both mice and cell cultures to better understand its therapeutic potential in treating psychiatric disease.

Along with allopregnanolone, we are investigating the mechanisms behind other neuroactive steroid analogues. This work forms part of the Conte Center, in particular, Project 3.

Mysterious GABA Receptors

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 a receptor antagonist.  In this way we pharmacologically isolate receptor populations to study their characteristics, including responses to drugs and roles in sculpting activity. 

Signaling from the Brain’s Trash

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.

Chemical Biology Tools

With collaborator 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.