Mechanistic studies of Neurosteroid Analogues

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Project Summary Neurosteroids such as allopregnanolone (AlloP) strongly potentiate GABAA receptor function, driving the view that these effects mediate psychoactive effects of neuroactive steroids (NAS). The rapid antidepressant actions of AlloP seem to belie a solely GABAergic mechanism. Understanding the additional mechanisms of NAS will allow evolution of the next generation of treatments. We seek to both understand mechanisms by which AlloP promotes therapeutic benefit and to improve on these benefits with NAS that possess additional and/or alternative mechanisms. The Center leverages a unique set of NAS analogues. This project's first Aim is to evaluate the impact of these analogues on underappreciated ion channel targets of NAS: voltage-gated Ca2+ channels and NMDA receptors. This aim will work in concert with Project 1 to identify sites of action on NMDA receptors. In addition, this aim will re-evaluate the GABAA receptor subtype selectivity of NAS in native cells. The second aim of the study is to limit NAS actions to plasma membrane receptors using novel tethered ligand approaches. This will reveal NAS effects in the absence of intracellular targets, which we will explore in Aim 3 with evaluation of compounds' activity on neuroinflammatory cytokines and autophagy pathways. This aim follows up on preliminary data that suggests that NAS unnatural enantiomers influence the function of these intracellular targets, and project 1 will explore potential relevant protein targets that mediate these effects. A final aim is to evaluate the impact of various NAS analogues on functional microcircuitry of ex vivo brain circuits. This project will identify the most interesting set of compounds for evaluation in project 3, which explores in vivo physiology and circuitry.