Brain neurosteroids are natural anxiolytics targeting α2 subunit γ-aminobutyric acid type-A receptors

Durkin, E. J.; Muessig, L.; Herlt, T.; Lumb, M. J.; Patel, R.; Thomas, P.; Bright, D. P.; Jurd, R.; Moss, S. J.; Dickenson, A. H.; Cacucci, F.; Smart, T. G.

doi:10.1101/462457

bioRxiv · 10.1101/462457

Brain neurosteroids are natural anxiolytics targeting α2 subunit γ-aminobutyric acid type-A receptors

Durkin, E. J.·Muessig, L.·Herlt, T.·Lumb, M. J.·Patel, R.·Thomas, P.·Bright, D. P.·Jurd, R.·Moss, S. J.·Dickenson, A. H.·Cacucci, F.·Smart, T. G.

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Abstract

Neurosteroids are naturally-occurring molecules in the brain that modulate neurotransmission. They are physiologically important since disrupting their biosynthesis precipitates neurological disorders, such as anxiety and depression. The endogenous neurosteroids, allopregnanolone and tetrahydro-deoxycorticosterone are derived from sex and stress hormones respectively, and exhibit therapeutically-useful anxiolytic, analgesic, sedative, anticonvulsant and antidepressant properties. Their main target is the {gamma}-aminobutyric acid type-A inhibitory neurotransmitter receptor (GABAAR), whose activation they potentiate. However, whether specific GABAAR isoforms and neural circuits differentially mediate endogenous neurosteroid effects is unknown. By creating a knock-in mouse that removes neurosteroid potentiation from 2-GABAAR subunits, we reveal that this isoform is a key target for neurosteroid modulation of phasic and tonic inhibition, and is essential for the anxiolytic role of endogenous neurosteroids, but not for their anti-depressant or analgesic properties. Overall, 2-GABAAR targeting neurosteroids may act as selective anxiolytics for the treatment of anxiety disorders, providing new therapeutic opportunities for drug development.

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Durkin, E. J., Muessig, L., Herlt, T., Lumb, M. J., Patel, R., Thomas, P., Bright, D. P., Jurd, R., Moss, S. J., Dickenson, A. H., Cacucci, F., Smart, T. G.. 2018-11-08. Brain neurosteroids are natural anxiolytics targeting α2 subunit γ-aminobutyric acid type-A receptors. https://doi.org/10.1101/462457

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