Allopregnanolone mediates affective switching through modulation of oscillatory states in the basolateral amygdala

Antonoudiou, P.; Colmers, P. L.; Walton, N. L.; Weiss, G. L.; Smith, A. C.; Nguyen, D. P.; Lewis, M.; Quirk, M. C.; Melon, L. C.; Maguire, J. L.

doi:10.1101/2021.03.08.434156

bioRxiv · 10.1101/2021.03.08.434156

Allopregnanolone mediates affective switching through modulation of oscillatory states in the basolateral amygdala

Antonoudiou, P.·Colmers, P. L.·Walton, N. L.·Weiss, G. L.·Smith, A. C.·Nguyen, D. P.·Lewis, M.·Quirk, M. C.·Melon, L. C.·Maguire, J. L.

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Abstract

Brexanolone (allopregnanolone), was recently approved by the FDA for the treatment of post-partum depression, demonstrating long-lasting antidepressant effects. Despite our understanding of the mechanism of action of neurosteroids as positive allosteric modulators (PAMs) of GABAO_SCPLOWAC_SCPLOW receptors, we still do not fully understand how allopregnanolone exerts these persistent antidepressant effects. Here, we demonstrate that allopregnanolone and similar synthetic neuroactive steroid analogs, SGE-516 (tool-compound) and zuranolone (SAGE-217, investigational-compound), are capable of modulating oscillatory states across species, which we propose may contribute to long-lasting changes in behavioral states. We identified a critical role for interneurons in generating oscillations in the basolateral amygdala (BLA) and a role for delta-containing GABAO_SCPLOWAC_SCPLOWRs in mediating the ability of neurosteroids to modulate network and behavioral states. Actions of allopregnanolone in the BLA is sufficient to alter behavioral states and enhance BLA high-theta oscillations (6-12Hz) through delta-containing GABAO_SCPLOWAC_SCPLOW receptors, a mechanism distinct from other GABAO_SCPLOWAC_SCPLOW PAMs, such as benzodiazepines. Moreover, treatment with the allopregnanolone analog SGE-516 induces long-lasting protection from chronic stress-induced disruption of network states, which correlates with improved behavioral outcomes. Our findings demonstrate a novel molecular and cellular mechanism mediating the well-established anxiolytic and antidepressant effects of neuroactive steroids.

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Antonoudiou, P., Colmers, P. L., Walton, N. L., Weiss, G. L., Smith, A. C., Nguyen, D. P., Lewis, M., Quirk, M. C., Melon, L. C., Maguire, J. L.. 2021-03-09. Allopregnanolone mediates affective switching through modulation of oscillatory states in the basolateral amygdala. https://doi.org/10.1101/2021.03.08.434156

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