Abstract
BACKGROUND: Brexanolone (allopregnanolone) was recently approved by the Food and Drug Administration for the treatment of postpartum depression, demonstrating long-lasting antidepressant effects. Despite our understanding of the mechanism of action of neurosteroids as positive allosteric modulators of GABA(A) (gamma-aminobutyric acid A) receptors, we still do not fully understand how allopregnanolone exerts persistent antidepressant effects. METHODS: We used electroencephalogram recordings in rats and humans along with local field potential, functional magnetic resonance imaging, and behavioral tests in mice to assess the impact of neurosteroids on network states in brain regions implicated in mood and used optogenetic manipulations to directly examine their relationship to behavioral states. RESULTS: We demonstrated that allopregnanolone and synthetic neuroactive steroid analogs with molecular pharmacology similar to allopregnanolone (SGE-516 [tool compound] and zuranolone [SAGE-217, investigational compound]) modulate oscillations across species. We further demonstrated a critical role for interneurons in generating oscillations in the basolateral amygdala (BLA) and a role for δ-containing GABA(A) receptors in mediating the ability of neurosteroids to modulate network and behavioral states. Allopregnanolone in the BLA enhances BLA high theta oscillations (6-12 Hz) through δ-containing GABA(A) receptors, a mechanism distinct from other GABA(A) positive allosteric modulators, such as benzodiazepines, and alters behavioral states. Treatment with the allopregnanolone analog SGE-516 protects mice from chronic stress-induced disruption of network and behavioral states, which is correlated with the modulation of theta oscillations in the BLA. Optogenetic manipulation of the network state influences the behavioral state after chronic unpredictable stress. CONCLUSIONS: Our findings demonstrate a novel molecular and cellular mechanism mediating the well-established anxiolytic and antidepressant effects of neuroactive steroids.