Neurosteroidogenesis Is Required for the Physiological Response to Stress: Role of Neurosteroid-Sensitive GABA-A Receptors

The study demonstrated that the neurosteroid tetrahydrodeoxycorticosterone (THDOC) modulated corticotropin-releasing hormone (CRH) neurons via δ subunit-containing GABA A receptors, influencing the hypothalamic-pituitary-adrenal (HPA) axis response to stress. Under normal conditions, THDOC enhanced GABA's inhibitory effects on CRH neurons, reducing HPA axis activity. However, following stress, THDOC activated the HPA axis by altering chloride gradients, leading to excitatory GABAergic transmission. This effect was absent in Gabrd −/− mice, indicating the role of GABA A R δ subunit-containing receptors. Blocking neurosteroidogenesis with finasteride prevented stress-induced corticosterone elevation and anxiety-like behaviors in mice. The findings suggested that neurosteroids' feedback on CRH neurons was essential for the stress response, and targeting GABA A R δ subunit-containing receptors and KCC2 phosphorylation could offer therapeutic potential for disorders like Cushing's syndrome, epilepsy, and major depression.