RT Journal Article SR Electronic T1 Neurosteroidogenesis Is Required for the Physiological Response to Stress: Role of Neurosteroid-Sensitive GABAA Receptors JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 18198 OP 18210 DO 10.1523/JNEUROSCI.2560-11.2011 VO 31 IS 50 A1 Jhimly Sarkar A1 Seth Wakefield A1 Georgina MacKenzie A1 Stephen J. Moss A1 Jamie Maguire YR 2011 UL http://www.jneurosci.org/content/31/50/18198.abstract AB The hypothalamic-pituitary-adrenal (HPA) axis, which mediates the body's response to stress, is largely under GABAergic control. Here we demonstrate that corticotropin-releasing hormone (CRH) neurons are modulated by the stress-derived neurosteroid, tetrahydrodeoxycorticosterone (THDOC), acting on δ subunit-containing GABAA receptors (GABAARs). Under normal conditions, THDOC potentiates the inhibitory effects of GABA on CRH neurons, decreasing the activity of the HPA axis. Counterintuitively, following stress, THDOC activates the HPA axis due to dephosphorylation of KCC2 residue Ser940, resulting in a collapse of the chloride gradient and excitatory GABAergic transmission. The effects of THDOC on CRH neurons are mediated by actions on GABAAR δ subunit-containing receptors since these effects are abolished in Gabrd−/− mice under both control and stress conditions. Interestingly, blocking neurosteroidogenesis with finasteride is sufficient to block the stress-induced elevations in corticosterone and prevent stress-induced anxiety-like behaviors in mice. These data demonstrate that positive feedback of neurosteroids onto CRH neurons is required to mount the physiological response to stress. Further, GABAAR δ subunit-containing receptors and phosphorylation of KCC2 residue Ser940 may be novel targets for control of the stress response, which has therapeutic potential for numerous disorders associated with hyperexcitability of the HPA axis, including Cushing's syndrome, epilepsy, and major depression.