Neurosteroidogenesis Is Required for the Physiological Response to Stress: Role of Neurosteroid-Sensitive GABAAReceptors
Open accessAbstract
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 GABA A receptors (GABA A Rs). 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 GABA A R 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, GABA A R 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.
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Allopregnanolone's inhibitory effect on the HPA axis is exerted through action at GABA_A receptors and subsequent inhibition of PVN neurons under both basal and stressful conditions.
“This effect of allopregnanolone seems to be exerted through its action at GABAA receptors, and subsequent inhibition on PVN neurons (80) under both basal and stressful conditions (81).”
From Higher Circulating Cortisol in the Follicular vs. Luteal Phase of the Menstrual Cycle: A Meta-Analysis (2020) · cites this paper as [80]
The Discussion says allopregnanolone’s contribution to HPA-axis regulation requires further study and anticipates that it may excite, rather than inhibit, CRH neurons. The Results section, “Neurosteroids increase the activity of CRH neurons following stress,” reports that GABA’s action switches from inhibitory under basal conditions to largely excitatory after stress. The paper therefore contradicts inhibition under both conditions. (LLM, conf=0.90)
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- Authors
- Sarkar, J., Wakefield, S., MacKenzie, G., Moss, S. J., & Maguire, J.
- Affiliations
- Tufts University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-12-14
- Volume
- 31
- Issue
- 50
- Pages
- 18198-18210
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3272883
- OpenAlex
- W2004846311
- Cited by
- 254
- References
- 66
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 13 · 2023: 9 · 2022: 18 · 2021: 16 · 2020: 20 · 2019: 22 · 2018: 20 · 2017: 12 · 2016: 16 · 2015: 26 · 2014: 27 · 2013: 25 · 2012: 13
- FWCI
- 8.16
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Federation for Aging Research
- Center for Neuroscience Research (P30 NS047243)
- National Institute of Neurological Disorders and Stroke (NS047243, R01NS051195, R56 NS073574, P30NS047243, R01NS073574, NS073574, R01NS081986, R01NS102937)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- neurosteroidogenesis, tetrahydrodeoxycorticosterone, GABAA receptor, delta subunit, corticotropin-releasing hormone neurons, hypothalamic-pituitary-adrenal axis, stress response, chloride gradient, GABAergic inhibition, finasteride, stress-induced anxiety, corticosterone, Cushing's syndrome, epilepsy, major depressive disorder
- MeSH terms
- Animals, Behavior, Animal, Corticotropin-Releasing Hormone, Desoxycorticosterone, Hypothalamo-Hypophyseal System, Hypothalamus, Male, Mice, Transgenic, Neurons, Pituitary-Adrenal System, Receptors, GABA-A, Stress, Physiological, Finasteride, Neurotransmitter Agents, Mice, 5-alpha Reductase Inhibitors
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