Abstract
Rationale
Neurosteroids are steroids synthesized within the brain with rapid effects on neuronal excitability. Allopregnanolone, allotetrahydrodeoxycorticosterone, and androstanediol are three widely explored prototype endogenous neurosteroids. They have very different targets and functions compared to conventional steroid hormones. Neuronal γ-aminobutyric acid (GABA) type A (GABAA) receptors are one of the prime molecular targets of neurosteroids.
Objective
This review provides a critical appraisal of recent advances in the pharmacology of endogenous neurosteroids that interact with GABAA receptors in the brain. Neurosteroids possess distinct, characteristic effects on the membrane potential and current conductance of the neuron, mainly via potentiation of GABAA receptors at low concentrations and direct activation of receptor chloride channel at higher concentrations. The GABAA receptor mediates two types of inhibition, now characterized as synaptic (phasic) and extrasynaptic (tonic) inhibition. Synaptic release of GABA results in the activation of low-affinity γ2-containing synaptic receptors, while high-affinity δ-containing extrasynaptic receptors are persistently activated by the ambient GABA present in the extracellular fluid. Neurosteroids are potent positive allosteric modulators of synaptic and extrasynaptic GABAA receptors and therefore enhance both phasic and tonic inhibition. Tonic inhibition is specifically more sensitive to neurosteroids. The resulting tonic conductance generates a form of shunting inhibition that controls neuronal network excitability, seizure susceptibility, and behavior.
Conclusion
The growing understanding of the mechanisms of neurosteroid regulation of the structure and function of the synaptic and extrasynaptic GABAA receptors provides many opportunities to create improved therapies for sleep, anxiety, stress, epilepsy, and other neuropsychiatric conditions.
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Abbreviations
- 3α-HSOR:
-
3α-Hydroxysteroid oxidoreductase
- 17PA:
-
(3α,5α)-17-Phenylandrost-16-en-3-ol
- AP:
-
Allopregnanolone (3α-hydroxy-5α-pregnan-20-one)
- CGC:
-
Cerebellar granule cell
- CNS:
-
Central nervous system
- DGGC:
-
Dentate gyrus granule cell
- DHEAS:
-
Dehydroepiandrosterone sulfate
- GABARAP:
-
GABAA receptor-associated protein
- IPSC:
-
Inhibitory postsynaptic current
- NMDA:
-
N-Methyl-d-aspartate
- P:
-
Progesterone
- PS:
-
Pregnenolone sulfate
- TBI:
-
Traumatic brain injury
- TBPS:
-
tert-Butylbicyclophosphorothionate
- THDOC:
-
Allotetrahydrodeoxycorticosterone (3α,21-dihydroxy-5α-pregnan-20-one)
- THIP:
-
4,5,6,7-Tetrahydroisoxazolo[5,4-c]pyridine-3-ol
- TLE:
-
Temporal lobe epilepsy
- TSPO:
-
Translocator protein
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Acknowledgments
This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke Grants NS051398, NS071597, and NS076426 (to D.S.R.). We thank Drs. William Griffith and Gerald Frye for comments on the manuscript. The authors would like to thank Xin Wu for technical help with illustrations.
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Carver, C.M., Reddy, D.S. Neurosteroid interactions with synaptic and extrasynaptic GABAA receptors: regulation of subunit plasticity, phasic and tonic inhibition, and neuronal network excitability. Psychopharmacology 230, 151–188 (2013). https://doi.org/10.1007/s00213-013-3276-5
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DOI: https://doi.org/10.1007/s00213-013-3276-5