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Neurosteroid interactions with synaptic and extrasynaptic GABAA receptors: regulation of subunit plasticity, phasic and tonic inhibition, and neuronal network excitability

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An Erratum to this article was published on 19 October 2013

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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  1. Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, 2008 Medical Research and Education Building, 8447 State Highway 47, Bryan, TX, 77807-3260, USA

    Chase Matthew Carver & Doodipala Samba Reddy

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  1. Chase Matthew Carver
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  2. Doodipala Samba Reddy
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Correspondence to Doodipala Samba Reddy.

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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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