Psychopharmacology

, Volume 230, Issue 2, pp 151–188

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

Review

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.

Keywords

GABA GABAA receptor Neurosteroid Allopregnanolone δ-Subunit Tonic inhibition Phasic inhibition Extrasynaptic receptors 

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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© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Department of Neuroscience and Experimental Therapeutics, College of MedicineTexas A&M University Health Science CenterBryanUSA

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