Neurosteroid interactions with synaptic and extrasynaptic GABAA receptors: regulation of subunit plasticity, phasic and tonic inhibition, and neuronal network excitability
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- Carver, C.M. & Reddy, D.S. Psychopharmacology (2013) 230: 151. doi:10.1007/s00213-013-3276-5
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.
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.
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.
KeywordsGABA GABAA receptor Neurosteroid Allopregnanolone δ-Subunit Tonic inhibition Phasic inhibition Extrasynaptic receptors
Cerebellar granule cell
Central nervous system
Dentate gyrus granule cell
GABAA receptor-associated protein
Inhibitory postsynaptic current
Traumatic brain injury
Temporal lobe epilepsy