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

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 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 provide many opportunities to create improved therapies for sleep, anxiety, stress, epilepsy, and other neuropsychiatric conditions.

Synaptic-Type α1β2γ2L GABAA Receptors Produce Large Persistent Currents in the Presence of Ambient GABA and Anesthetic Drugs

“…Under physiologic conditions, GABA A receptors, including synaptic receptors, are exposed to endogenous modulators such as neuroactive steroids (Carver and Reddy, 2013). Under clinical conditions, GABA A receptors can be exposed to GABAergic sedative drugs such as propofol, etomidate, or barbiturates.…”

GABA Receptors: Pharmacological Potential and Pitfalls

“…Synaptic GABAA receptors are activated transiently after the release of GABA from presynaptic vesicles, while extrasynaptic GABAA receptors are in general activated continuously, controlling neuronal excitability and the strength of synaptic transmission [37][38][39][40][41].…”

“…In general, they potently enhance function of synaptic and extrasynaptic GABAA receptors by an allosteric mechanism [31,40,166,167]. Neurosteroids possess distinct, characteristic effects on the membrane potential and current conductance mainly via potentiation of GABAA receptors at low doses, and direct activation of receptor chloride channel at higher concentrations.…”

“…Neurosteroids possess distinct, characteristic effects on the membrane potential and current conductance mainly via potentiation of GABAA receptors at low doses, and direct activation of receptor chloride channel at higher concentrations. As a results, upon administration neurosteroids exert anxiolytic, analgesic, anticonvulsive, sedative and hypnotic effects, while applied at higher doses may induce a state of general anesthesia [40,[168][169][170][171]. Although the most important effects of neurosteroids are mediated via GABAA receptors, they also exert various effects on an array of ligand-gated ion channels and distinct…”

Current and Future Issues in the development of spinal agents for the management of pain

“…This binding forces a conformation where GABA displays a higher affinity increasing the frequency of opening of the ion channel [234]. Similarly, several neurosteroids such as allopregnanolone will bind to the GABA-A ionophore and force conformational changes enhancing GABA effects [235,236]. Immunohistochemical studies have shown dense staining in spinal Rexed laminae for several alpha, beta and gamma subunits likely corresponding to primary afferents [237,238] presumably localized on primary afferent terminals.…”