The neurobiological consequences of early stress and childhood maltreatment

GABA(A) (gamma-aminobutyric acid type A) receptors mediate most of the 'fast' synaptic inhibition in the mammalian brain and are targeted by many clinically important drugs. Certain naturally occurring pregnane steroids can potently and specifically enhance GABA(A) receptor function in a nongenomic (direct) manner, and consequently have anxiolytic, analgesic, anticonvulsant, sedative, hypnotic and anaesthetic properties. These steroids not only act as remote endocrine messengers, but also can be synthesized in the brain, where they modify neuronal activity locally by modulating GABA(A) receptor function. Such 'neurosteroids' can influence mood and behaviour in various physiological and pathophysiological situations, and might contribute to the behavioural effects of psychoactive drugs.

Neurosteroids: endogenous regulators of the GABAA receptor

The neurobiology and control of anxious states

Neuroactive steroids are potent modulators of γ-aminobutyric acid type A receptors (GABAARs), and their behavioral effects are generally viewed in terms of altered inhibitory synaptic transmission. Here we report that, at concentrations known to occur in vivo, neuroactive steroids specifically enhance a tonic inhibitory conductance in central neurons that is mediated by extrasynaptic δ subunit-containing GABAARs. The neurosteroid-induced augmentation of this tonic conductance decreases neuronal excitability. Fluctuations in the circulating concentrations of endogenous neuroactive steroids have been implicated in the genesis of premenstrual syndrome, postpartum depression, and other anxiety disorders. Recognition that δ subunit-containing GABAARs responsible for a tonic conductance are a preferential target for neuroactive steroids may lead to novel pharmacological approaches for the treatment of these common conditions.

Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by δ subunit-containing GABAA receptors

Although general anaesthesia has been of tremendous importance for the development of surgery, the underlying mechanisms by which this state is achieved are only just beginning to be understood in detail. In this review, we describe the neuronal systems that are thought to be involved in mediating clinically relevant actions of general anaesthetics, and we go on to discuss how the function of individual drug targets, in particular GABA(A)-receptor subtypes, can be revealed by genetic studies in vivo.

Molecular and neuronal substrates for general anaesthetics.

γ-Aminobutyric acid (GABA) type A receptors mediate fast inhibitory synaptic transmission and have been implicated in responses to sedative/hypnotic agents (including neuroactive steroids), anxiety, and learning and memory. Using gene targeting technology, we generated a strain of mice deficient in the δ subunit of the GABA type A receptors. In vivo testing of various behavioral responses revealed a strikingly selective attenuation of responses to neuroactive steroids, but not to other modulatory drugs. Electrophysiological recordings from hippocampal slices revealed a significantly faster miniature inhibitory postsynaptic current decay time in null mice, with no change in miniature inhibitory postsynaptic current amplitude or frequency. Learning and memory assessed with fear conditioning were normal. These results begin to illuminate the novel contributions of the δ subunit to GABA pharmacology and sedative/hypnotic responses and behavior and provide insights into the physiology of neurosteroids.

https://www.pnas.org/content/pnas/96/22/12905.full.pdf

Attenuated sensitivity to neuroactive steroids in γ-aminobutyrate type A receptor delta subunit knockout mice

The δ subunit of the γ-aminobutyric acid (A) receptor (GABAAR) is expressed postnatally mostly in the cerebellum, thalamus, and dentate gyrus. Previous studies in mice with a targeted disruption of...

Reduced Inhibition and Sensitivity to Neurosteroids in Hippocampus of Mice Lacking the GABAA Receptor δ Subunit

Summary:  Purpose: Mice with a targeted disruption of the γ-aminobutyric acid (A) receptor (GABAAR) δ subunit exhibited spontaneous seizures and a strikingly selective attenuation of responses to neuroactive steroids, but not to other neuromodulators. This study further characterized the behavior and physiology of the δ mutants.



Methods: Seizure susceptibility to pentylenetetrazol (PTZ) injection, intracellular recordings, and whole-cell patch recordings in dentate granule neurons was determined.



Results: Susceptibility to PTZ-induced convulsive seizures was significantly higher in −/− versus +/+ mice. In intracellular recordings, the evoked inhibitory postsynaptic potentials (IPSPs) had much faster decay τ in −/− mutants (25 ± 3.5 ms) compared with +/+ controls (51 ± 5.2 ms). In whole-cell patch recordings, the decay τ of pharmacologically isolated miniature spontaneous GABAAR-mediated synaptic currents (mIPSCs) from −/− mice was only slightly, but significantly faster (5.7 ± 0.13 ms; n = 18) than that of +/+ controls (6.8 ± 0.32 ms; n = 20). Furthermore, mIPSC prolongation by bath application of alphaxalone (10 μM), was much smaller in −/− mice (52 ± 12%; n = 3) compared with +/+ littermates (192 ± 14%; n = 3).



Conclusions: Faster decay of evoked IPSPs and mIPSCs is consistent with altered GABAAR subunit composition in the δ mutants, but suggests predominant extrasynaptic δ subunit location in the dentate gyrus of normal mice. Faster-decaying IPSPs likely contribute to the proepileptic phenotype of the δ mutants. Reduced neurosteroid sensitivity might also contribute to seizure susceptibility. It remains to be determined whether δ subunit–containing GABAARs represent the actual target of neurosteroids or whether the behavioral and physiologic sensitivity to neurosteroids is indirectly altered in the δ−/− mice.

Zhiwei Li

Papers

Attenuated sensitivity to neuroactive steroids in γ-aminobutyrate type A receptor delta subunit knockout mice

Reduced Inhibition and Sensitivity to Neurosteroids in Hippocampus of Mice Lacking the GABAA Receptor δ Subunit

Behavior and Physiology of Mice Lacking the GABAA‐Receptor δ Subunit

Receptors Mediating Tonic Inhibition and Neurosteroid Sensitivity A