Increasing evidence points to an association between major depressive disorders (MDDs) and diverse types of GABAergic deficits. In this review, we summarize clinical and preclinical evidence supporting a central and causal role of GABAergic deficits in the etiology of depressive disorders. Studies of depressed patients indicate that MDDs are accompanied by reduced brain concentration of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) and by alterations in the subunit composition of the principal receptors (GABA(A) receptors) mediating GABAergic inhibition. In addition, there is abundant evidence that suggests that GABA has a prominent role in the brain control of stress, the most important vulnerability factor in mood disorders. Furthermore, preclinical evidence suggests that currently used antidepressant drugs (ADs) designed to alter monoaminergic transmission and nonpharmacological therapies may ultimately act to counteract GABAergic deficits. In particular, GABAergic transmission has an important role in the control of hippocampal neurogenesis and neural maturation, which are now established as cellular substrates of most if not all antidepressant therapies. Finally, comparatively modest deficits in GABAergic transmission in GABA(A) receptor-deficient mice are sufficient to cause behavioral, cognitive, neuroanatomical and neuroendocrine phenotypes, as well as AD response characteristics expected of an animal model of MDD. The GABAergic hypothesis of MDD suggests that alterations in GABAergic transmission represent fundamentally important aspects of the etiological sequelae of MDDs that are reversed by monoaminergic AD action.

The GABAergic deficit hypothesis of major depressive disorder

This chapter provides an overview of neurosteroids, especially their impact on the brain, sex differences and their therapeutic potentials. Neurosteroids are synthesized within the brain and rapidly modulate neuronal excitability. They are classified as pregnane neurosteroids, such as allopregnanolone and allotetrahydrodeoxycorticosterone, androstane neurosteroids, such as androstanediol and etiocholanolone, and sulfated neurosteroids such as pregnenolone sulfate. Neurosteroids such as allopregnanolone are positive allosteric modulators of GABA-A receptors with powerful anti-seizure activity in diverse animal models. Neurosteroids increase both synaptic and tonic inhibition. They are endogenous regulators of seizure susceptibility, anxiety, and stress. Sulfated neurosteroids such as pregnenolone sulfate, which are negative GABA-A receptor modulators, are memory-enhancing agents. Sex differences in susceptibility to brain disorders could be due to neurosteroids and sexual dimorphism in specific structures of the human brain. Synthetic neurosteroids that exhibit better bioavailability and efficacy and drugs that enhance neurosteroid synthesis have therapeutic potential in anxiety, epilepsy, and other brain disorders. Clinical trials with the synthetic neurosteroid analog ganaxolone in the treatment of epilepsy have been encouraging. Neurosteroidogenic agents that lack benzodiazepine-like side effects show promise in the treatment of anxiety and depression.

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Neurosteroids: Endogenous role in the human brain and therapeutic potentials

Revisiting the roles of progesterone and allopregnanolone in the nervous system: Resurgence of the progesterone receptors

Neurosteroid regulation of GABAA receptors: Focus on the α4 and δ subunits

The gamma-aminobutyric acid (GABA) type A receptor system, the main fast-acting inhibitory neurotransmitter system in the brain, is the pharmacological target for many drugs used clinically to treat, for example, anxiety disorders and epilepsy, and to induce and maintain sedation, sleep, and anesthesia. These drugs facilitate the function of pentameric GABA(A) receptors that exhibit widespread expression in all brain regions and large structural and pharmacological heterogeneity as a result of composition from a repertoire of 19 subunit variants. One of the main problems in clinical use of GABA(A) receptor agonists is the development of tolerance. Most drugs, in long-term use and during withdrawal, have been associated with important modulations of the receptor subunit expression in brain-region-specific manner, participating in the mechanisms of tolerance and dependence. In most cases, the molecular mechanisms of regulation of subunit expression are poorly known, partly as a result of neurobiological adaptation to altered neuronal function. More knowledge has been obtained on the mechanisms of GABA(A) receptor trafficking and cell surface expression and the processes that may contribute to tolerance, although their possible pharmacological regulation is not known. Drug development for neuropsychiatric disorders, including epilepsy, alcoholism, schizophrenia, and anxiety, has been ongoing for several years. One key step to extend drug development related to GABA(A) receptors is likely to require deeper understanding of the adaptational mechanisms of neurons, receptors themselves with interacting proteins, and finally receptor subunits during drug action and in neuropsychiatric disease processes.

Regulation of GABA(A) receptor subunit expression by pharmacological agents.

Steroid requirements for regulation of the α4 subunit of the GABAA receptor in an in vitro model

Expression levels of the α4 subunit of the GABAA receptor in differentiated neuroblastoma cells are correlated with GABA-gated current

Endoplasmic reticulum (ER) stress and oxidative stress (OS) are often related states in cells as part of normal physiology but more frequently manifested in the pathophysiology of many diseases, particularly diseases involving acute or chronic inflammation. In this study, we reviewed recent findings about the role of ER stress and OS in the pathogenesis of inflammatory diseases.

Endoplasmic Reticulum Stress and Oxidative Stress in Inflammatory Diseases.

Endothelial cell injury is a key factor in the spread of infection and pathogenicity of Treponema pallidum. The migration and adhesion reaction mediated by T. pallidum lipoprotein plays an important role. This study aimed to systematically explore the migration and adhesion effect of T. pallidum lipoprotein Tp0768 and its molecular mechanism. Stimulating vascular endothelial cells with Tp0768 increased the expression of ICAM‐1, MCP‐1, and IL‐8. Moreover, it promoted the migration and adhesion of THP‐1 cells to vascular endothelial cells. Our results revealed that Tp0768 promoted the THP‐1 cells migrating and adhering to vascular endothelial cells by the PERK and IRE‐1α pathways of endoplasmic reticulum (ER) stress. We further demonstrated that the inhibition of the NF‐κB pathway and the downregulation of hypoxia‐inducible factor 1 alpha (HIF‐1α) reduced the mRNA levels of ICAM‐1, MCP‐1, and IL‐8 induced by Tp0768. Also, the adhesion rate of THP‐1 cells to endothelial cells decreased. After inhibiting ER stress, NF‐κB p65 nuclear translocation was weakened, and the mRNA level of HIF‐1α was also significantly downregulated. Our results indicated that T. pallidum lipoprotein Tp0768 promoted the migration and adhesion of THP‐1 cells to vascular endothelial cells through ER stress and NF‐κB/HIF‐1α pathway.

Treponema pallidum lipoprotein Tp0768 promotes the migration and adhesion of THP‐1 cells to vascular endothelial cells through stress of the endoplasmic reticulum and the NF‐κB/HIF‐1α pathway

Xiangping Zhou

Papers

Neurosteroid regulation of GABAA receptors: Focus on the α4 and δ subunits

Steroid requirements for regulation of the α4 subunit of the GABAA receptor in an in vitro model

Expression levels of the α4 subunit of the GABAA receptor in differentiated neuroblastoma cells are correlated with GABA-gated current

Endoplasmic Reticulum Stress and Oxidative Stress in Inflammatory Diseases.

Treponema pallidum lipoprotein Tp0768 promotes the migration and adhesion of THP‐1 cells to vascular endothelial cells through stress of the endoplasmic reticulum and the NF‐κB/HIF‐1α pathway