The GABAergic deficit hypothesis of major depressive disorder

Abstract

Increasing evidence points to an association between major depressive disorders (MDDs) and diverse types of GABAergic deficits. Here 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) as well as alterations in the subunit composition of the principal receptors (GABAA receptors) mediating GABAergic inhibition. In addition, there is abundant evidence that GABA plays 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 designed to alter monoaminergic transmission as well as non-pharmacologic therapies may ultimately act to counteract GABAergic deficits. In particular, GABAergic transmission plays 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. Lastly, comparatively modest deficits in GABAergic transmission in GABAA-receptor-deficient mice are sufficient to cause behavioral, cognitive, neuroanatomical, and neuroendocrine phenotypes as well as antidepressant drug 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 major depressive disorders that are reversed by monoaminergic antidepressant drug action.

Developmental Influence of the Serotonin Transporter on the Expression of Npas4 and GABAergic Markers: Modulation by Antidepressant Treatment

“…These findings suggest that antidepressant treatment can normalize the dysfunction of the GABAergic system (Luscher et al, 2011), which may lead to the increase in GABA release observed in patients (Carter and McCormack, 2009;Sanacora et al, 2002). Collectively, animal and clinical studies indicate that a deficit for GABAergic activity may be crucial in the pathophysiology of mood disorders, and that effective modulation of GABAergic transmission may represent another important mechanism through which antidepressant drugs exert their therapeutic activity (Luscher et al, 2011).…”

“…Parvalbumin alteration in hippocampal interneurons may lead to a loss of perisomatic inhibition of pyramidal neurons, which in turn affects network synchronization and memory formation (Bartos et al, 2007;Lewis et al, 2005). Disturbances in the anatomy and function of the GABAergic system have been postulated in animal models of depression and in different stress-related psychiatric disorders (Benes and Berretta, 2001;Brambilla et al, 2003;Krystal et al, 2002;Luscher et al, 2011;Sanacora et al, 1999). In fact, GABA A receptors can be downregulated in different brain regions of rats exposed to the learned helplessness paradigm (Drugan et al, 1992), whereas lower CSF and plasma GABA levels have been found in depressed patients, as compared with control subjects (Gerner et al, 1984;Gerner and Hare, 1981;Kasa et al, 1982;Petty et al, 1992).…”

“…As clinical and preclinical evidence suggest that GABAergic deficits may be relevant for the etiology and manifestation of mood disorders (Luscher et al, 2011), we decided to investigate the expression of Npas4 in the hippocampus of SERT + /À and SERT À/À rats, and their controls, SERT + / + rats. The SERT-knockout rat represents an animal model for anxiety and depression (Olivier et al, 2008), and thereby offers an important tool to investigate the mechanisms underlying the pathological condition in humans.…”

“…Several clinical and preclinical studies support a central and causal role of the GABAergic system in the etiology of depressive disorders (Luscher et al, 2011;Sanacora et al, 1999). This led us to hypothesize that the transcription factor Npas4 may be altered in animal models of depression, and may eventually link alterations of neuroplastic markers, such as Bdnf, with an impaired function of the GABAergic system.…”

Allopregnanolone and Pregnanolone Analogues Modified in the C Ring: Synthesis and Activity

“…Ther. 2007 or recent papers [3][4][5][6] ). Unlike the family of other steroid hormones, neurosteroids do not bind to nuclear but to membrane receptors for neurotransmitters.…”