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. 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.

Conflict of interest statement

Conflicts of Interest. The authors declare no conflict of interest

Figures

Figure 1. HPA axis hyperactivation by frontocortical and hippocampal deficits in GABAergic inhibition

The GABAergic deficit hypothesis of MDD presented here suggests that local GABAergic deficits in hippocampus and frontal cortex due to reduced GABA release, uncoordinated GABAAR subunit gene expression or anomalous signaling mechanisms that affect GABAAR accumulation at the plasma membrane lead to local hyperexcitability, which is relayed by projections (In the case of frontal cortex through the BNST ) to the PVN of the hypothalamus. In the hippocampus such local GABAergic deficits may involve loss of parvalbumin positive interneurons , reduced GABAergic synaptic inhibition and reduced maturation and survival of adult-born granule cells , which is sufficient to activate the HPA axis . Cortical deficits in GABAergic inhibition include reduced GABA levels in patients ,. In addition, GABAergic deficits may be induced by chronic stress, which down-regulates the expression and function of GABAARs in the frontal cortex . Hyperexcitability of the cortex and hippocampus is relayed by projections to the PVN. Local GABAergic inhibition of PVN neurons may be independently compromised by a stress-induced shift in the neural Cl− reversal potential . The ensuing excessive release of CRH from the PVN results in increased release of ACTH from the anterior pituitary, which promotes the release of glucocorticoids, thereby closing a positive feedback loop that amplifies cortical and hippocampal GABAergic deficits. Adrenal neurosteroids normally potentiate GABA-mediated activation of GABAARs on dentate gyrus granule cells ,. Moreover THDOC upregulates the expression of α4βδ receptors in hippocampal granule cells . However, in CA1 pyramidal cells of the hippocampus the same neurosteroids facilitate GABA-induced desensitization of α4βδ receptors , which increases neural excitability .

Figure 2. Mechanisms of AD action in immature neurons of the dentate gyrus involving GABAergic transmission

A. GABAARs in immature neurons conduct an inward current (Cl ions moving out of the cell) due to the more positive Cl− reversal potential in these cells. The ensuing membrane depolarization facilitates Ca2+ entry through V-gated ion channels such as the T-type and L-type voltage gated Ca2+ channels, and in more mature neurons also NMDARs. The cytoplasmic increase in Ca2+ results in an increased activity of protein kinases (CaMKII, PKC, PKA, others) that phosphorylate CREB on Ser133. Phosphorylated CREB translocates to the nucleus where it activates a number of target genes including that encoding BDNF. B. Increased production and release of BDNF acts on GABAergic terminals and promotes the release of GABA by TrkB/MAPK-mediated phosphorylation of synapsin and mobilization of GABA-containing vesicles, and by activation of P/Q-type voltage-gated Ca2+ channels that activate the neurotransmitter release machinery. C, Monoamine transmitters, which are presumed to be elevated in the hippocampus upon AD treatment, act on presynaptic β-adrenergic and 5-HTRs that activate voltage-gated Ca2+ channels on terminals and soma of GABAergic interneurons. D, Some effects of monoamine transmitters may be mediated by GPCRs on granule cells. However, the expression of these receptors on neural progenitors and immature granule cells has not been documented.