Cortical GABAergic Dysfunction in Stress and Depression: New Insights for Therapeutic Interventions

Manoela V Fogaça, Ronald S Duman, Manoela V Fogaça, Ronald S Duman

Abstract

Major depressive disorder (MDD) is a debilitating illness characterized by neuroanatomical and functional alterations in limbic structures, notably the prefrontal cortex (PFC), that can be precipitated by exposure to chronic stress. For decades, the monoaminergic deficit hypothesis of depression provided the conceptual framework to understand the pathophysiology of MDD. However, accumulating evidence suggests that MDD and chronic stress are associated with an imbalance of excitation-inhibition (E:I) within the PFC, generated by a deficit of inhibitory synaptic transmission onto principal glutamatergic neurons. MDD patients and chronically stressed animals show a reduction in GABA and GAD67 levels in the brain, decreased expression of GABAergic interneuron markers, and alterations in GABAA and GABAB receptor levels. Moreover, genetically modified animals with deletion of specific GABA receptors subunits or interneuron function show depressive-like behaviors. Here, we provide further evidence supporting the role of cortical GABAergic interneurons, mainly somatostatin- and parvalbumin-expressing cells, required for the optimal E:I balance in the PFC and discuss how the malfunction of these cells can result in depression-related behaviors. Finally, considering the relatively low efficacy of current available medications, we review new fast-acting pharmacological approaches that target the GABAergic system to treat MDD. We conclude that deficits in cortical inhibitory neurotransmission and interneuron function resulting from chronic stress exposure can compromise the integrity of neurocircuits and result in the development of MDD and other stress-related disorders. Drugs that can establish a new E:I balance in the PFC by targeting the glutamatergic and GABAergic systems show promising as fast-acting antidepressants and represent breakthrough strategies for the treatment of depression.

Keywords: GABA; depression; ketamine; parvalbumin; prefrontal cortex; somatostatin; stress.

Figures

FIGURE 1
FIGURE 1
Proposed mechanisms underlying the action of ketamine and GABA-related drugs in the reestablishment of cortical excitatory–inhibitory (E:I) balance. Chronic stress induces spine loss and dendritic atrophy in pyramidal glutamatergic cells, and decreased GABAergic interneuron markers, leading to a reduction in the levels and function of GABA in the PFC. GABAergic dysfunction disturbs the optimal E:I balance in the brain and compromises the integrity of neurocircuits, contributing to the development of major depressive disorder (MDD) and other stress-related disorders. The E:I imbalance can be reversed by drugs via different GABA-related mechanisms. (1) Low doses of ketamine induce a glutamate burst in the PFC via blockade of NMDA receptors located in GABAergic interneurons; the tonic firing of these interneurons, notably parvalbumin (PV) and somatostatin (SST), is driven by NMDA receptors that are more sensitive to ketamine because of activity dependent of the Mg2+ block. This leads to disinhibition of pyramidal neurons causing activation of post-synaptic AMPA receptors; this in turn induces neuronal depolarization and activation of voltage-dependent Ca2+ channels (VDCCs). The enhancement of intracellular Ca2+ influx leads to BDNF release and stimulation of TrkB receptors, which activates mTORC1 signaling inducing protein synthesis required for the formation of new spines and synaptic plasticity. Ketamine also facilitates GABA-mediated effects, increasing IPSCs, VGAT, GAD, and gephyrin in the PFC, reversing the GABA deficits caused by chronic stress exposure. (2) Likewise, α5-GABAA negative allosteric modulators (α5-NAMs) and (3) GABAB receptors antagonists, probably located in GABAergic interneurons, enhance glutamatergic neurotransmission and produce ketamine-like effects. (4) Infusions of SST or SST analogs into limbic brain regions produce antidepressant-like effects through activation of SST2 receptors. (5) Finally, activation of post-synaptic GABAB receptors by agonists or positive allosteric modulators (PAMs), as well as activation of α5-GABAA by PAMs, and other GABAA subunits by neurosteroids, notably allopregnanolone (6), can also recruit BDNF expression and signaling that could contribute to antidepressant responses (dashed arrows).

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