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

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.

Prefrontal excitatory/inhibitory balance in stress and emotional disorders: Evidence for over-inhibition

“…Chronically, stress impedes glutamatergic transmission and causes prefrontal hypoactivity, along with emotional dysfunction(Musazzi et al, 2015;Son et al, 2018) (Figure 2). There are numerous reports of GABAergic deficits in stress and emotional disorders(Lüscher et al, 2011;Ghosal et al, 2017;Fogaça and Duman, 2019) alongside contradictory evidence for increased prefrontal inhibition(McKlveen et al, 2016;Shepard et al, 2016).Chapter 2 supports the hypothesis that increased prefrontal inhibition decreases prefrontal activity and drives anxiety in female mice. A major open question for this line of research is the nature of the interactions between the excitatory and inhibitory systems in the PFC in stress and emotional disorders.…”

“…The time course of GABAergic dysfunction has also not yet been comprehensively studied, but similarly to the glutamatergic system, there may be biphasic or even multiphasic effects of stress on the GABAergic system that help explain the bidirectional findings. Many studies report reduced GABA concentrations and markers of the GABAergic system in the stressed and/or anxious and depressed PFC (Ghosal et al, 2017;Fogaça and Duman, 2019). An MRS study of humans with panic disorder found decreased GABA levels in the anterior cingulate cortex and medial PFC (Long et al, 2013), as did an MRS study of major depressive disorder patients (Hasler et al, 2007).…”

“…Chapter 6: Conclusions Summary: Evidence for over-inhibition Excitatory/inhibitory (E/I) balance in the prefrontal cortex plays an integral role in emotional behaviors and is affected by chronic stress (Wieronska et al, 2011;Lener et al, 2017;McKlveen et al, 2019). Both the excitatory, glutamatergic side and the inhibitory, GABAergic side of E/I balance are perturbed by stress, and aberrations in both systems have been associated with emotional pathology (Sanacora et al, 2012;Musazzi et al, 2015;Fogaça and Duman, 2019). Most studies support the conclusion that glutamatergic activity in the PFC is reduced by chronic stress (Popoli et al, 2011;Musazzi et al, 2015).…”

Systematic impacts of chronic unpredictable mild stress on metabolomics in rats

“…L-glutamic acid, also referred to as glutamate, obtained from the hydrolysis of glutamine, is a key molecule in cellular metabolism. Glutamate and glutamine are precursors of the major natural antioxidant glutathione (GSH), playing important roles in maintaining the cellular redox equilibrium 21 . The serum glutamate was elevated in the serum of CUMS rats in our study and the results was in inconsistent with a previous study 22 , additionally, glutamate was increased in hippocampus but decreased in thalamus and the remaining brain regions in a earlier study also using GC-MS to evaluate four brain regions of chronic unpredictable mild stress-model rats 23 .…”

Identification of major depressive disorder disease-related genes and functional pathways based on system dynamic changes of network connectivity

“…The PFC plays an important role in the regulation of the hypothalamo-pituitary-adrenal (HPA)-axis in stress response and also depression. There is increasing evidence that MDD and chronic stress are associated with an excitatory inhibition (E:I) imbalance within PFC which is caused by a deficit of inhibitory synaptic transmission onto principal glutamatergic neurons (14). A recent functional magnetic resonance imaging study showed reduced functional connectivity of medial PFC in patients with MDD (15).Accordingly, depression is a heterogeneous syndrome with distinct causes and pathophysiologies.…”