Cortical GABAergic Dysfunction in Depression

Cortical GABAergic Dysfunction in Stress and Depression: New Insights for Therapeutic Interventions – free full-text /30914923/Front. Cell. Neurosci., March 2019

This is a recent article with many technical details explaining how GABA is involved in stress, depression, and anxiety.

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 (excitatory to inhibition) 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 (excitation-inhibition) 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.

Those of us with EDS suffer a biological propensity toward anxiety, so our anxiety is less a “cognitive” issue (as in Cognitive Behavioral Therapy) than a biologically determined mood disorder that comes with EDS hypermobility (see Enhanced Interoception Links EDS and Anxiety).

In this case, I believe psychotherapy won’t be as effective as a medication targeting the biological mechanism generating anxiety.

GABAergic System in the PFC

GABA is the major inhibitory mediator of cortical interneurons in the brain that serves to modulate a wide range of local neurotransmitter systems, most notably, the glutamatergic excitatory counterpart.

By targeting specific somatic domains of neighboring glutamatergic principal neurons, GABA interneurons control the E:I balance in the PFC as well as the excitatory output to projecting areas.

Due to this network orchestration of firing patterns, cortical GABAergic interneurons play an essential role in mediating complex emotional and cognitive processes in the brain.

One-third of all synapses in the central nervous system (CNS) connects via GABA interneurons, which comprise 20–30% of neocortical neurons and can be classified accordingly to their diverse morphological, electrophysiological, and molecular characteristics.

GABA interneurons express two subtypes of GABA receptors: GABAA and GABAB.

The most prominent receptor, GABAA, is a ligand-gated Cl ion channel (ionotropic) and has been extensively characterized as the target of many psychotropic agents, including benzodiazepines, ethanol, and barbiturates.

Given the broad spectrum of neuronal activity controlled by GABA interneurons, it is increasingly clear that imbalance in the GABAergic system and hence in the E:I balance can contribute to the pathophysiology of several psychiatric disorders, including MDD.

Cortical Dysregulation of GABA Neurotransmission in Chronic Stress and Depression

Although the adaptive, innate stress response is essential for body homeostasis and survival, it is widely recognized that responses to sustained, chronic stress can become dysregulated and result in illness and abnormal behaviors.

In the brain, chronic stress can produce changes in neurotransmitter function and appropriate neuroplasticity responses that could precipitate depression in humans and, therefore, has been extensively used as a rodent model for depression.

GABAergic neurons play an important role in the termination of stress response through regulation of the hypothalamus–pituitary–adrenal (HPA) axis, and disruption of this regulatory response contributes to the abnormal effects of chronic stress exposure.

Collectively, these data provide support for the hypothesis that stress causes major changes in the GABAergic system in the PFC that could result in abnormal behavioral and synaptic responses, including dendritic reorganization of interneurons, as well as alterations of electrophysiological respones that results in defective output from pyramidal neurons to other brain areas.

However, even though numerous reports suggest that chronic stress decreases GABA levels and function, other studies have reported opposite effects.

This is so frustrating! Just when I’m reading something that makes perfect sense and explains my own issues, I see that there is also contrary evidence. However, this is the way science works when research is *not* biased to show consensus.

While difficult to reconcile, it is important to highlight that the results of stress studies may differ depending on the type and duration of the stressor, the GABA receptor subunit analyzed, and the specific subregions of the PFC studied.

In addition to these preclinical studies, there is accumulating evidence that dysfunction of the GABAergic system is associated with the pathophysiology of MDD and that normalization of GABA is associated with the remission of depressive symptoms.

GABA levels are reduced in unmedicated patients with MDD in several cortical areas, including the prefrontal, occipital, and anterior cingulate (ACC) cortices.

Besides GABA levels, several studies reported decreased expression of GABAA receptors subunit genes in MDD cortice

However, there were also reports of increased expression of certain subunits, including α5, γ2, β3, and δ in MDD subjects suggesting that different GABAA receptor subunits may play distinct roles in the etiology of MDD.

Just like with pain, there are different types/flavors of depression. Treating all depression as a monolithic entity could obscure exactly the correlations they are looking for.

Studies regarding the participation of GABAB receptors in the pathophysiology of MDD have received less attention and, therefore, the literature remains unclear. Although GABAB1 and GABAB2 subunits were reported to be decreased in the lateral cerebellum of MDD subjects no evidence was found for altered GABAB receptor binding in the frontal cortex or hippocampus.

Taken together, the results demonstrate that modulation of GABAB receptors induces antidepressant effects, and warrant additional studies with more cutting edge tools to further investigate the role of GABAB receptors in depression and treatment response.

GABA Interneuron-Related Deficits in Depression

MDD patients show a reduced volume of brain areas such as the PFC and hippocampus . Also, abnormalities in the GABAergic system in cortical areas can also robustly affect other brain regions

The GABAergic System as a Therapeutic Target for the Treatment of MDD

Although extensive efforts have been conducted to develop new therapeutic interventions, the current pharmacological treatment approaches still recommend the use of SSRIs as first-line medications for the treatment of MDD. 

However, the emergence of fast-acting antidepressants, notably ketamine, provide evience for other neurotransmitter systems for the treatment, as well as pathophysiology of MDD.

Evidence that normalization of GABA-mediated E:I imbalance in the PFC is a shared mechanism of action between different classes of antidepressants, providing further support for the involvement of GABAergic dysfunction in the etiology of MDD

In this section, we will review the literature showing how first-line monoaminergic antidepressants and rapid-acting agents can influence the GABAergic system.

Classic Monoaminergic Antidepressants: Effects Beyond Monoamines

SSRIs, electroconvulsive therapy, and transcranial magnetic stimulation normalize the reduction in cortical and plasmatic GABA levels, as well as in GAD67 expression in MDD subjects and rodents subjected to chronic stress

Besides decreased GABA levels, MDD patients and chronically stressed animals have reduced levels of allopregnanolone (brain and plasma), an endogenous neurosteroid that acts as a GABAA receptor positive allosteric modulator (discussed in more detail below). This deficit was reversed by chronic administration of SSRIs.

Fast-Acting Glutamatergic Antidepressants: Is It All Glutamate?

The molecular and cellular mechanisms underlying the rapid enhancement of glutamatergic signaling in the PFC by ketamine have been of particular interest.

Also, a SPECT study reports that S-ketamine administration leads to alterations of GABAA receptor binding in the dorsomedial PFC of healthy subjects.

Likewise, studies in cultured murine neurons provide evidence that ketamine increases the activity of extrasynaptic GABAA receptors in the cortex and hippocampus.


Endogenous neuroactive ligands synthetized from progesterone, deoxycorticosterone, or testosterone, referred to as neurosteroids interact with a number of targets, most notably GABAA receptors and act as positive or negative allosteric modulators.

Numerous preclinical evidence demonstrate that neurosteroids modulate the HPA axis and adaptive responses to stress exposure and exert anxiolytic or antidepressant effects in rodent models.

Specifically, the progesterone-derived neurosteroids, allopregnanolone, a potent positive allosteric modulator of both synaptic and extrasynaptic GABAA receptors, were shown to rapidly modulate BDNF expression in the rat brain, which could explain its fast onset for antidepressant responses

GABAB Receptors Ligands

The first prototypical GABAB receptor agonist, bacoflen, was synthetized in 1962 and it was an invaluable pharmacological tool that influenced studies that led to the characterization of GABAB receptors in the 1980s

Preclinical studies suggest that GABAB agonists, positive allosteric modulators, and antagonists can produce antidepressant effects

Thus, considering that:

 (i) MDD patients in general have an upregulation of GABAB receptors;

 (ii) genetic deletion of GABAB receptors produce antidepressant-like effects; 

(iii) GABAB receptors are implicated in the antidepressant actions of fast agents such as ketamine; and 

(iv) GABAB receptors antagonists offer a promising strategy for the development of novel fast-acting antidepressants,

more studies and clinical trials are warranted to identify effective and safe agents.


Because of the postmortem evidence of selective alterations of GABA interneuron subytpes, it is interesting to speculate on approaches to target the function of specific subpopulations of interneurons based on expression of selective neuropeptides.

Cannabinoid Agents

Endocannabinoids, such as anandamide and 2-arachidonoylglycerol, are pivotal endogenous neuromodulators that control GABA and glutamate release in the brain, mainly through actions on cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2) receptors (although some endocannabinoids can also activate transient receptor potential vanilloid type 1 receptors)


For decades, the monoaminergic deficit hypothesis of depression was the prevalent theoretical basis for studies of the mechanisms underlying the pathophysiology and treatment of depression.

However, although increased extracellular monoamines underlies the acute actions of monoamingergic agents, altered monoamine levels alone in forebrain areas are insufficient to explain the molecular and cellular changes underlying the antidepressant actions of these agents

Given growing consensus that MDD patients have a decrease in GABA levels in the brain and the revolutionary discovery that NMDA receptors antagonists, such as ketamine, can produce rapid and sustained antidepressant responses, efforts have been made to link the deficits in amino acid neurotransmitter systems to the pathophysiology of depression.

Notably, the GABA deficit and the imbalance of cortical E:I (excitation–inhibition) hypothesis of depression provide a broader understanding of depression, as it offers connections with other important conceptual frameworks, such as altered glutamate and neurotrophic factor deficit hypotheses.

Despite recent advances, significant challenges remain, including development of more selective GABA, NMDA, and neuropeptide receptor agonists, antagonists, and modulators, characterization of optimal doses and treatment schedules, and better design of clinical trials.

I have hope that this theory of depression (and anxiety by extension) will hold up because we already have drugs to increase levels of GABA in the antiepileptic category, like Gabapentin (Neurontin) and Pregabalin (Lyrica).

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