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A recent review in the Journal of Trends in Pharmacological Sciences was written by four scientists from different universities -- Dr. Bernhard Luscher from Penn State University, Dr. Jamie Maguire from Tufts University, Dr. Uwe Rudolph from University of Illinois Urbana-Champaign, and Dr. Etienne Sibille from the University of Toronto -- who have a longstanding interest in the role that GABA_A receptors play in the brain, specifically for the development and therapy of depression.

The brain is dependent on the right balance between excitation and inhibition, and the naturally occurring amino acid y-aminobutyric acid, abbreviated GABA, is the most important inhibitory neurotransmitter in the brain. GABA is released from nerve cells and binds to receptors called GABA_A receptors on neighboring nerve cells, which typically dampens the activity of these cells.

“It was known from studies in humans that many patients with depression have lower levels of GABA in their brain,” review author Rudolph told us. “Also, mice with a reduction in the number of GABA_A receptors develop symptoms reminiscent of depression. This raises the question whether chemical compounds increasing the activity of GABA_A receptors might have antidepressant actions.”

Indeed, it turned out that a pharmaceutical version (Brexanolone) of a naturally occurring compound, the neuroactive steroid allopregnanolone, is active - and FDA-approved - against peripartum depression. Moreover, recently the FDA approved another neuroactive steroid, Zuranolone, which can be taken orally, for peripartum depression.

“It is not entirely clear why neuroactive steroids have antidepressant effects that benzodiazepines, which also modulate GABA_A receptors and are used, e.g., for anxiety reduction and sedation, do not have similar antidepressant effects,” Rudolph told us. “Recent research indicates that both positive and negative modulators of a subset of GABA_A receptors called x5-GABA_A receptors can have antidepressant-like actions, and in the current review we propose potential explanations for these perplexing observations. Of note, none of the currently available treatments for depression targets the cognitive deficits that may ensue, and there is evidence from preclinical studies that positive modulation of x5-GABA_A receptors may address such deficits.”

For more than half a century, benzodiazepines which modulate GABA_A receptors have been used to treat anxiety disorders, and it has been estimated that 60% of those with anxiety also have symptoms of depression. Studies in mice in which the amount of certain GABA_A receptors were reduced also revealed both anxiety-related and depression-related behaviors.

“While the currently available benzodiazepines do not have antidepressant actions, it was clear that some deficits in neuronal inhibition by GABA frequently may play a role in the development of depression,” Rudolph told us. “It has been discovered in mice lacking a unique type of GABA_A receptors, i.e., those that contain the s-subunit, that depression develops in mothers after giving birth, and the currently available treatments for peripartum depression targets this receptor subtype.”

This is thus an area where academic research provided clues that aided in the development of currently available treatments. Current academic research on x5-GABA_A receptors indicates that this receptor subtype is involved in the response to stress and that the modulation of the activity of these receptors leads to antidepressant-like actions in mice.

“In preclinical research reviewed in the recent article, chemical compounds that increase the activity of x5-GABA_A receptors as well as chemical compounds that decrease the activity of these receptors with high selectivity have been found to exert antidepressant-like actions,” Rudolph told us. “In the recent article, we provide a model trying to explain these apparently contradictory findings. Chronic stress results in reduced GABAergic inhibitory and glutamatergic excitatory neurotransmission.”

Administration of a compound that activates x5-GABA_A receptors leads to a gradual recovery of GABAergic inhibition followed by recovery of excitatory neurotransmission and thus synaptic transmission, the process by which one nerve cell talks to its neighboring nerve cells. In contrast, activation of a compound that inhibits the activity of x5-GABA_A receptors leads to a rapidly enhanced glutamatergic excitation followed by normalization of GABAergic inhibition. 

“One could think of it in analogy to an electric shock that is used in cardiac arrest,” Rudolph told us. “A temporary rapid change in the activity of glutamatergic excitation sets processes in motion that lead to a normalization of excitatory and inhibitory neurotransmission that may last for a long time. Other preclinical studies showed that stress-induced impairment of cognitive function can be rescued with a compound increasing the activity of x5-containing GABA_A receptors. It had previously shown in humans that depression results in decreased expression of x5-GABA_A receptors.”

The compound increasing the activity of x5-GABA_A receptors then functionally reverses this loss, potentially normalizing cognition. While the preclinical studies on x5-GABA_ARs as targets for the treatment of affective and cognitive symptoms of depression are interesting, it is currently unknown whether similar effects of compounds modulating this receptor subtype will also be seen in humans.

“When most physicians or neuroscientists hear the word ‘GABA_A receptors’, the association that comes to mind first is ‘benzodiazepines’, the formerly widely used class of drugs that have anxiety-reducing, sedative, muscle relaxant and anticonvulsant actions,” Rudolph told us. “The clinically used benzodiazepines rather non-selectively increase the activity of x1-, x2-, x3- and x5-GABA_A receptors.”

It is interesting to see that chemical compounds that quite selectively modulate x5-GABA_A receptors have properties that the more promiscuous benzodiazepines do not have. This is an example how less (relatively selective modulation of a single GABA_A receptor subtype) can be better than more (modulation of multiple GABA_A receptor subtypes at once).

“As pointed out previously, one exciting outstanding question is whether selectively targeting x5-GABA_A receptors will have effects on symptoms of depression in humans as we would predict from preclinical studies,” Rudolph told us. “If this is the case, this could become another example of publicly funded basic science research creating knowledge that may one day be considered the starting point for the development of novel therapeutic options that improve human health, as it was the case with respect to the development of neuroactive steroids for the treatment of peripartum depression.”