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GABA-A Receptor Subtypes as Targets for Fast-Acting Antidepressants

Monday April 04, 2022

3:30 pm - 5:00 pm Central Time (CT)

113 A


Chair :

Uwe Rudolph
University of Illinois at Urbana-Champaign

This session will explore the role of inhibitory neurotransmission and specifically of molecularly defined GABA-A receptor subtypes in the response to chronic stress, which has been implicated in the development of depression. Speakers will present basic science and translational aspects linking different GABA-A receptor subtypes to depressive-like behaviors. A combination of pharmacological, biochemical, molecular modeling, medicinal chemistry, electrophysiological and behavioral approaches has been applied to elucidate the mechanisms behind the surprising observation that both positive and negative allosteric modulation of a5-containing GABA-A receptors exhibit fast antidepressant actions and the suitability of this receptor subtype as a drug target for a novel class of antidepressants will be discussed.


Uwe Rudolph - University of Illinois at Urbana-Champaign

Alpha2-containing GABA-A Receptors Promote Stress Resiliency in Mice

Brain alpha2-containing GABA-A receptors play a critical role in the modulation of anxiety- and fear-like behavior. However, it is unknown whether these receptors also play a role in modulating resilience to chronic stress, and in which brain areas and cell types such an effect would be mediated. We evaluated the role of alpha2-containing GABA-A receptors following chronic social defeat stress using mice deficient in the alpha2 subunit globally or conditionally in dopamine D1- or D2-receptor expressing neurons, e.g., within the nucleus accumbens (NAc). In addition, we examined the effect of lack of the alpha2-subunit on intermediates of the glutathione synthesis pathway. We found that alpha2-containing GABA-A receptors on D2-receptor positive but not on D1-receptor positive neurons promote resiliency to chronic social defeat stress, as reflected in social interaction tests. The pro-resiliency effects of alpha2-containing GABA-A receptors on D2-receptor positive neurons do not appear to be directly related to alterations in anxiety-like behavior, as reflected in the light-dark box and novel open field tests. Increases in indices of oxidative stress—reflected by increases in cystathionine levels and reductions in GSH/GSSG ratios—were found in the NAc and prefrontal cortex but not in the hippocampus of mice lacking alpha2-containing GABA-A receptors. We conclude that alpha2-containing GABA-A receptors within specific brain areas and cell populations promote stress resiliency independently of direct effects on anxiety-like behaviors. A potential mechanism contributing to this increased resiliency is the protection that alpha2-containing GABA-A receptors provide against oxidative stress in NAc and prefrontal cortex.

Etienne Sibille - Campbell Family Mental Health Research Institute, University of Toronto and DAMONA Pharmaceuticals

Brain Inhibitory GABAergic Function and Cognitive Deficits in Depression and During Aging: Mechanisms and Therapeutic Targeting

Neurophysiological and postmortem molecular studies report altered brain excitation inhibition balance, characterized by reduced dendritic-targeting GABAergic neuron markers and function in neuropsychiatric and neurodegenerative disorders. We now show that novel molecules that activate dendritic inhibition through a5-containing GABAA receptors reverse stress- and age-related neuronal atrophy and exert robust pro-cognitive, as well as anxiolytic and antidepressant effects in mice. These results suggest a novel therapeutic approach for the unmet clinical need of reducing cognitive symptoms across brain disorders.

Scott Thompson - University of Maryland School of Medicine

The Potential of Negative Allosteric Modulators of Alpha5-containing GABA Receptors for the Treatment of Neuropsychiatric Disorders

I will review preclinical evidence that a5-selective GABA NAMs exert a rapid and persistent antidepressant-like action in mice. These anti-anhedonic and synaptic strengthening actions are prevented when the GABA-NAM is administered together with the benzodiazepine binding site antagonist flumazenil and when GABA-NAMs were administered in mice with genetic deletion of a5 GABA receptor subunits. I suggest that the antidepressant-like actions of GABA NAMs result from an increase in synchronous oscillatory activity, which results in an activity-dependent restoration of synaptic strength within the cortico-mesolimbic reward circuitry, thereby restoring the normal response to rewarding stimuli and, in humans, mood.

Miguel Madeira - Stony Brook University

Abstract #5715 - Immune Phenotypes of Oligodendroglial-Lineage Cells in MDD and in Response to Chronic Stress-Induced Microglial Inflammation

Last Updated: March 27, 2022
Key Dates

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