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.

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.

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.