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GABAA Receptor Subtypes as Targets for Fast-Acting Antidepressants

Monday April 04, 2022

3:30 pm - 5:00 pm Eastern Time (ET)



BEH DDD MP NEU

Chair :

Uwe Rudolph
University of Illinois at Urbana-Champaign



This session will explore the role of inhibitory neurotransmission and specifically of molecularly defined GABAA 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 GABAA 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 GABAA 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.

Speakers

Jamie Maguire

Antidepressant Effects of GABA PAMs Involve the Ability to Modulate Network States Inolved in Emotional Processing

This talk will review the timeline from the identification of neuroactive steroids as positive allosteric modulators of GABAA receptors, to their preclinical development, and finally FDA approval as the first treatment specifically for postpartum depression.  We will discuss the potential mechanisms mediating the prolonged antidepressant effects of these compounds, involving the ability to modulate network states involved in emotional processing. Finally, we will provide evidence that treatment with neuroactive steroids may be targeting an underlying neurobiological mechanism of depression.

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.

Talks will be selected from submitted abstracts.

Last Updated: August 31, 2021
Key Dates
 
November 30, 2021

Abstract Submission Deadline

February 7, 2022

Early Registration Deadline

April 2 – 5, 2022

ASPET Annual Meeting at EB 2022

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