Control of contextual memory through interneuronal α5-GABAA receptors

Abstract

γ-Aminobutyric acid type A receptors that incorporate α5 subunits (α5-GABAARs) are highly enriched in the hippocampus and are strongly implicated in control of learning and memory. Receptors located on pyramidal neuron dendrites have long been considered responsible, but here we report that mice in which α5-GABAARs have been eliminated from pyramidal neurons (α5-pyr-KO) continue to form strong spatial engrams and that they remain as sensitive as their pseudo-wild-type (p-WT) littermates to etomidate-induced suppression of place cells and spatial engrams. By contrast, mice with selective knockout in interneurons (α5-i-KO) no longer exhibit etomidate-induced suppression of place cells. In addition, the strength of spatial engrams is lower in α5-i-KO mice than p-WT littermates under control conditions. Consistent with the established role of the hippocampus in contextual fear conditioning, α5-i-KO mice resisted etomidate’s suppression of freezing to context, but so too did α5-pyr-KO mice, supporting a role for extra-hippocampal regions in the development of contextual fear memory. Overall, our results indicate that interneuronal α5-GABAARs serve a physiological role in promoting spatial learning and that they mediate suppression of hippocampus-dependent contextual memory by etomidate.

Synthesis and Receptor Binding Studies of α5 GABAAR Selective Novel Imidazodiazepines Targeted for Psychiatric and Cognitive Disorders

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Benzodiazepine-induced anterograde amnesia: detrimental side effect to novel study tool

“…Recent studies have used the positive allosteric modulator of GABAa receptors, etomidate, known for its memory impairment properties, to understand how α5 subunits on both pyramidal and interneurons affect memory in a CFC paradigm ( Zhu et al, 2023 ). Results indicate that etomidate affects α5 subunits in pyramidal and interneurons to impair memory, as mice with α5 knockouts in both cell types exhibited comparable freezing with and without etomidate treatment, while wild-type controls exhibited significantly less freezing after etomidate treatment ( Zhu et al, 2023 ). While etomidate and BZDs both have memory impairment effects, these compounds have different binding sites on GABAa receptors ( Chiara et al, 2013 ).…”

Spatial-numeric method application to the movable wedge problem for Physics First pedagogy

“…The decline of spatial ability scores in the studied online cohort in the United States should encourage more spatial-numeric pedagogy, since perceptual intelligence is accepted as being similar to fluid intelligence which uses spatial abilities in the problem solving skills (Dworak et al 2023). Spatial learning has been traced to the interneurons at receptor level (Zhu et al 2023), as well as gamma oscillatory neural circuit level (Fernandez-Ruiz et al 2023). Last but not the least, recent advances in cancer migration studies are incorporating spatial forces visually in the proposed models (Chabache et al 2021;Javanmardi et al 2023).…”