Control of contextual memory through interneuronal α5-GABAA receptors

Mengwen Zhu; Alifayaz Abdulzahir; Mark G Perkins; Chan C Chu; Bryan M Krause; Cameron Casey; Richard Lennertz; David Ruhl; Harald Hentschke; Rajasekar Nagarajan; Edwin R Chapman; Uwe Rudolph; Michael S Fanselow; Robert A Pearce

doi:10.1093/pnasnexus/pgad065

Control of contextual memory through interneuronal α5-GABA_A receptors

PNAS Nexus. 2023 Apr 11;2(4):pgad065. doi: 10.1093/pnasnexus/pgad065. eCollection 2023 Apr.

Authors

Mengwen Zhu¹, Alifayaz Abdulzahir¹, Mark G Perkins¹, Chan C Chu^{1

2}, Bryan M Krause¹, Cameron Casey¹, Richard Lennertz¹, David Ruhl^{3

4}, Harald Hentschke⁵, Rajasekar Nagarajan⁶, Edwin R Chapman³, Uwe Rudolph^{6

7}, Michael S Fanselow^{8

9}, Robert A Pearce¹

Affiliations

¹ Department of Anesthesiology, University of Wisconsin-Madison, Madison, WI 53705, USA.
² Present address: Lawrence University, Appleton, WI 54911, USA.
³ Department of Neuroscience, University of Wisconsin-Madison, Madison, WI 53705, USA.
⁴ Present address: Neurocrine Biosciences, San Diego, CA 92130, USA.
⁵ Freelance Data Scientist, Berlin 12555, Germany.
⁶ Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, Urbana, IL 61802, USA.
⁷ Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61802, USA.
⁸ Department of Psychology, University of California, Los Angeles, Los Angeles, CA 61801, USA.
⁹ Department of Psychiatry, University of California, Los Angeles, Los Angeles, CA 90095, USA.

Abstract

γ-Aminobutyric acid type A receptors that incorporate α5 subunits (α5-GABA_ARs) 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-GABA_ARs 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-GABA_ARs serve a physiological role in promoting spatial learning and that they mediate suppression of hippocampus-dependent contextual memory by etomidate.

Abstract

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