Chrna5 and lynx prototoxins identify acetylcholine super-responder subplate neurons

Sridevi Venkatesan; Tianhui Chen; Yupeng Liu; Eric E. Turner; Shreejoy J. Tripathy; Evelyn K. Lambe

iScience (Feb 2023)

Chrna5 and lynx prototoxins identify acetylcholine super-responder subplate neurons

Sridevi Venkatesan,
Tianhui Chen,
Yupeng Liu,
Eric E. Turner,
Shreejoy J. Tripathy,
Evelyn K. Lambe

Affiliations

Sridevi Venkatesan: Department of Physiology, Temerty Faculty of Medicine, University of Toronto, 1 King’s College Circle, Toronto, ON, Canada
Tianhui Chen: Department of Physiology, Temerty Faculty of Medicine, University of Toronto, 1 King’s College Circle, Toronto, ON, Canada
Yupeng Liu: Department of Physiology, Temerty Faculty of Medicine, University of Toronto, 1 King’s College Circle, Toronto, ON, Canada
Eric E. Turner: Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, WA, USA
Shreejoy J. Tripathy: Department of Physiology, Temerty Faculty of Medicine, University of Toronto, 1 King’s College Circle, Toronto, ON, Canada; Krembil Centre for Neuroinformatics, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada
Evelyn K. Lambe: Department of Physiology, Temerty Faculty of Medicine, University of Toronto, 1 King’s College Circle, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Department of Obstetrics and Gynecology, University of Toronto, Toronto, ON, Canada; Corresponding author

Journal volume & issue: Vol. 26, no. 2
p. 105992

Abstract

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Summary: Attention depends on cholinergic excitation of prefrontal neurons but is sensitive to perturbation of α5-containing nicotinic receptors encoded by Chrna5. However, Chrna5-expressing (Chrna5+) neurons remain enigmatic, despite their potential as a target to improve attention. Here, we generate complex transgenic mice to probe Chrna5+ neurons and their sensitivity to endogenous acetylcholine. Through opto-physiological experiments, we discover that Chrna5+ neurons contain a distinct population of acetylcholine super-responders. Leveraging single-cell transcriptomics, we discover molecular markers conferring subplate identity on this subset. We determine that Chrna5+ super-responders express a unique complement of GPI-anchored lynx prototoxin genes (Lypd1, Ly6g6e, and Lypd6b), predicting distinct nicotinic receptor regulation. To manipulate lynx regulation of endogenous nicotinic responses, we developed a pharmacological strategy guided by transcriptomic predictions. Overall, we reveal Chrna5-Cre mice as a transgenic tool to target the diversity of subplate neurons in adulthood, yielding new molecular strategies to manipulate their cholinergic activation relevant to attention disorders.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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