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

doi:10.1016/j.isci.2023.105992

Chrna5 and lynx prototoxins identify acetylcholine super-responder subplate neurons

iScience. 2023 Jan 14;26(2):105992. doi: 10.1016/j.isci.2023.105992. eCollection 2023 Feb 17.

Authors

Sridevi Venkatesan¹, Tianhui Chen¹, Yupeng Liu¹, Eric E Turner², Shreejoy J Tripathy^{1

3

4

5}, Evelyn K Lambe^{1

4

6}

Affiliations

¹ Department of Physiology, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON, Canada.
² Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.
³ Krembil Centre for Neuroinformatics, Centre for Addiction and Mental Health, Toronto, ON, Canada.
⁴ Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
⁵ Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
⁶ Department of Obstetrics and Gynecology, University of Toronto, Toronto, ON, Canada.

Abstract

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.

Keywords: Biological sciences; Molecular neuroscience; Neuroscience; Transcriptomics.