Chrna5 and lynx prototoxins identify acetylcholine super-responder subplate neurons

Attention depends on cholinergic excitation of prefrontal neurons but is sensitive to perturbation of alpha 5-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.

Automated summary

The study reveals that Chrna5-expressing neurons play a crucial role in attention and offer potential targets for improvement. By using opto-physiological experiments and single-cell transcriptomics, researchers identify a distinct population of acetylcholine super-responders within Chrna5+ neurons and discover molecular markers that define their identity. Manipulation of the regulation of nicotinic responses in these neurons provides new strategies for the treatment of attention disorders.