Chrna5 and lynx prototoxins identify acetylcholine super-responder subplate neurons

Abstract

Attention depends on cholinergic excitation of prefrontal neurons. Knockout/knockdown studies indicate nicotinic alpha5 subunits encoded by Chrna5 are required for this response, but their native cellular roles and molecular interactions are unknown. Here, we probe endogenous cholinergic regulation of prefrontal Chrna5-expressing neurons (Chrna5+) using compound transgenic mice. Chrna5+ neurons show high sensitivity to acetylcholine, with a subpopulation clearly different from nearby, well-examined Syt6+ cells. Transcriptomic analysis reveals this distinct Chrna5+ population as subplate neurons, a diverse group of firstborn cells that have eluded previous transgenic characterization. Intriguingly, Chrna5+ subplate neurons express a distinct profile of GPI-anchored lynx prototoxins, suggesting specialized regulation of their cholinergic responses. In brain slices, endogenous nicotinic responses can be bidirectionally altered by perturbing GPI-anchored lynxes with phospholipase C activation or exogenous application of recombinant Ly6g6e prototoxin. Our work reveals cell-type specific Chrna5 and Lynx modulation leading to exquisite cholinergic sensitivity of prefrontal subplate neurons in adulthood.TeaserChrna5-expression identifies subplate neurons in the adult prefrontal cortex with enhanced cholinergic sensitivity.

FOXP2-immunoreactive, corticothalamic pyramidal cells in neocortical layers 6a and 6b are tightly regulated by neuromodulatory systems

“…In addition, a recent study identified excitatory subplate neurons termed 'ACh super-responders' due to their pronounced ACh-induced depolarisations (Venkatesan et al, 2022), a feature resembling the L6b CT PCs described here. Layer 6b is considered to be a remnant of the subplate (Hoerder-Suabedissen and Molnar, 2012; Marx et al, 2017;Reep, 2000;Torres-Reveron and Friedlander, 2007), which suggests that L6b excitatory neurons retain the high ACh responsiveness akin to the 'ACh super-responder' subplate neurons during early postnatal development.…”

Xanomeline restores endogenous nicotinic acetylcholine receptor signaling in mouse prefrontal cortex

“…The atropine-sensitivity and postsynaptic PKC-dependence of its nicotinic receptor upregulation points to an excitatory muscarinic mechanism, but xanomeline has also been shown to inhibit M4 receptors [100,101] and could potentially disinhibit glutamate release. Our data implicate the involvement of PKC, typically activated by Gαq-signaling, but this signaling also triggers activation of PLC [102] and may regulate GPI-anchored lynx family proteins [103] that also modulate nicotinic receptors [104,105] directly [106–108] or indirectly [107,109]. We find an improvement in apparent nicotinic receptor availability, however, the question of the density and localization of nicotinic receptors prior to-and after treatment remains outstanding.…”