Cholinergic Modulation of Chandelier Cells via Heteromeric Nicotinic Receptors in Prefrontal Cortex
Chandelier cells (ChCs) are a highly specialized subtype of GABAergic interneurons and one of the most distinctive elements of cortical circuitry, exerting powerful and strategic control over pyramidal neuron output by selectively innervating their axon initial segment. They are particularly abundant in the prefrontal cortex, where cholinergic inputs modulate cognitive functions and shape ChC axonal development, but the way in which the cholinergic system--a master modulator of attention and arousal--regulates these cells in the adult brain has long remained unexplored. In this study, by employing an intersectional genetic strategy in adult mice, we reveal that ChCs in the secondary motor cortex are direct targets of cholinergic modulation. Through patch-clamp recordings and functional imaging, we demonstrate that acetylcholine persistently activates ChCs via heteromeric nicotinic receptors containing the {beta}2 subunit, triggering robust depolarization and a significant increase in intrinsic excitability. This regulation does not rely on fast synaptic transmission; instead, it arises from a diffuse and sustained cholinergic signaling mode, orchestrated from the basal forebrain. Intriguingly, our in vivo observations show that ChC activity is positively correlated with behavioral markers of high arousal, such as locomotion and pupil dilation--a signature of activity that diminished upon the blockade of nicotinic receptors. Our findings strongly suggest that ChCs serve as a link between global arousal and local cortical control, thereby offering deeper insights into the mechanisms of state-dependent information processing.