Beta2* Nicotinic Receptors Tune Prefrontal Behavior Through Distinct Neuronal Populations

Abstract

Beta2 subunit-containing nicotinic acetylcholine receptors (beta2*nAChRs) are highly expressed in the prefrontal cortex (PFC) and critically regulate behavioral and cognitive domains that are disrupted in neuropsychiatric disorders. Despite their therapeutic potential, the cell-type- and circuit-specific functions of beta2* nAChRs remain poorly defined, partially due to the lack of selective pharmacological tools. Here, we delineate the cellular expression patterns and behavioral roles of beta2* nAChRs expressed in a general vs. highly specific neuronal populations of the mouse PFC. Using fluorescence in situ hybridization (FISH), we mapped beta2 nicotinic subunit expression across cortical layers and major neuronal classes. We then employed CRISPR-mediated knockdown (KD) to reduce beta2* nAChRs expression selectively in two distinct PFC neuronal populations and, for comparison, in a striatal population. The KD of beta2* nAChRs in a mixed population of excitatory and inhibitory neurons in deep PFC layers resulted in a mild impairment of social and exploratory behaviors. In contrast, KD in a highly selective population of superficial-layer interneurons expressing the serotonin receptor 5HT3a induced a robust hypersocial phenotype, accompanied by changes in exploratory behavior. Notably, KD of beta2* nAChRs in a rare NPY-expressing striatal population slightly affected similar behavioral domains, but in the opposite direction to PFC manipulations. Together, these findings reveal opposing, cell-type- and region-specific contributions of beta2* nAChRs to behavioral regulations, highlighting the necessity of circuit-resolved targeting strategies to improve the precision and efficacy of therapeutic intervention for neuropsychiatric disorders.