Nicotinic Acetylcholine Receptors in the Brain: Subunit Diversity, Circuit and Behavioral Functions, Therapeutic Potential, and Disease Implications

Nicotinic acetylcholine receptors (nAChRs) are among the most widely distributed and structurally diverse ligand-gated ion channels in the central nervous system. Over the past decade, advances in molecular genetics, high-resolution structural biology, circuit-level functional mapping, behavioral pharmacology, and preclinical drug discovery have begun to reveal a new landscape of nAChR complexity, one in which receptor subtype composition dynamically tunes synaptic plasticity, neuromodulatory tone, cognitive processing, and vulnerability to disease. A growing body of work now highlights that individual nAChR subunits, including the less explored α5-, α6-, β3-, and hybrid configurations, play highly specialized roles in neurotransmitter release, excitability, dendritic integration, and local microcircuit computations. These findings raise fundamental questions about how receptor subtype expression is developmentally programmed, how it adapts in response to experience or injury, and how perturbations in nAChR composition contribute to neurodevelopmental, neuropsychiatric, neurodegenerative, and behavioral conditions. Recent methodological innovations, such as cryo-EM structures of heteromeric receptors, single-cell and spatial transcriptomics, CRISPR-based subunit manipulation, and in vivo imaging of cholinergic signalling, have accelerated efforts to precisely define the molecular logic of nAChR function. At the same time, translational research has linked subtype-specific dysfunction to addiction, cognitive impairment, Parkinson’s disease, schizophrenia, Alzheimer’s disease, and rare channelopathies. Collectively, these advances position nAChRs as a highly promising set of targets for therapeutic development and for the design of novel pharmacological interventions. This Research Topic will showcase recent breakthroughs and emerging questions in the molecular, cellular, circuit, behavioral, and disease-related biology of nicotinic acetylcholine receptors. Our goal is to integrate subunit-resolved molecular mechanisms with circuit-level principles, behaviorally relevant phenotypes, and translational and drug discovery perspectives to advance a cohesive understanding of how nicotinic acetylcholine receptors shape the brain function and resilience of the nervous system.Areas of interest include, but are not limited to:· nAChR contributions to synaptic plasticity, neuromodulation, and cognitive processes· Subunit-specific functions in circuit, behavior, and disease.· Therapeutic strategies targeting specific nAChR subunits· Structural and biophysical insights into nAChR assembly, trafficking, and modulation· Mapping nAChR subtype distribution across brain regions, circuits, and developmental stages· Integration of nAChR signalling with cholinergic, dopaminergic, and glutamatergic pathways· Molecular and genetic alterations of nAChRs in neurodevelopmental, neuropsychiatric, and neurodegenerative disorders· Emerging pharmacological, chemogenetic, or optogenetic tools to probe nAChR function· Interactions between cholinergic activity, receptor plasticity, and compensatory/homeostatic mechanisms· Mechanisms linking nAChR dysfunction to addiction, stress responses, and behavioral phenotypes· Preclinical and translational studies targeting nAChR subtypes· Model organisms (mouse, zebrafish, Drosophila, C. elegans) for dissecting receptor subtype roles in defined neural circuitsnAChR and contribution to cell-type specific omics.· Novel methodological approaches, including single-cell -omics, spatial profiling, and circuit-specific manipulation Topic editors: Charles Albert Hoeffer, Guanxiao Qi, Koji Toda Source: https://www.frontiersin.org/research-topics/76342/nicotinic-acetylcholine-receptors-in-the-brain-subunit-diversity-circuit-and-behavioral-functions-therapeutic-potential-and-disease-implications