Serotonin 5‐ HT 7 receptor signaling in neuropsychiatric disorders

Abstract Serotonin 7 receptor (5‐HT 7 R) has emerged as a multifunctional G protein‐coupled receptor that regulates neuronal excitability, structural plasticity, and circuit function across the central nervous system. Beyond canonical Gs‐dependent signaling, accumulating evidence indicates that 5‐HT 7 R also engages G12‐associated Rho GTPase pathways and β ‐arrestin/SRC family kinase‐mediated signaling, thereby enabling diverse and context‐dependent regulation of intracellular effectors involved in cytoskeletal remodeling, translational control, and sustained kinase activation. In this review, we summarize three representative 5‐HT 7 R signaling axes and discuss how these pathways may differentially contribute to the pathophysiology of major neuropsychiatric disorders, with a particular focus on autism spectrum disorder, depression, and schizophrenia. Across these disorders, 5‐HT 7 R‐linked signaling is associated with developmental wiring, synaptic maturation, stress‐responsive plasticity, glutamatergic dysfunction, and cognitive circuit regulation. Importantly, the functional consequences of 5‐HT 7 R activation appear to depend on developmental stage, brain region, cell type, ligand condition, and subcellular signaling context, indicating that similar downstream readouts may carry distinct mechanistic meanings. By adopting a pathway–disease mapping perspective, this review highlights 5‐HT 7 R as a versatile molecular interface connecting serotonergic signaling to disease‐relevant neural plasticity and suggests that future therapeutic strategies may benefit from pathway‐informed modulation rather than a simple agonist–antagonist framework.