Orphan G Protein-Coupled Receptors: A Novel Research Frontier in Autism and Associated Disorders

G-protein coupled receptors (GPCRs) are a diverse group of membrane proteins crucial for transmitting extracellular signals into cells, regulating numerous neurological processes. Among GPCRs, orphan receptors, whose natural ligands and functions remain unidentified, have garnered increasing research attention. Olfactory receptors (ORs), the most diverse GPCR family, are widely expressed in the central nervous system (CNS) and are implicated in autism spectrum disorder (ASD) and related behavioral and psychiatric conditions. This review highlights the altered expression of specific orphan and olfactory GPCRs-such as RORα, RORβ, GPR37, GPR62, OR1C1, and OR52M1-and their roles in ASD development. It explores their mechanisms of action, neural network interactions, and contributions to ASD etiology, as well as associated disorders like ADHD, schizophrenia, epilepsy, anxiety, depression, and sleep disorders. The review also addresses challenges in orphan GPCR research, such as identifying ligands and understanding their physiological roles, while emphasizing their potential as therapeutic targets. By summarizing preclinical and clinical findings, this review underscores the emerging significance of orphan receptors in ASD, offering a foundation for future research to advance understanding and develop innovative treatments for autism and related conditions.