S1P–S1PR1 Dysregulation Is Associated With Brain-Wide S1PR1 Molecular Covariance Reorganization and Compulsive-Like Behaviors in Sapap3-Deficient Mice

Background Obsessive-compulsive disorder (OCD) is a debilitating neuropsychiatric disorder with heterogeneous clinical manifestations and incompletely understood biological mechanisms. Although dysfunction of cortico-striato-thalamo-cortical (CSTC) circuits has been extensively implicated in OCD pathophysiology, emerging evidence indicates that compulsive symptoms also involve distributed alterations across large-scale brain systems, the molecular basis of which remains poorly understood. The sphingosine-1-phosphate (S1P)/S1P receptor 1 (S1PR1) axis regulates neuroimmune signaling, synaptic plasticity, and cellular homeostasis; however, its role in organizing brain-wide molecular architecture in compulsive pathology remains unknown. Methods Using Sapap3 knockout (KO) mice, we integrated striatal metabolomics, S1PR1-targeted [¹⁸F]TZ4877 PET imaging, ex vivo validation, whole-brain molecular covariance analysis, and individualized S1PR1 profile deviation scoring (PDS) to define multiscale alterations in S1P–S1PR1 biology. We further examined relationships among regional S1PR1 availability, molecular covariance architecture, individualized molecular deviation, and compulsive-like behaviors. Results Sapap3 deficiency was associated with altered sphingolipid metabolism, characterized by increased S1P abundance in peripheral and central tissues and reduced regional S1PR1 availability across the brain. Whole-brain S1PR1 molecular covariance analysis revealed genotype-associated remodeling of receptor-level molecular organization, characterized by increased interregional covariance, reduced modular segregation, and hypothalamus-centered covariance alterations extending beyond classical CSTC regions. Individualized PDS analysis demonstrated that greater deviation from the normative S1PR1 spatial profile was associated with greater expression of compulsive-like phenotypes, including repetitive grooming and tic-like behaviors. Conclusions This study identifies S1P–S1PR1 dysregulation as a receptor-level molecular feature associated with large-scale brain organization in compulsive pathology. By integrating receptor-specific molecular imaging, molecular covariance analysis, and individualized deviation profiling, we provide a systems-level framework linking distributed molecular organization with behavioral variability.