Premorbid Characteristics of the SAPAP3-Mouse Model of Obsessive-Compulsive Disorder: Behavior, Neuroplasticity, and Psilocybin Treatment

Deletion of the SAPAP3 gene in mice results in a characteristic phenotype that manifests from the age of 4-6 months and consists of repetitive bouts of self-grooming, head-body twitches, and anxiety-related behaviors. The phenotype is attenuated by sub-chronic fluoxetine and by single injections of ketamine and psilocybin and is considered a model for OCD. We investigated the premorbid characteristics of SAPAP3 knockout (SAPAP3-KO) mice. Two cohorts of juvenile SAPAP3-KO mice (aged 10-13 weeks) were assessed for anxiety and other behavioral phenotypes. Compared to wild-type (WT) mice, male and female homozygous SAPAP3-KO mice manifested significant anxiety-like behaviors in the open field and elevated plus maze tests, reduced marble burying, and altered performance on the buried Oreo test. These behaviors were not alleviated by psilocybin treatment. Adult male SAPAP3-KO mice showed increased levels of synaptic proteins (GAP43, synaptophysin, and SV2A) in the frontal cortex, hippocampus, and amygdala, while adult female SAPAP3-KO mice showed increased SV2A in the frontal cortex. These findings suggest enhanced synaptic growth and vesicle-associated plasticity in adult SAPAP3-KO mice that may reflect a compensatory mechanism. Increased synaptic proteins were not observed in juvenile mice, suggesting age-dependent alterations in neuroplasticity. Our finding that SAPAP3-KO mice exhibit anxiety-like behaviors before the onset of compulsive grooming is analogous to prodromal anxiety observed in patients with OCD. The study provides a basis for further research into the development of OCD-like behaviors and associated neuroplasticity changes and for studying potential treatments.