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

Background: SAPAP3-knockout (SAPAP3-KO) mice develop excessive self-grooming behavior at 4-6 months of age, serving as a model for obsessive-compulsive disorder (OCD). Given that anxiety often precedes OCD diagnosis in humans, this study investigated whether juvenile SAPAP3-KO mice exhibit anxiety-like behaviors before developing the self-grooming phenotype, and whether such behaviors respond to psilocybin treatment. The study also examined four key neuroplasticity-related synaptic proteins-GAP43, PSD95, synaptophysin, and SV2A - as SAPAP3 is a postsynaptic scaffold protein that interacts with PSD95 and may affect synaptic function.

Methods: Two studies were conducted using male and female juvenile (10-13 weeks) SAPAP3-KO mice. Study 1 compared behavioral phenotypes between homozygous (HOM), heterozygous (HET), and wild-type (WT) mice. Study 2 evaluated a different sample of HOM and WT mice and assessed the effect of psilocybin (4.4 mg/kg) on identified behavioral differences. Both studies included comprehensive behavioral testing focused on anxiety-like behavior, social interaction, and cognitive function. Additionally, levels of four synaptic proteins were measured by western blots in the frontal cortex, hippocampus, amygdala, and striatum of juvenile and adult SAPAP3-KO mice.

Results: In both studies, juvenile HOM SAPAP3-KO mice showed significant anxiety-like behaviors compared to WT mice, spending less time in open field center, and elevated plus maze open arms. They also buried fewer marbles and found fewer buried Oreos than WT mice. Psilocybin treatment did not improve these behavioral manifestations. Analysis of synaptic proteins revealed significant increases in GAP43, synaptophysin, and SV2A across multiple brain regions in adult male HOM mice and of SV2A in the frontal cortex of HOM females compared to WT, but not in juvenile mice of either sex.

Conclusions: Juvenile SAPAP3-KO mice exhibit anxiety-like behaviors before developing the characteristic excessive self-grooming phenotype, paralleling the prodromal anxiety often seen in human OCD. Unlike in adult SAPAP3-KO mice, these manifestations were not responsive to psilocybin treatment. The age-dependent increases in synaptic proteins observed in adult (but not juvenile) male SAPAP3-KO mice homozygous for the deletion and to a lesser extent in female homozygotes, may represent compensatory plasticity changes in response to the phenotype. These results provide insights into the developmental trajectory of OCD-like behaviors and associated neuroplastic adaptations.