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

Juvenile mice lacking the SAPAP3 gene, a model of obsessive-compulsive disorder (OCD), show anxiety-like behaviors before they develop the excessive self-grooming that mimics OCD compulsions. Compared to normal mice, these knockout mice spent less time in open areas, buried fewer marbles, and found fewer hidden objects. A single dose of psilocybin (4.4 mg/kg) did not reduce these anxiety-like behaviors. In adult but not juvenile male knockout mice, levels of several synaptic proteins (GAP43, synaptophysin, SV2A) were elevated across brain regions, suggesting compensatory plasticity changes that emerge with age. The findings parallel the clinical observation that anxiety often precedes OCD in humans and indicate that psilocybin's therapeutic effects may be age-dependent.

Study at a glance

Abstract

Abstract Background SAPAP3-knockout (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, 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 early manifestations were not responsive to psilocybin treatment. The age-dependent increases in synaptic proteins observed in adult but not juvenile male SAPAP3-KO mice and to a lesser extent in females, 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. Significance Statement Obsessive-compulsive disorder (OCD) frequently emerges during adolescence, with anxiety as a common prodromal symptom. This study investigated behavioral and molecular characteristics of juvenile SAPAP3 knockout (KO) mice, an established preclinical model of OCD, prior to manifestation of their characteristic excessive grooming phenotype. Juvenile SAPAP3 KO mice exhibited significant anxiety-like behaviors on multiple behavioral measures. While psilocybin treatment reduces OCD-like behaviors in adult SAPAP3 knockout mice, it did not ameliorate anxiety-like behaviors in juvenile mice, indicating age-dependent therapeutic effects. Notably, adult male SAPAP3 KO mice showed elevated levels of synaptic plasticity-related proteins in emotion-regulatory brain regions, whereas juvenile KO showed no such alterations. These findings demonstrate that anxiety precedes compulsive behaviors in this model and reveal age- dependent neuroplasticity changes. This developmental trajectory parallels clinical observations in OCD and provides a framework for investigating early intervention strategies.