Premorbid characteristics of the SAPAP3 mouse model of obsessive-compulsive disorder: behavior, neuroplasticity, and psilocybin treatment
Michal Lazar, Michal Brownstien, Alexander Botvinnik, Chloe Shevakh, Orr Shahar, Tzuri Lifschytz, Bernard Lerer
The International Journal of Neuropsychopharmacology March 29, 2025 DOI: 10.1093/ijnp/pyaf022 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal study with two sub-studies: behavioral phenotyping (Study 1) and psilocybin treatment (Study 2), plus western blot protein analysis Peer reviewed |
|---|---|
| Population | Juvenile (10–13 weeks) and adult SAPAP3-knockout mice (homozygous, heterozygous, wild-type), both sexes |
| Intervention | Psilocybin |
| Dose | 4.4 mg/kg |
| Topics | Anxiety Neuroplasticity Psilocybin |
| Keywords | Synaptophysin Hippocampus Amygdala Gap-43 protein Elevated plus maze Open field Postsynaptic density Juvenile Endocrinology Obsessive-compulsive spectrum disorders |
| Citations | 3 |
| Key points | Juvenile SAPAP3-KO mice exhibit anxiety-like behaviors before developing excessive self-grooming, and these behaviors are not improved by psilocybin treatment. |
Abstract
Abstract 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 (PSIL) treatment. The study also examined 4 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, and wild-type (WT) mice. Study 2 evaluated a different sample of HOM and WT mice and assessed the effect of PSIL (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 4 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 PSIL treatment. The age-dependent increases in synaptic proteins observed in adult (but not juvenile) male SAPAP3-KO mice HOM 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.