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Premorbid characteristics of the SAPAP3 mouse model of obsessive-compulsive disorder: behavior, neuroplasticity, and psilocybin treatment

Summary

This research examined young genetically modified mice that lack the SAPAP3 gene to understand early signs of obsessive-compulsive disorder-like behavior. The study found that these juvenile mice showed anxiety-like behaviors before developing the excessive grooming typical of the adult model. Surprisingly, psilocybin treatment—which works in adult mice—did not help reduce anxiety in the younger mice, suggesting that the brain needs to mature for this treatment to be effective.

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). Anxiety often precedes OCD diagnosis in humans, but it is unclear whether juvenile SAPAP3-KO mice exhibit anxiety-like behaviors before developing the self-grooming phenotype.

Objective

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 neuroplasticity-related synaptic proteins (GAP43, PSD95, synaptophysin, and SV2A) in juvenile and adult SAPAP3-KO mice.

Results

Juvenile homozygous SAPAP3-KO mice showed significant anxiety-like behaviors compared to wild-type mice on open field and elevated plus maze tests. Psilocybin treatment did not improve these behavioral manifestations in juvenile mice. Adult male homozygous mice showed significant increases in GAP43, synaptophysin, and SV2A across multiple brain regions, but these changes were absent in juvenile mice.

Conclusion

Juvenile SAPAP3-KO mice exhibit anxiety-like behaviors before developing the characteristic excessive self-grooming phenotype, paralleling prodromal anxiety in human OCD. Unlike in adult SAPAP3-KO mice, these manifestations were not responsive to psilocybin treatment, indicating age-dependent therapeutic effects and neuroplastic adaptations.
  • Published in:International Journal of Neuropsychopharmacology,
  • Study Type:Experimental Animal Study,
  • Source: PMID: 40156912
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