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Related Experiment Video

Updated: Feb 12, 2026

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Repetitive and compulsive-like behaviors lead to cognitive dysfunction in Disc1Δ2-3/Δ2-3 mice.

B Wulaer1, T Nagai1, A Sobue1

  • 1Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Genes, Brain, and Behavior
|April 11, 2018
PubMed
Summary

Mice lacking Disrupted-in-schizophrenia 1 (Disc1) show cognitive deficits and compulsive behaviors linked to brain hyperactivity. Clozapine treatment improved these behaviors, suggesting Disc1

Keywords:
DREADDDisc1c-Fosclozapinecognitiontouchscreen

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Area of Science:

  • Neuroscience
  • Genetics
  • Psychiatry

Background:

  • Disrupted-in-schizophrenia 1 (Disc1) is a critical gene implicated in the pathophysiology of mental disorders.
  • Previous research generated Disc1-deficient mice (Disc1Δ2-3/Δ2-3) exhibiting a lack of full-length Disc1 protein.
  • Understanding Disc1's role in cognitive function and behavior is crucial for developing targeted therapies for mental diseases.

Purpose of the Study:

  • To investigate the role of Disc1 in cognitive function and associated behaviors.
  • To explore the neurobiological underpinnings of Disc1 deficiency-related behavioral alterations.
  • To assess the therapeutic potential of clozapine in ameliorating Disc1-related behavioral deficits.

Main Methods:

  • Utilized a touchscreen-based visual discrimination (VD) task to assess cognitive performance in Disc1Δ2-3/Δ2-3 mice and wild-type (WT) controls.
  • Employed behavioral tests including marble burying and nestlet shredding to evaluate perseverative/compulsive behaviors.
  • Measured c-Fos expression in specific brain regions (dorsomedial striatum - DMS, dorsolateral striatum - DLS) to assess neuronal activity.
  • Administered clozapine and clozapine-N-oxide (CNO) to evaluate their effects on behavior and DMS activity.

Main Results:

  • Disc1Δ2-3/Δ2-3 mice exhibited impaired performance in the VD task, characterized by increased perseverative responses compared to WT mice.
  • Disc1Δ2-3/Δ2-3 mice displayed significantly higher marble burying and nestlet shredding, indicating perseverative/compulsive behaviors.
  • Clozapine treatment successfully ameliorated the cognitive and behavioral deficits observed in Disc1Δ2-3/Δ2-3 mice.
  • Elevated c-Fos expression was observed in the DMS, but not DLS, of Disc1Δ2-3/Δ2-3 mice after the VD task, suggesting DMS hyperactivity.
  • Pharmacogenetic activation of DMS neurons using CNO in hM3Dq-expressing mice impaired VD task performance.

Conclusions:

  • Disc1 deficiency leads to cognitive impairments and perseverative/compulsive behaviors in mice.
  • The observed behavioral deficits are associated with hyperactivity in the dorsomedial striatum (DMS).
  • Clozapine demonstrates therapeutic potential for ameliorating Disc1-related cognitive and behavioral abnormalities.