The puzzle box as a simple and efficient behavioral test for exploring impairments of general cognition and executive functions in mouse models of schizophrenia

Exp Neurol. 2011 Jan;227(1):42-52. doi: 10.1016/j.expneurol.2010.09.008. Epub 2010 Sep 17.


Deficits in executive functions are key features of schizophrenia. Rodent behavioral paradigms used so far to find animal correlates of such deficits require extensive effort and time. The puzzle box is a problem-solving test in which mice are required to complete escape tasks of increasing difficulty within a limited amount of time. Previous data have indicated that it is a quick but highly reliable test of higher-order cognitive functioning. We evaluated the use of the puzzle box to explore executive functioning in five different mouse models of schizophrenia: mice with prefrontal cortex and hippocampus lesions, mice treated sub-chronically with the NMDA-receptor antagonist MK-801, mice constitutively lacking the GluA1 subunit of AMPA-receptors, and mice over-expressing dopamine D2 receptors in the striatum. All mice displayed altered executive functions in the puzzle box, although the nature and extent of the deficits varied between the different models. Deficits were strongest in hippocampus-lesioned and GluA1 knockout mice, while more subtle deficits but specific to problem solving were found in the medial prefrontal-lesioned mice, MK-801-treated mice, and in mice with striatal overexpression of D2 receptors. Data from this study demonstrate the utility of the puzzle box as an effective screening tool for executive functions in general and for schizophrenia mouse models in particular.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Cognition Disorders / diagnosis*
  • Cognition Disorders / drug therapy
  • Cognition Disorders / etiology
  • Cognition Disorders / mortality
  • Disease Models, Animal
  • Dizocilpine Maleate / therapeutic use
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Agonists / toxicity
  • Excitatory Amino Acid Antagonists / therapeutic use
  • Executive Function / drug effects
  • Executive Function / physiology*
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Hippocampus / drug effects
  • Kaplan-Meier Estimate
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • N-Methylaspartate / toxicity
  • Prefrontal Cortex / drug effects
  • Problem Solving / drug effects
  • Problem Solving / physiology*
  • Reaction Time / drug effects
  • Receptors, AMPA / deficiency
  • Receptors, Dopamine D2 / metabolism
  • Schizophrenia / chemically induced
  • Schizophrenia / complications*
  • Schizophrenia / mortality


  • Excitatory Amino Acid Agonists
  • Excitatory Amino Acid Antagonists
  • Receptors, AMPA
  • Receptors, Dopamine D2
  • N-Methylaspartate
  • Dizocilpine Maleate
  • glutamate receptor ionotropic, AMPA 1