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Abstract

Deficits in executive functions are key features of schizophrenia. Rodent behavioral paradigms used so far to 29 find animal correlates of such deficits require extensive effort and time. The puzzle box is a problem−solving 30 test in which mice are required to complete escape tasks of increasing difficulty within a limited amount 31 of time. Previous data have indicated that it is a quick but highly reliable test of higher−order cognitive 32 functioning. 33 We evaluated the use of the puzzle box to explore executive functioning in five different mouse models of 34 schizophrenia: mice with prefrontal cortex and hippocampus lesions, mice treated sub−chronically with the 35 NMDA−receptor antagonist MK−801, mice constitutively lacking the GluA1 subunit of AMPA−receptors, and 36 mice over−expressing dopamine D2 receptors in the striatum. All mice displayed altered executive functions 37 in the puzzle box, although the nature and extent of the deficits varied between the different models. Deficits 38 were strongest in hippocampus−lesioned and GluA1 knockout mice, while more subtle deficits but specific to 39 problem solving were found in the medial prefrontal−lesioned mice, MK−801−treated mice, and in mice with 40 striatal overexpression of D2 receptors. 41 Data from this study demonstrate the utility of the puzzle box as an effective screening tool for executive 42 functions in general and for schizophrenia mouse models in particular