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Abnormal neurodevelopment, neurosignaling and behaviour in Npas3-deficient mice

Authors

  • Eric W. Brunskill,

    1. Division of Cardiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA
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  • Lisa A. Ehrman,

    1. Division of Developmental Biology, Cincinnati Children's Research Foundation and University of Cincinnati College of Medicine, Cincinnati, OH 45229–3038, USA
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  • Michael T. Williams,

    1. Division of Child Neurology, Cincinnati Children's Research Foundation and University of Cincinnati College of Medicine, Cincinnati, OH 45229–3039, USA
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  • Justin Klanke,

    1. Division of Cardiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA
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  • Daniel Hammer,

    1. Division of Cardiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA
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  • Tori L. Schaefer,

    1. Division of Child Neurology, Cincinnati Children's Research Foundation and University of Cincinnati College of Medicine, Cincinnati, OH 45229–3039, USA
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  • Renu Sah,

    1. Department of Psychiatry, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA
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  • Gerald W. Dorn Il,

    1. Division of Cardiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA
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  • S. Steven Potter,

    1. Division of Developmental Biology, Cincinnati Children's Research Foundation and University of Cincinnati College of Medicine, Cincinnati, OH 45229–3038, USA
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  • Charles V. Vorhees

    1. Division of Developmental Biology, Cincinnati Children's Research Foundation and University of Cincinnati College of Medicine, Cincinnati, OH 45229–3038, USA
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Dr Eric W. Brunskill, as above.
E-mail: eric.brunskill@uc.edu

Abstract

Npas3 is a member of the bHLH-PAS superfamily of transcription factors that is expressed broadly in the developing neuroepithelium. To study the function of this gene, mice deficient in Npas3 were generated and characterized. Npas3–/– mice were growth-retarded and exhibited developmental brain abnormalities that included a reduction in size of the anterior hippocampus, hypoplasia of the corpus callosum and enlargement of the ventricles. A number of behavioural abnormalities were identified in Npas3–/– mice including locomotor hyperactivity, subtle gait defects, impairment of prepulse inhibition of acoustic startle, deficit in recognition memory and altered anxiety-related responses. Characterization of neurosignaling pathways using several pharmacological agents revealed dysfunctional glutamate, dopamine and serotonin neurotransmitter signaling. Consistent with these findings, we identified a significant alteration in cortical PSD-95 expression, a PDZ-containing protein that has been shown to be involved in postsynaptic signal transduction. Together, our observations indicate an important role for Npas3 in controlling normal brain development and neurosignaling pathways.

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