Animals lacking endothelin-converting enzyme-2 are deficient in learning and memory

Authors

  • R. M. Rodriguiz,

    1. Department of Psychiatry and Behavioral Sciences and Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC, §Department of Pharmacology and Systems Therapeutics and Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, **Department of Biophysics and Molecular Genetics, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, and ††Department of Cell Biology and ‡‡Department of Neurobiology, Duke University Medical Center, Durham, NC, USA
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  • , K. Gadnidze,

    1. Department of Psychiatry and Behavioral Sciences and Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC, §Department of Pharmacology and Systems Therapeutics and Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, **Department of Biophysics and Molecular Genetics, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, and ††Department of Cell Biology and ‡‡Department of Neurobiology, Duke University Medical Center, Durham, NC, USA
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  • A. Ragnauth,

    1. Department of Psychiatry and Behavioral Sciences and Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC, §Department of Pharmacology and Systems Therapeutics and Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, **Department of Biophysics and Molecular Genetics, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, and ††Department of Cell Biology and ‡‡Department of Neurobiology, Duke University Medical Center, Durham, NC, USA
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  • N. Dorr,

    1. Department of Psychiatry and Behavioral Sciences and Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC, §Department of Pharmacology and Systems Therapeutics and Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, **Department of Biophysics and Molecular Genetics, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, and ††Department of Cell Biology and ‡‡Department of Neurobiology, Duke University Medical Center, Durham, NC, USA
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  • M. Yanagisawa,

    1. Department of Psychiatry and Behavioral Sciences and Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC, §Department of Pharmacology and Systems Therapeutics and Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, **Department of Biophysics and Molecular Genetics, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, and ††Department of Cell Biology and ‡‡Department of Neurobiology, Duke University Medical Center, Durham, NC, USA
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  • W. C. Wetsel,

    Corresponding author
    1. Department of Psychiatry and Behavioral Sciences and Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC, §Department of Pharmacology and Systems Therapeutics and Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, **Department of Biophysics and Molecular Genetics, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, and ††Department of Cell Biology and ‡‡Department of Neurobiology, Duke University Medical Center, Durham, NC, USA
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  • and ,,,, L. A. Devi ,

    1. Department of Psychiatry and Behavioral Sciences and Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC, §Department of Pharmacology and Systems Therapeutics and Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, **Department of Biophysics and Molecular Genetics, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, and ††Department of Cell Biology and ‡‡Department of Neurobiology, Duke University Medical Center, Durham, NC, USA
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* W. C. Wetsel, Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, 028 CARL Building, Durham, NC 27710, USA. E-mail: wetse001@mc.duke.edu

Abstract

Endothelin-converting enzyme (ECE)-2 is a metalloprotease that possesses many properties consistent with it being a neuropeptide-processing enzyme. This protease is found primarily in neural tissues, with high levels of expression in midbrain, cerebellum, hypothalamus, frontal cortex and spinal cord and moderate levels in hippocampus and striatum. To evaluate its role in neural function, mice have been generated lacking this enzyme. Physical appearance, autonomic reflexes, motor co-ordination, balance, locomotor activity and spontaneous emotional responses appear normal in these knockout (KO) mice. However, these mutants display deficits in learning and memory as evidenced by marked impairment in the Morris water maze. Knockout mice are also deficient in object recognition memory where they show delays in discerning changes in object location and in recognizing the introduction of a novel object. In this study, perseveration appears to interfere with learning and memory. Finally, mutants are impaired in social transmission of food preference where they show poor short-term memory and perturbations in long-term memory; the latter can be ameliorated by reminder cues. As ECE-2 has been implicated in Alzheimer’s disease, the deficits in learning and memory in the KO mice may provide unique insights into processes that may contribute to this disease and possible other disorders of cognition.

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