Glutamate-mediated excitotoxicity in neonatal hippocampal neurons is mediated by mGluR-induced release of Ca++ from intracellular stores and is prevented by estradiol

Authors

  • Genell D. Hilton,

    Corresponding author
    1. Department of Physiology, University of Maryland, Baltimore, Maryland 21201, USA
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    • G.D.H. and J.L.N. contributed equally to this work.

  • Joseph L. Nunez,

    1. Neuroscience Program and Psychology Department, Michigan State University, East Lansing, Michigan, USA
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    • G.D.H. and J.L.N. contributed equally to this work.

  • Linda Bambrick,

    1. Department of Physiology, University of Maryland, Baltimore, Maryland 21201, USA
    2. Department of Anaesthesiology, University of Maryland,Baltimore, Maryland 21201, USA
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  • Scott M. Thompson,

    1. Department of Physiology, University of Maryland, Baltimore, Maryland 21201, USA
    2. Program in Neuroscience, University of Maryland, Baltimore, Maryland 21201, USA
    3. Department of Psychiatry, University of Maryland, School of Medicine, Baltimore, Maryland 21201, USA
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  • Margaret M. McCarthy

    1. Department of Physiology, University of Maryland, Baltimore, Maryland 21201, USA
    2. Program in Neuroscience, University of Maryland, Baltimore, Maryland 21201, USA
    3. Department of Psychiatry, University of Maryland, School of Medicine, Baltimore, Maryland 21201, USA
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  • *

    Present address: Department of Neuroscience, Georgetown University Medical Center, 3970 Reservoir Road. N.W., Room WG 03, Washington D.C., 20057, USA.

Dr Genell Hilton, *present address below.
E-mail: Gdh4@georgetown.edu

Abstract

Hypoxic/ischemic (HI) brain injury in newborn full-term and premature infants is a common and pervasive source of life time disabilities in cognitive and locomotor function. In the adult, HI induces glutamate release and excitotoxic cell death dependent on NMDA receptor activation. In animal models of the premature human infant, glutamate is also released following HI, but neurons are largely insensitive to NMDA or AMPA/kainic acid (KA) receptor-mediated damage. Using primary cultured hippocampal neurons we have determined that glutamate increases intracellular calcium much more than kainic acid. Moreover, glutamate induces cell death by activating Type I metabotropic glutamate receptors (mGluRs). Pretreatment of neurons with the gonadal steroid estradiol reduces the level of the Type I metabotropic glutamate receptors and completely prevents cell death, suggesting a novel therapeutic approach to excitotoxic brain damage in the neonate.

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