Activation of microglial N-methyl-D-aspartate receptors triggers inflammation and neuronal cell death in the developing and mature brain

Authors

  • Angela M. Kaindl MD, PhD,

    Corresponding author
    1. French Institute of Health and Medical Research U676, Robert Debré Hospital, Paris, France
    2. Denis Diderot Faculty of Medicine, University of Paris 7, Paris, France
    3. PremUP, Paris, France
    4. Department of Pediatric Neurology, Charité–Universitätsmedizin Berlin, Berlin, Germany
    5. Institute of Neurobiology and Cell Biology, Universitätsmedizin Berlin, Berlin, Germany
    • Pediatric Neurology and Institute of Cell Biology and Neurobiology, Charité–Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
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  • Vincent Degos MD, PhD,

    1. French Institute of Health and Medical Research U676, Robert Debré Hospital, Paris, France
    2. Denis Diderot Faculty of Medicine, University of Paris 7, Paris, France
    3. PremUP, Paris, France
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  • Stéphane Peineau PhD,

    1. French Institute of Health and Medical Research U676, Robert Debré Hospital, Paris, France
    2. Denis Diderot Faculty of Medicine, University of Paris 7, Paris, France
    3. PremUP, Paris, France
    4. Medical Research Council Centre for Synaptic Plasticity, Department of Anatomy, School of Medical Sciences, Bristol, United Kingdom
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  • Elodie Gouadon PhD,

    1. National Center for Scientific Research, UMR 8162, Le Plessis-Robinson, France
    2. Marie Lannelongue Hospital, Le Plessis-Robinson, France
    3. University of Paris-South, Le Plessis-Robinson, France
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  • Vibol Chhor MD,

    1. French Institute of Health and Medical Research U676, Robert Debré Hospital, Paris, France
    2. Denis Diderot Faculty of Medicine, University of Paris 7, Paris, France
    3. PremUP, Paris, France
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  • Gauthier Loron MD,

    1. French Institute of Health and Medical Research U676, Robert Debré Hospital, Paris, France
    2. Denis Diderot Faculty of Medicine, University of Paris 7, Paris, France
    3. PremUP, Paris, France
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  • Tifenn Le Charpentier,

    1. French Institute of Health and Medical Research U676, Robert Debré Hospital, Paris, France
    2. Denis Diderot Faculty of Medicine, University of Paris 7, Paris, France
    3. PremUP, Paris, France
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  • Julien Josserand,

    1. French Institute of Health and Medical Research U676, Robert Debré Hospital, Paris, France
    2. Denis Diderot Faculty of Medicine, University of Paris 7, Paris, France
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  • Carine Ali PhD,

    1. French Institute of Health and Medical Research U919, Caen, France
    2. National Center for Scientific Research, Mixed Unit of Research 6232, Caen, France
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  • Denis Vivien PhD,

    1. French Institute of Health and Medical Research U919, Caen, France
    2. National Center for Scientific Research, Mixed Unit of Research 6232, Caen, France
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  • Graham L. Collingridge PhD,

    1. Medical Research Council Centre for Synaptic Plasticity, Department of Anatomy, School of Medical Sciences, Bristol, United Kingdom
    2. Department of Brain and Cognitive Sciences, Seoul National University, Seoul, South Korea
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  • Alain Lombet PhD,

    1. Institute of Neurobiology and Cell Biology, Universitätsmedizin Berlin, Berlin, Germany
    2. Medical Research Council Centre for Synaptic Plasticity, Department of Anatomy, School of Medical Sciences, Bristol, United Kingdom
    3. National Center for Scientific Research, UMR 8162, Le Plessis-Robinson, France
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  • Lina Issa,

    1. Department of Pediatric Neurology, Charité–Universitätsmedizin Berlin, Berlin, Germany
    2. Institute of Neurobiology and Cell Biology, Universitätsmedizin Berlin, Berlin, Germany
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  • Frédérique Rene,

    1. French Institute of Health and Medical Research U692, Strasbourg, France
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  • Jean-Philippe Loeffler,

    1. French Institute of Health and Medical Research U692, Strasbourg, France
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  • Annemieke Kavelaars PhD,

    1. University Medical Center Utrecht, Utrecht, the Netherlands
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  • Catherine Verney PhD,

    1. French Institute of Health and Medical Research U676, Robert Debré Hospital, Paris, France
    2. Denis Diderot Faculty of Medicine, University of Paris 7, Paris, France
    3. PremUP, Paris, France
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  • Jean Mantz MD, PhD,

    1. French Institute of Health and Medical Research U676, Robert Debré Hospital, Paris, France
    2. Denis Diderot Faculty of Medicine, University of Paris 7, Paris, France
    3. PremUP, Paris, France
    4. Anesthesiology and Intensive Care Service, Clichy, Beaujon Hospital, Public Assistance Hospitals of Paris, Paris, France
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  • Pierre Gressens MD, PhD

    Corresponding author
    1. French Institute of Health and Medical Research U676, Robert Debré Hospital, Paris, France
    2. Denis Diderot Faculty of Medicine, University of Paris 7, Paris, France
    3. PremUP, Paris, France
    4. Centre for the Developing Brain, Institute of Reproductive and Developmental Biology, Imperial College, Hammersmith Campus, London, United Kingdom
    • Inserm, U676, Hôpital Robert Debré, 75019 Paris, France
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Abstract

Objective:

Activated microglia play a central role in the inflammatory and excitotoxic component of various acute and chronic neurological disorders. However, the mechanisms leading to their activation in the latter context are poorly understood, particularly the involvement of N-methyl-D-aspartate receptors (NMDARs), which are critical for excitotoxicity in neurons. We hypothesized that microglia express functional NMDARs and that their activation would trigger neuronal cell death in the brain by modulating inflammation.

Methods and Results:

We demonstrate that microglia express NMDARs in the murine and human central nervous system and that these receptors are functional in vitro. We show that NMDAR stimulation triggers microglia activation in vitro and secretion of factors that induce cell death of cortical neurons. These damaged neurons are further shown to activate microglial NMDARs and trigger a release of neurotoxic factors from microglia in vitro, indicating that microglia can signal back to neurons and possibly induce, aggravate, and/or maintain neurologic disease. Neuronal cell death was significantly reduced through pharmacological inhibition or genetically induced loss of function of the microglial NMDARs. We generated Nr1 LoxP+/+LysM Cre+/− mice lacking the NMDAR subunit NR1 in cells of the myeloid lineage. In this model, we further demonstrate that a loss of function of the essential NMDAR subunit NR1 protects from excitotoxic neuronal cell death in vivo and from traumatic brain injury.

Interpretation:

Our findings link inflammation and excitotoxicity in a potential vicious circle and indicate that an activation of the microglial NMDARs plays a pivotal role in neuronal cell death in the perinatal and adult brain. ANN NEUROL 2012;72:536–549

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