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Negative feedback control of neuronal activity by microglia

机译:微胶质细胞神经元活动的负反馈控制

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摘要

Microglia, the brain's resident macrophages, help to regulate brain function by removing dying neurons, pruning non-functional synapses, and producing ligands that support neuronal survival(1). Here we show that microglia are also critical modulators of neuronal activity and associated behavioural responses in mice. Microglia respond to neuronal activation by suppressing neuronal activity, and ablation of microglia amplifies and synchronizes the activity of neurons, leading to seizures. Suppression of neuronal activation by microglia occurs in a highly region-specific fashion and depends on the ability of microglia to sense and catabolize extracellular ATP, which is released upon neuronal activation by neurons and astrocytes. ATP triggers the recruitment of microglial protrusions and is converted by the microglial ATP/ADP hydrolysing ectoenzyme CD39 into AMP; AMP is then converted into adenosine by CD73, which is expressed on microglia as well as other brain cells. Microglial sensing of ATP, the ensuing microglia-dependent production of adenosine, and the adenosine-mediated suppression of neuronal responses via the adenosine receptor A(1)R are essential for the regulation of neuronal activity and animal behaviour. Our findings suggest that this microglia-driven negative feedback mechanism operates similarly to inhibitory neurons and is essential for protecting the brain from excessive activation in health and disease.
机译:微胶质细胞,大脑的常规巨噬细胞,通过去除染色神经元,修剪非功能性突触并产生支持神经元存活的配体来调节脑功能(1)。在这里,我们表明微胶质细胞也是小鼠神经元活动的关键调节剂和小鼠的相关行为反应。微胶质细胞通过抑制神经元活性来响应神经元激活,并烧蚀微胶质细胞放大并同步神经元的活性,导致癫痫发作。微胶质细胞抑制了微胶质细胞的神经元激活以高度区域特异性的方式发生,并且取决于微胶质细胞感测和分解细胞外ATP的能力,其在神经元和星形胶质细胞的神经元激活时释放。 ATP触发了微胶质突起的募集,并通过微胶质层ATP / ADP水解胞外胞胎CD39转化为AMP;然后通过CD73将AMP转化为腺苷,其在小胶质细胞和其他脑细胞上表达。 ATP的显微胶质感测,随后的腺苷依赖于腺苷的微胶质依赖性生产,以及通过腺苷受体A(1)R的神经元响应的腺苷介导的抑制对于神经元活性和动物行为的调节至关重要。我们的研究结果表明,这种微胶束驱动的负反馈机制与抑制性神经元相似,对于保护大脑免受健康和疾病的过度活化是必不可少的。

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  • 来源
    《Nature》 |2020年第7829期|417-423|共7页
  • 作者单位

    Icahn Sch Med Mt Sinai Nash Family Dept Neurosci New York NY 10029 USA|Icahn Sch Med Mt Sinai Dept Psychiat New York NY 10029 USA|Icahn Sch Med Mt Sinai Ctr Glial Biol New York NY 10029 USA;

    Icahn Sch Med Mt Sinai Nash Family Dept Neurosci New York NY 10029 USA|Icahn Sch Med Mt Sinai Dept Psychiat New York NY 10029 USA|Icahn Sch Med Mt Sinai Ctr Glial Biol New York NY 10029 USA;

    Icahn Sch Med Mt Sinai Nash Family Dept Neurosci New York NY 10029 USA|Icahn Sch Med Mt Sinai Dept Psychiat New York NY 10029 USA|Icahn Sch Med Mt Sinai Ctr Glial Biol New York NY 10029 USA|Icahn Sch Med Mt Sinai Ronald M Loeb Ctr Alzheimers Dis New York NY 10029 USA;

    CALTECH Div Biol & Biol Engn Pasadena CA 91125 USA;

    CALTECH Div Biol & Biol Engn Pasadena CA 91125 USA;

    Nagoya Univ Grad Sch Med Dept Anat & Mol Cell Biol Nagoya Aichi Japan|Kobe Univ Grad Sch Med Div Syst Neurosci Kobe Hyogo Japan;

    Icahn Sch Med Mt Sinai Nash Family Dept Neurosci New York NY 10029 USA|Icahn Sch Med Mt Sinai Dept Psychiat New York NY 10029 USA|Icahn Sch Med Mt Sinai Ctr Glial Biol New York NY 10029 USA;

    Icahn Sch Med Mt Sinai Nash Family Dept Neurosci New York NY 10029 USA|Icahn Sch Med Mt Sinai Dept Psychiat New York NY 10029 USA|Icahn Sch Med Mt Sinai Ctr Glial Biol New York NY 10029 USA;

    Univ Minnesota Dept Pharmacol 3-249 Millard Hall Minneapolis MN 55455 USA;

    Univ Virginia Dept Neurosci Ctr Brain Immunol & Glia Charlottesville VA USA;

    Harvard Med Sch Beth Israel Deaconess Med Ctr Dept Surg Boston MA 02115 USA;

    Vanderbilt Univ Dept Pharmacol Nashville TN USA;

    Harvard Med Sch Brigham & Womens Hosp Ann Romney Ctr Neurol Dis Boston MA 02115 USA;

    CALTECH Div Biol & Biol Engn Pasadena CA 91125 USA;

    Icahn Sch Med Mt Sinai Nash Family Dept Neurosci New York NY 10029 USA;

    Icahn Sch Med Mt Sinai Icahn Inst Data Sci & Genom Technol Dept Genet & Genom Sci New York NY 10029 USA;

    Icahn Sch Med Mt Sinai Nash Family Dept Neurosci New York NY 10029 USA;

    Univ Texas Hlth Sci Ctr San Antonio Dept Biochem & Struct Biol San Antonio TX 78229 USA;

    Northwestern Univ Feinberg Sch Med Dept Physiol Chicago IL 60611 USA;

    Beth Israel Deaconess Med Ctr Dept Anesthesia Boston MA 02215 USA|Harvard Med Sch Boston MA 02115 USA|Beth Israel Deaconess Med Ctr Dept Med Boston MA 02215 USA;

    Harvard Med Sch Beth Israel Deaconess Med Ctr Dept Surg Boston MA 02115 USA;

    Icahn Sch Med Mt Sinai Icahn Inst Data Sci & Genom Technol Dept Genet & Genom Sci New York NY 10029 USA;

    Vanderbilt Univ Dept Pharmacol Nashville TN USA|Vanderbilt Univ Vanderbilt Brain Inst 221 Kirkland Hall Nashville TN 37235 USA|Vanderbilt Univ Vanderbilt Ctr Addict Res 221 Kirkland Hall Nashville TN 37235 USA|Vanderbilt Univ Dept Mol Physiol & Biophys Nashville TN 37232 USA|Vanderbilt Univ Dept Psychiat & Behav Sci 221 Kirkland Hall Nashville TN 37235 USA;

    Icahn Sch Med Mt Sinai Nash Family Dept Neurosci New York NY 10029 USA;

    Univ Virginia Dept Neurosci Ctr Brain Immunol & Glia Charlottesville VA USA;

    Washington Univ Sch Med Dept Pathol & Immunol St Louis MO USA;

    Harvard Med Sch Brigham & Womens Hosp Ann Romney Ctr Neurol Dis Boston MA 02115 USA|Broad Inst MIT & Harvard Cambridge MA 02142 USA;

    Nagoya Univ Grad Sch Med Dept Anat & Mol Cell Biol Nagoya Aichi Japan|Kobe Univ Grad Sch Med Div Syst Neurosci Kobe Hyogo Japan;

    CALTECH Div Biol & Biol Engn Pasadena CA 91125 USA;

    Icahn Sch Med Mt Sinai Nash Family Dept Neurosci New York NY 10029 USA|Icahn Sch Med Mt Sinai Dept Psychiat New York NY 10029 USA|Icahn Sch Med Mt Sinai Ctr Glial Biol New York NY 10029 USA|Icahn Sch Med Mt Sinai Ronald M Loeb Ctr Alzheimers Dis New York NY 10029 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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