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Chemico-genetic discovery of astrocytic control of inhibition in vivo

机译：化学 - 基因发现体内抑制的星形胶质细胞控制

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A cell-surface fragment complementation strategy is used to identify the proteome at the junction of astrocytes and synapses in vivo, and shows that NRCAM expressed in astrocytes has a key role in regulating inhibitory synapse function.Perisynaptic astrocytic processes are an integral part of central nervous system synapses(1,2); however, the molecular mechanisms that govern astrocyte-synapse adhesions and how astrocyte contacts control synapse formation and function are largely unknown. Here we use an in vivo chemico-genetic approach that applies a cell-surface fragment complementation strategy, Split-TurboID, and identify a proteome that is enriched at astrocyte-neuron junctions in vivo, which includes neuronal cell adhesion molecule (NRCAM). We find that NRCAM is expressed in cortical astrocytes, localizes to perisynaptic contacts and is required to restrict neuropil infiltration by astrocytic processes. Furthermore, we show that astrocytic NRCAM interacts transcellularly with neuronal NRCAM coupled to gephyrin at inhibitory postsynapses. Depletion of astrocytic NRCAM reduces numbers of inhibitory synapses without altering glutamatergic synaptic density. Moreover, loss of astrocytic NRCAM markedly decreases inhibitory synaptic function, with minor effects on excitation. Thus, our results present a proteomic framework for how astrocytes interface with neurons and reveal how astrocytes control GABAergic synapse formation and function.
机译：用于细胞表面片段互补策略用于鉴定半胶质细胞和体内突触结合的蛋白质组，并且表明在星形胶质细胞中表达的NRCAM在调节抑制突触功能中具有关键作用。梗延星形细胞过程是中枢神经的一个组成部分系统突触（1,2）;然而，治理星形胶质细胞突触粘连以及星形胶质细胞如何接触控制突触形成和功能的分子机制在很大程度上是未知的。在这里，我们使用体内化学遗传方法，该方法应用细胞表面片段互补策略，分裂涡轮突发，并鉴定富含在体内的星形胶质细胞 - 神经元结的蛋白质组，其包括神经元细胞粘附分子（NRCAM）。我们发现NRCAM以皮质星形胶质细胞表达，本地化为蠕动触点，并且需要通过星形胶质细胞过程限制神经潜入渗透。此外，我们表明星形胶质细胞NRCAM与神经元NRCAM相互作用，该神经元NRCAM偶联于抑制后炔皂甙。星形胶质细胞NRCAM的耗竭减少了抑制突触的数量，而不改变谷氨酸突触突触密度。此外，星形胶质性NRCAM的丧失显着降低了抑制突触功能，对激发有微小的影响。因此，我们的结果为星形胶质细胞与神经元界面的界面以及揭示星形胶质细胞如何控制胃细胞突触形成和功能的蛋白质组框架。

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  • 来源
    《Nature》 |2020年第7837期|296-302|共7页
  • 作者

    Takano Tetsuya; Wallace John T.; Baldwin Katherine T.; Purkey Alicia M.; Uezu Akiyoshi; Courtland Jamie L.; Soderblom Erik J.; Shimogori Tomomi; Maness Patricia F.; Eroglu Cagla; Soderling Scott H.;

  • 作者单位

    Duke Univ Med Sch Dept Cell Biol Durham NC 27708 USA;

    Duke Univ Med Sch Dept Cell Biol Durham NC 27708 USA;

    Duke Univ Med Sch Dept Cell Biol Durham NC 27708 USA;

    Duke Univ Med Sch Dept Cell Biol Durham NC 27708 USA;

    Duke Univ Med Sch Dept Cell Biol Durham NC 27708 USA;

    Duke Univ Dept Neurobiol Med Sch Durham NC 27708 USA;

    Duke Univ Med Sch Dept Cell Biol Durham NC 27708 USA|Duke Univ Duke Prote & Metabol Shared Resource Med Sch Durham NC USA|Duke Univ Duke Ctr Genom & Computat Biol Med Sch Durham NC USA;

    RIKEN Ctr Brain Sci CBS Mol Mech Brain Dev Saitama Japan;

    Univ N Carolina Sch Med Dept Biochem Chapel Hill NC 27515 USA|Univ N Carolina Sch Med Dept Biophys Chapel Hill NC 27515 USA;

    Duke Univ Med Sch Dept Cell Biol Durham NC 27708 USA|Duke Univ Dept Neurobiol Med Sch Durham NC 27708 USA;

    Duke Univ Med Sch Dept Cell Biol Durham NC 27708 USA|Duke Univ Dept Neurobiol Med Sch Durham NC 27708 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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