研究揭示機體調控星形細胞抑制的化學遺傳學

研究揭示機體調控星形細胞抑制的化學遺傳學

作者：

小柯機器人

發布時間：2020/11/14 23:35:22

美國杜克大學醫學院Scott H. Soderling、Tetsuya Takano和Cagla Eroglu研究組的最新研究揭示了機體調控星形細胞抑制的化學遺傳學。 該研究於2020年11月11日發表於國際學術期刊《自然》雜誌。

研究人員使用基於細胞表面片段互補策略Split-TurboID的體內化學遺傳學方法，鑑定了在體內星形膠質細胞-神經元連接處富集的蛋白質組，其中包括神經元細胞粘附因子（NRCAM）。 研究發現，NRCAM在皮質星形膠質細胞中表達，其定位於突觸周圍的接觸面，並需要通過星形膠質細胞活化過程來限制神經纖維的浸潤。

此外，研究表明星形膠質細胞NRCAM在抑制性突觸後與gephyrin偶聯神經元的NRCAM跨細胞相互作用。星形細胞NRCAM的敲除減少了抑制性突觸的數量，而沒有改變穀氨酸能突觸的密度。並且，星形細胞NRCAM的缺失顯著降低了抑制性突觸的功能，對興奮性突觸的影響較小。

因此，該研究結果為星形膠質細胞與神經元的相互作用提供了蛋白質組學框架，並揭示了星形膠質細胞如何控制GABAergic突觸的形成和功能。

據悉，突觸周圍的星形細胞是中樞神經系統突觸的組成部分; 然而，尚不清楚調控星形膠質細胞-突觸粘附的分子機制以及星形膠質細胞接觸如何控制突觸形成和功能。

附：英文原文

Title: Chemico-genetic discovery of astrocytic control of inhibition in vivo

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

Issue&Volume: 2020-11-11

Abstract: Perisynaptic astrocytic processes are an integral part of central nervous system synapses1,2; 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.

DOI: 10.1038/s41586-020-2926-0

Source: https://www.nature.com/articles/s41586-020-2926-0