Specialized astrocytes mediate glutamatergic gliotransmission in the CNS.
Specialized astrocytes mediate glutamatergic gliotransmission in the CNS.
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专门的星形胶质细胞介导中枢神经系统中的谷氨酸能神经胶质细胞传递。
DOI：
10.1038/s41586-023-06502-w
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发表时间：
2023-10
期刊：
影响因子：
64.8
通讯作者：
Volterra, Andrea
中科院分区：
文献类型：
--
作者：
de Ceglia, Roberta;Ledonne, Ada;Litvin, David Gregory;Lind, Barbara Lykke;Carriero, Giovanni;Latagliata, Emanuele Claudio;Bindocci, Erika;Di Castro, Maria Amalia;Savtchouk, Iaroslav;Vitali, Ilaria;Ranjak, Anurag;Congiu, Mauro;Canonica, Tara;Wisden, William;Harris, Kenneth;Mameli, Manuel;Mercuri, Nicola;Telley, Ludovic;Volterra, Andrea
多模式星形胶质细胞-神经元通信控制大脑电路组装和功能。例如，通过快速释放谷氨酸，星形胶质细胞可以控制突触网络的兴奋性，可塑性和同步活动，同时也有助于它们在神经精神疾病中的失调。对于星形胶质细胞通过快速局灶性谷氨酸释放进行通信，它们应该具有类似于神经元的Ca 2+依赖性胞吐装置。然而，由于数据不一致和缺乏直接证据，这一机制的存在受到质疑。在这里，我们重新考虑星形胶质细胞谷氨酸胞吐假说，考虑新兴的分子异质性的星形胶质细胞和使用分子，生物信息学和成像方法，连同细胞特异性遗传工具，干扰谷氨酸胞吐在体内。通过分析现有的单细胞RNA测序数据库和我们的patch-seq数据，我们确定了9个分子上不同的海马星形胶质细胞簇，其中我们发现了一个值得注意的亚群，它选择性地表达突触样谷氨酸释放机制，并定位于离散的海马部位。使用基于GluSnFR的谷氨酸成像在原位和体内，我们确定了一个相应的星形胶质细胞亚群，可靠地响应星形胶质细胞选择性刺激与亚秒级谷氨酸释放事件在空间上精确的热点，这是抑制星形胶质细胞靶向删除囊泡谷氨酸转运蛋白1（VGLUT 1）。此外，这种转运蛋白或其亚型VGLUT 2的缺失揭示了在正常行为和病理过程中皮质-海马和黑质纹状体回路中海马能星形胶质细胞的特异性贡献。通过揭示这种非典型亚群的专门星形胶质细胞在成人大脑中，我们提供了深入了解星形胶质细胞在中枢神经系统（CNS）的生理和疾病的复杂作用，并确定一个潜在的治疗靶点。星形胶质细胞的亚群选择性地表达突触样谷氨酸释放机制，积极分泌递质，并定位于海马体中的离散位点。
Multimodal astrocyte–neuron communications govern brain circuitry assembly and function. For example, through rapid glutamate release, astrocytes can control excitability, plasticity and synchronous activity of synaptic networks, while also contributing to their dysregulation in neuropsychiatric conditions. For astrocytes to communicate through fast focal glutamate release, they should possess an apparatus for Ca2+-dependent exocytosis similar to neurons. However, the existence of this mechanism has been questioned owing to inconsistent data and a lack of direct supporting evidence. Here we revisited the astrocyte glutamate exocytosis hypothesis by considering the emerging molecular heterogeneity of astrocytes and using molecular, bioinformatic and imaging approaches, together with cell-specific genetic tools that interfere with glutamate exocytosis in vivo. By analysing existing single-cell RNA-sequencing databases and our patch-seq data, we identified nine molecularly distinct clusters of hippocampal astrocytes, among which we found a notable subpopulation that selectively expressed synaptic-like glutamate-release machinery and localized to discrete hippocampal sites. Using GluSnFR-based glutamate imaging in situ and in vivo, we identified a corresponding astrocyte subgroup that responds reliably to astrocyte-selective stimulations with subsecond glutamate release events at spatially precise hotspots, which were suppressed by astrocyte-targeted deletion of vesicular glutamate transporter 1 (VGLUT1). Furthermore, deletion of this transporter or its isoform VGLUT2 revealed specific contributions of glutamatergic astrocytes in cortico-hippocampal and nigrostriatal circuits during normal behaviour and pathological processes. By uncovering this atypical subpopulation of specialized astrocytes in the adult brain, we provide insights into the complex roles of astrocytes in central nervous system (CNS) physiology and diseases, and identify a potential therapeutic target. A subpopulation of astrocytes selectively expresses synaptic-like glutamate-release machinery, actively secretes the transmitter and is localized to discrete sites in the hippocampus.
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影响因子：
15.9
作者：
Banerjee A;Larsen RS;Philpot BD;Paulsen O
通讯作者：
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影响因子：
64.5
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通讯作者：
Tolias AS
影响因子：
56.9
作者：
Bindocci, Erika;Savtchouk, Iaroslav;Volterra, Andrea
通讯作者：
Volterra, Andrea