小柯机器人

瑞士洛桑大学Andrea Volterra等研究人员合作发现，特化的星形胶质细胞介导中枢神经系统的谷氨酸能神经胶质传导。相关论文于2023年9月6日在线发表在《自然》杂志上。

研究人员考虑到星形胶质细胞新出现的分子异质性，并使用分子、生物信息学和成像方法，以及干扰体内谷氨酸外排的细胞特异性遗传工具，重新审视了星形胶质细胞谷氨酸外排假说。通过分析现有的单细胞RNA序列数据库和patch-seq数据，研究人员确定了九个分子上不同的海马星形胶质细胞群，其中发现了一个显著的亚群，它选择性地表达类似突触的谷氨酸释放机制，并定位到离散的海马部位。利用基于GluSnFR的谷氨酸原位和体内成像，研究人员确定了一个相应的星形胶质细胞亚群，该亚群对星形胶质细胞选择性刺激有可靠的反应，在空间精确的热点处有亚秒级谷氨酸释放事件，星形胶质细胞靶向删除膀胱谷氨酸转运体1（VGLUT1）可抑制这种反应。

此外，这种转运体或其亚型VGLUT2的缺失揭示了在正常行为和病理过程中，谷氨酸能星形胶质细胞在皮层-海马和黑质环路中的特殊贡献。通过揭示成人大脑中这一非典型特化星形胶质细胞亚群，研究人员深入了解了星形胶质细胞在中枢神经系统（CNS）生理和疾病中的复杂作用，并确定了一个潜在的治疗靶点。

据介绍，星形胶质细胞与神经元之间的多模式通讯控制着大脑回路的组装和功能。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，同时也会导致神经精神疾病中的失调。星形胶质细胞要想通过快速局灶谷氨酸释放进行交流，就必须拥有与神经元类似的Ca²⁺依赖性外泌装置。然而，由于数据不一致和缺乏直接支持证据，这一机制的存在一直受到质疑。

附：英文原文

Title: Specialized astrocytes mediate glutamatergic gliotransmission in the CNS

Author: 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

Issue&Volume: 2023-09-06

Abstract: Multimodal astrocyte–neuron communications govern brain circuitry assembly and function1. For example, through rapid glutamate release, astrocytes can control excitability, plasticity and synchronous activity2,3 of synaptic networks, while also contributing to their dysregulation in neuropsychiatric conditions4–7. For astrocytes to communicate through fast focal glutamate release, they should possess an apparatus for Ca2+-dependent exocytosis similar to neurons8–10. However, the existence of this mechanism has been questioned11–13 owing to inconsistent data14–17 and a lack of direct supporting evidence. Here we revisited the astrocyte glutamate exocytosis hypothesis by considering the emerging molecular heterogeneity of astrocytes18–21 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 imaging22 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.

DOI: 10.1038/s41586-023-06502-w

Source: https://www.nature.com/articles/s41586-023-06502-w

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html