脑未来科普 | 合作才是YYDS（永远滴神）！——星形胶质细胞和神经元在突触精细化过程中的协同合作
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第一期
中国神经科学学会
神经科学研究技术分会
系列原创科普推文活动
提到大脑，人们首先都会想到神经元，它让我们可以享受感官输入带来的愉悦体验，可以闻香，赏景，听曲，大快朵颐；还可以输出行为运动，可以跑步，潜水，打球，冲浪……但是大脑中除了神经元，还有许多胶质细胞，比如星形胶质细胞，少突胶质细胞和小胶质细胞等等。这些胶质细胞在大脑中发挥着独一无二的功能，同样是不可或缺的。比如说少突胶质细胞类似于树干外面的树皮，主要是形成髓鞘保护神经元，帮助神经冲动的快速传导；小胶质细胞则像医生，主要在大脑有炎症的时候对大脑进行初步的治疗。而本文中将着重介绍的星形胶质细胞则是大脑中最丰富的细胞类群，它在大脑中的作用非常重要。可以作为支架，支撑神经元的形态和结构；可以作为水库，蓄积神经元释放的多余的神经递质；可以作为营养储备室和垃圾转运站，为神经元提供营养和代谢废物等等。但是这些都是大脑发育成熟后星形胶质细胞的作用，那么在发育过程中，星形胶质细胞和神经元之间又会有怎样的故事呢？
图1 神经元和星形胶质细胞的生长精细化过程（Marc R. Freeman, 2010）
在小鼠发育过程中，神经元的形成发生在胚胎期，而星形胶质细胞的形成从胚胎期开始，在出生后的第8天左右达到高峰，随后下降。而在星形胶质细胞形成的开始，神经元的突触就开始通过与星形胶质细胞相互交流，逐渐确定两者的形态和相对应的空间位置，以实现今后密切有效的协作（Marc R. Freeman, 2010）。
图2 发育过程中星形胶质细胞影响神经元突触的形成、成熟和精细化（Laura E. Clarke and Ben A. Barres，2013）
在这种密切交流中，更多的研究把关注点放在了星形胶质细胞如何影响神经元上。他们发现星形胶质细胞可以分泌不同的分子来指导突触结构的形成，诱导突触的成熟，以及和小胶质细胞一起修剪不需要的突触连接（Laura E. Clarke and Ben A. Barres，2013）。但是却很少有人关注在发育过程中神经元会不会影响星形胶质细胞的，两者在突触精细化的过程中活性变化的时间和空间上存在什么关系。
图3 听觉系统的音区定位图（Travis A. Babola et al., 2018）
为了研究这个问题，首先需要将问题简单化，找到一个特定的研究场景。Dwight E. Bergles团队一直关注发育中的听觉系统，2018年，他们发现小鼠在还没有听力之前，也就是出生后第14天之前，神经元会出现自发的活动。这种自发的低频神经活动从耳蜗（cochlea）的顶端开始，传递到下丘（Inferior Colliculus, IC）的中间区域，然后传递到听觉皮层（Auditory Cortex, AC）的特定区域；而自发的高频神经活动从耳蜗的基部开始，传递到下丘的边缘区域，然后传递到听觉皮层的不同位置（Travis A. Babola et al., 2018）。因此，在耳蜗，下丘和听觉皮层都形成了相对应的音区定位图（tonotopic map）。基于听觉系统中神经元活动的音区定位图，研究人员就可以比较研究星形胶质细胞和神经元之间活性变化的时空对应关系。
图4 发育过程中神经元和星形胶质细胞表现出时空对应的协调活动（Vered Kellner et al., 2021）
有了2018年的研究结果，在2021年，Dwight E. Bergles团队借助多种转基因小鼠和钙成像技术实现了在麻醉新生儿小鼠上实时观察神经元和星形胶质细胞的钙信号变化。他们发现在早期发育阶段，强烈的神经元活动才有可能诱发星形胶质细胞的钙信号，而且星形胶质细胞钙信号的发生有特定的时空限制，时间上发生在神经元活动之后，空间上局限于活跃突触附近的区域；而且星形胶质细胞在下丘和听觉皮层形成跟神经元活动对应的音区定位图。这说明星形胶质细胞和神经元的活性存在时空对应关系。除此之外，他们还发现在小鼠拥有听力后，星形胶质细胞不像神经元一样，会对不同频率的声音按照没有听力之前形成的音区定位图一样起反应，说明星形胶质细胞和神经元之间的协作活动仅限于早期突触精细化期间。星形胶质细胞在早期的主要任务是帮助突触连接的准确高效，在后期真正对特定活动起响应的还是神经元。而两种细胞的交流需要谷氨酸这种神经递质，以及星形胶质细胞上的谷氨酸代谢型受体mGluR5和mGluR3的协同合作（Vered Kellner et al., 2021）。
在早期发育过程中，虽然研究人员仅以听觉系统为研究对象发现神经元和星形胶质细胞活性存在时空对应，但是他们更倾向认为两种细胞的协同合作并不仅仅是听觉系统所独有的，这应该是一个普适的真理。这种协作能保证在发育过程中快速完成大脑内各个细胞的准确连接，在需要调用的时候能高效处理来自各个感觉输入的信息，最终完成一系列的行为动作。
References
1. Freeman M.R. (2010). Specification and morphogenesis of astrocytes. Science 330, 774–778.
Abstract: Astrocytes are the most abundant cell type in the mammalian brain. Interest in astrocyte function has increased dramatically in recent years because of their newly discovered roles in synapse formation, maturation, efficacy, and plasticity. However, our understanding of astrocyte development has lagged behind that of other brain cell types. We do not know the molecular mechanism by which astrocytes are specified, how they grow to assume their complex morphologies, and how they interact with and sculpt developing neuronal circuits. Recent work has provided a basic understanding of how intrinsic and extrinsic mechanisms govern the production of astrocytes from precursor cells and the generation of astrocyte diversity. Moreover, new studies of astrocyte morphology have revealed that mature astrocytes are extraordinarily complex, interact with many thousands of synapses, and tile with other astrocytes to occupy unique spatial domains in the brain. A major challenge for the field is to understand how astrocytes talk to each other, and to neurons, during development to establish appropriate astrocytic and neuronal network architectures.
2. Clarke L.E., and Barres B.A. (2013). Emerging roles of astrocytes in neural circuit development. Nat. Rev. Neurosci. 14, 311–321.
Abstract: Astrocytes are now emerging as key participants in many aspects of brain development, function and disease. In particular, new evidence shows that astrocytes powerfully control the formation, maturation, function and elimination of synapses through various secreted and contact-mediated signals. Astrocytes are also increasingly being implicated in the pathophysiology of many psychiatric and neurological disorders that result from synaptic defects. A better understanding of how astrocytes regulate neural circuit development and function in the healthy and diseased brain might lead to the development of therapeutic agents to treat these diseases.
3. Babola T.A., et al. (2018). Homeostatic Control of Spontaneous Activity in the Developing Auditory System. Neuron 99, 511–524.e5.
Abstract: Neurons in the developing auditory system exhibit spontaneous bursts of activity before hearing onset. How this intrinsically generated activity influences development remains uncertain, because few mechanistic studies have been performed in vivo. We show using macroscopic calcium imaging in unanesthetized mice that neurons responsible for processing similar frequencies of sound exhibit highly synchronized activity throughout the auditory system during this critical phase of development. Spontaneous activity normally requires synaptic excitation of spiral ganglion neurons (SGNs). Unexpectedly, tonotopic spontaneous activity was preserved in a mouse model of deafness in which glutamate release from hair cells is abolished. SGNs in these mice exhibited enhanced excitability, enabling direct neuronal excitation by supporting cell-induced potassium transients. These results indicate that homeostatic mechanisms maintain spontaneous activity in the prehearing period, with significant implications for both circuit development and therapeutic approaches aimed at treating congenital forms of deafness arising through mutations in key sensory transduction components.
4. Vered Kellner, et al. (2021). Dual metabotropic glutamate receptor signaling enables coordination of astrocyte and neuron activity in developing sensory domains. Neuron S0896-6273, 00425-6.
Abstract: Astrocytes play an essential role in the development of neural circuits by positioning transporters and receptors near synapses and secreting factors that promote synaptic maturation. However, the mechanisms that coordinate astrocyte and neural maturation remain poorly understood. Using in vivo imaging in unanesthetized neonatal mice, we show that bursts of neuronal activity passing through nascent sound processing networks reliably induce calcium transients in astrocytes. Astrocyte transients were dependent on intense neuronal activity and constrained to regions near active synapses, ensuring close spatial and temporal coordination of neuron and astrocyte activity. Astrocyte responses were restricted to the pre-hearing period and induced by synergistic activation of two metabotropic glutamate receptors, mGluR5 andmGluR3, which promoted IP3R2-dependent calcium release from intracellular stores. The widespread expression of these receptors by astrocytes during development and the prominence of neuronal burst firing in emerging neural networks may help coordinate the maturation of excitatory synapses.
作者介绍
马少华，2018年于中国科学院大学本科毕业，同年继续在中国科学院大学攻读博士学位。
培养单位：中国科学院深圳先进技术研究院
导师：王立平研究员
研究方向：视觉本能恐惧的神经环路机制
图文：马少华
编辑：翟雅琦
审核：刘雪梅
脑科学与脑技术
中科院深圳先进技术研究院
脑认知与脑疾病研究所
深港脑科学创新研究院
严谨治学 创新驱动