NFIA

在一项新的研究中，来自美国贝勒医学院的研究人员揭开了使星形胶质细胞具有特殊的浓密形状的过程，这对大脑功能来说是至关重要的。他们指出神经元活动对于星形胶质细胞形成其复杂的形状是必要和充分的。 星形胶质细胞是大脑中最丰富的胶质细胞。在一项新的研究中，来自美国贝勒医学院的研究人员揭开了使星形胶质细胞具有特殊的浓密形状的过程，这对大脑功能来说是至关重要的。他们指出神经元活动对于星形胶质细胞形成其复杂的形状是必要和充分的，而中断这一发育过程会导致大脑功能紊乱。相关研究结果于2023年4月26日在线发表在Nature期刊上，论文标题为“Inhibitory input directs astrocyte morphogenesis through glial GABABR”。论文通讯作者为贝勒医学院症神经科学中心主任、神经外科系教授Benjamin Deneen博士。 论文第一作者、Deneen实验室研究生Yi-Ting Cheng说，“星形胶质细胞发挥着不同的作用，对大脑的正常功能至关重要。例如，它们支持其他基本脑细胞、神经元的活动；参与突触---神经元之间的连接---的形成和功能；释放神经递质，即介导神经元交流的化学物；以及制造血脑屏障。” 在成年大脑中，星形胶质细胞的浓密形状与有效的大脑功能有着根本的联系。分支的星形胶质细胞结构的两端与神经元相互作用，调节突触活动。 Deneen说，“如果星形胶质细胞失去它们的结构，那么突触的行为就不正常，大脑功能就会出问题。弄清楚星形胶质细胞如何获得其复杂的浓密结构，对于理解大脑的发育和功能至关重要，并可能为神经发育疾病的出现带来新的见解。在这项新的研究中，我们研究了指导星形胶质细胞结构发育的细胞和过程。” 神经元引领方向 当星形胶质细胞发育时，神经元已经存在并活跃，那么神经元是否影响星形胶质细胞如何获得其复杂的形状？ Cheng说，“我们人为地激活或沉默神经元，并确定这是否会加快或减慢星形胶质细胞的成熟。我们发现，神经元的活动对于推动星形胶质细胞完全成熟为浓密形状的细胞既是必要的，也是充分的。” 那么，星形胶质细胞是如何接收引导它们走向正确成熟之路的信号的呢？通过几种实验方法，这些作者发现，神经元产生一种叫做GABA的神经递质，它通过星形胶质细胞表面上的一种名为GABAB受体的分子与之结合。 Cheng说，“我们敲除了星形胶质细胞表面上的GABAB受体并激活了神经元。在这种情况下，神经元没有促进星形胶质细胞典型形状的发育，这就支持了神经元通过GABAB受体与星形胶质细胞沟通以促进它们成熟的观点。” Deneen说，“这一发现令人惊讶，非常有趣。已知GABA等神经递质在神经元之间的突触处发出信号，但我们发现神经递质也向星形胶质细胞发出信号，通过触发它们结构的变化来影响它们的发育。” 成年时，抑制性神经元发育激活后星形胶质细胞形态的正常化。图片来自Nature, 2023, doi:10.1038/s41586-023-06010-x。 其他实验揭示了神经元如何引导星形胶质细胞形成它们的浓密形状的更多谜团。Cheng说，“神经元产生GABA，它通过GABAB受体与星形胶质细胞结合。反过来，这激活了一系列的事件，包括触发另一种叫做Ednrb的受体的表达，它驱动细胞内部与细胞形状相关的细胞结构重塑的途径。” 这些作者还研究了与星形胶质细胞发育有关的另一个谜题。他们发现，对星形胶质细胞表面上GABAB受体表达的调节在不同大脑区域的发生方式并不相同。Deneen说，“这个结果完全出乎意料。GABAB受体是星形胶质细胞在所有大脑区域中形成浓密形状普遍所需的。它是如何在大脑的不同区域受到不同调节的呢？” 通过生物信息学分析，这些作者发现这种区域调节是由两种蛋白---大脑皮层中的LHX2和嗅球中的NPAS3，可与蛋白SOX9和NFIA发生区域特异性相互作用---赋予的，这两种蛋白存在于所有星形胶质细胞中，在那里它们调节GABAB受体表达。在大脑皮层中，LHX2只与NFIA结合，而在嗅球中，NPS3只与SOX9结合，从而使得每种蛋白都能在特定的大脑区域调节GABAB受体表达。 总之，这些发现表明，星形胶质细胞的发育和功能涉及由神经元活动引发的复杂事件和蛋白模式，并以区域特异性的方式运作。（生物谷 Bioon.com） 参考资料： Yi-Ting Cheng et al. Inhibitory input directs astrocyte morphogenesis through glial GABABR. Nature, 2023, doi:10.1038/s41586-023-06010-x.

Researchers report that neuronal activity is necessary and sufficient for astrocytes to develop their complex shape, and interrupting this developmental process results in disrupted brain function. Researchers at Baylor College of Medicine have unraveled the processes that give astrocytes, the most abundant glial cell in the brain, their special bushy shape, which is fundamental for brain function. They report in the journal Nature that neuronal activity is necessary and sufficient for astrocytes to develop their complex shape, and interrupting this developmental process results in disrupted brain function. "Astrocytes play diverse roles that are vital for proper brain function," said first author Yi-Ting Cheng, a graduate student in Dr. Benjamin Deneen's lab at Baylor. "For instance, they support the activity of other essential brain cells, neurons; participate in the formation and function of synapses, or neuron-to-neuron connections; release neurotransmitters, chemicals that mediate neuronal communication; and make the blood-brain barrier." In the adult brain, the bushy shape of astrocytes is fundamentally linked to effective brain function. The ends of the branched-out astrocyte structure interact with neurons and regulate synaptic activity. "If astrocytes lose their structure, then synapses do not behave properly and brain function goes awry," said Deneen, professor and Dr. Russell J. and Marian K. Blattner Chair in the Department of Neurosurgery and director of the Center for Cancer Neuroscience at Baylor. He also is the corresponding author of the work. "Figuring out how astrocytes acquire their complex, bushy structure is essential to understanding how the brain develops and functions and may bring new insight into how neurodevelopmental conditions emerge. In this study, we investigated the cells and processes that direct the development of astrocyte structure." Neurons lead the way When astrocytes develop, neurons are already present and active, so do neurons influence how astrocytes acquire their complex shape? "We artificially activated or silenced neurons and determined whether this would speed up or slow down astrocyte maturation," Cheng said. "We found that neuronal activity is both necessary and sufficient to drive full astrocyte maturation into a bushy-shaped cell." So how are astrocytes receiving the signals that direct them down to the proper maturation path? Through several experimental approaches the team discovered that neurons produce a neurotransmitter called GABA that binds to astrocytes via a molecule on their surface named GABAB receptor. "We knocked out the GABAB receptor in astrocytes and activated the neurons. In this situation, the neurons did not promote the development of a typical astrocyte shape, supporting the idea that neurons communicate with astrocytes via the GABAB receptor to promote their maturation." "This finding was surprising and very interesting," Deneen said. "Neurotransmitters such as GABA are known to signal between neurons at synapses, but we discovered that neurotransmitters also signal astrocytes, influencing their development by triggering changes in their structure." Other experiments revealed more pieces of the puzzle of how neurons lead astrocytes to develop their bushy shape. "Neurons produce GABA, which binds to astrocytes via the GABAB receptor. In turn, this activates a series of events, including triggering the expression of another receptor called Ednrb, which drives pathways that remodel cellular architecture inside the cells associated with cell shape," Cheng said. The researchers also investigated another mystery related to astrocyte development. They found that regulation of the expression of GABAB receptor in astrocytes does not occur in the same way in different brain regions. "This result was totally unexpected," Deneen said. "The GABAB receptor is universally required for astrocytes to develop their bushy shape in all brain regions. How is it regulated differently in different areas of the brain?" Through bioinformatics analyses the researchers discovered that this regional regulation is conferred by two proteins, LHX2 in the brain cortex and NPAS3 in the olfactory bulb through their region-specific interactions with proteins SOX9 and NFIA, which are present in all astrocytes where they regulate GABAB receptor expression. In the cortex, LHX2 only binds to NFIA, while in the olfactory bulb NPS3 only binds to SOX9, enabling each one to regulate GABAB receptor expression in a specific brain region. Altogether, the findings suggest that astrocyte development and function involve a complex pattern of events and proteins triggered by the activity of neurons and that operate in a region-specific manner. Estefania Luna-Figueroa, Junsung Woo, Hsiao-Chi Chen, Zhung-Fu Lee1 and Akdes Serin Harmanci, all at Baylor College of Medicine, also contributed to this work. This work was supported by National Institutes of Health (NIH) grants NS071153, AG071687 and NS096096, the David and Eula Wintermann Foundation, NIH shared instrument grants S10OD023469, S10OD025240 and P30EY002520, the Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from the CPRIT Core Facility Support Award (CPRIT-RP180672), the NIH (CA125123 and RR024574) and the NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development under Award Number P50HD103555.