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分化中的皮质神经元的化学遗传学沉默会损害树突和轴突的生长。

Chemogenetic Silencing of Differentiating Cortical Neurons Impairs Dendritic and Axonal Growth.

作者信息

Gasterstädt Ina, Schröder Max, Cronin Lukas, Kusch Julian, Rennau Lisa-Marie, Mücher Brix, Herlitze Stefan, Jack Alexander, Wahle Petra

机构信息

Developmental Neurobiology, Faculty of Biology and Biotechnology, Ruhr University Bochum, Bochum, Germany.

Department of General Zoology and Neurobiology, Faculty of Biology and Biotechnology, Ruhr University Bochum, Bochum, Germany.

出版信息

Front Cell Neurosci. 2022 Jul 15;16:941620. doi: 10.3389/fncel.2022.941620. eCollection 2022.

Abstract

Electrical activity is considered a key driver for the neurochemical and morphological maturation of neurons and the formation of neuronal networks. Designer receptors exclusively activated by designer drugs (DREADDs) are tools for controlling neuronal activity at the single cell level by triggering specific G protein signaling. Our objective was to investigate if prolonged silencing of differentiating cortical neurons can influence dendritic and axonal maturation. The DREADD hM4Di couples to G signaling and evokes hyperpolarization GIRK channels. HM4Di was biolistically transfected into neurons in organotypic slice cultures of rat visual cortex, and activated by clozapine-N-oxide (CNO) dissolved in HO; controls expressed hM4Di, but were mock-stimulated with HO. Neurons were analyzed after treatment for two postnatal time periods, DIV 5-10 and 10-20. We found that CNO treatment delays the maturation of apical dendrites of L2/3 pyramidal cells. Further, the number of collaterals arising from the main axon was significantly lower, as was the number of bouton terminaux along pyramidal cell and basket cell axons. The dendritic maturation of L5/6 pyramidal cells and of multipolar interneurons (basket cells and bitufted cells) was not altered by CNO treatment. Returning CNO-treated cultures to CNO-free medium for 7 days was sufficient to recover dendritic and axonal complexity. Our findings add to the view that activity is a key driver in particular of postnatal L2/3 pyramidal cell maturation. Our results further suggest that inhibitory G protein signaling may represent a factor balancing the strong driving force of neurotrophic factors, electrical activity and calcium signaling.

摘要

电活动被认为是神经元神经化学和形态成熟以及神经网络形成的关键驱动因素。仅由设计药物激活的设计受体(DREADDs)是通过触发特定G蛋白信号在单细胞水平控制神经元活动的工具。我们的目标是研究分化中的皮质神经元的长期沉默是否会影响树突和轴突的成熟。DREADD hM4Di与G信号偶联并引起GIRK通道超极化。将HM4Di通过生物弹道转染到大鼠视觉皮质器官型切片培养物中的神经元中,并用溶解在HO中的氯氮平N-氧化物(CNO)激活;对照组表达hM4Di,但用HO进行模拟刺激。在出生后的两个时间段(DIV 5-10和10-20)处理后对神经元进行分析。我们发现CNO处理会延迟L2/3锥体细胞核顶端树突的成熟。此外,从主要轴突产生的侧支数量明显减少,沿锥体细胞核篮状细胞轴突的终扣数量也明显减少。CNO处理并未改变L5/6锥体细胞核多极中间神经元(篮状细胞和双簇细胞)的树突成熟。将经CNO处理的培养物放回无CNO的培养基中7天足以恢复树突和轴突的复杂性。我们的研究结果进一步支持了这样一种观点,即活动特别是出生后L2/3锥体细胞成熟的关键驱动因素。我们的结果还表明,抑制性G蛋白信号可能是平衡神经营养因子、电活动和钙信号强大驱动力的一个因素。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dffb/9336219/0b10272b280e/fncel-16-941620-g001.jpg

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