Department of Basic and Clinical Neuroscience, King's College London, SE5 9NU London, United Kingdom.
Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France.
J Neurosci. 2019 Jul 3;39(27):5269-5283. doi: 10.1523/JNEUROSCI.1833-18.2019. Epub 2019 May 7.
The fruitfly has been extensively used as a genetic model for the maintenance of nervous system's functions. Glial cells are of utmost importance in regulating the neuronal functions in the adult organism and in the progression of neurological pathologies. Through a microRNA-based screen in adult glia, we uncovered the essential role of a major glia developmental determinant, , in the adult fly. Here, we report that Repo expression is continuously required in adult glia to transcriptionally regulate the highly conserved function of neurotransmitter recycling in both males and females. Transient loss of Repo dramatically shortens fly lifespan, triggers motor deficits, and increases the sensibility to seizures, partly due to the impairment of the glutamate/GABA/glutamine cycle. Our findings highlight the pivotal role of transcriptional regulation of genes involved in the glutamate/GABA/glutamine cycle in glia to control neurotransmitter levels in neurons and their behavioral output. The mechanism identified here in exemplifies how adult functions can be modulated at the transcriptional level and suggest an active synchronized regulation of genes involved in the same pathway. The process of neurotransmitter recycling is of essential importance in human epileptic and psychiatric disorders and our findings may thus have important consequences for the understanding of the role that transcriptional regulation of neurotransmitter recycling in astrocytes has in human disease. Glial cells are an essential support to neurons in adult life and have been involved in a number of neurological disorders. What controls the maintenance and modulation of glial functions in adult life is not fully characterized. Through a miR overexpression screen in adult glia in , we identify an essential role in adult glia of , which directs glial differentiation during embryonic development. Repo levels modulate, via transcriptional regulation, the ability of glial cells to support neurons in the glutamate/GABA/glutamine cycle. This leads to significant abnormalities in motor behavior as assessed through a novel automated paradigm. Our work points to the importance of transcriptional regulation in adult glia for neurotransmitter recycling, a key process in several human neurological disorders.
果蝇被广泛用作维持神经系统功能的遗传模型。神经胶质细胞在调节成年生物体内神经元功能和神经病理学进展方面至关重要。通过成年胶质细胞中的 microRNA 筛选，我们揭示了主要胶质细胞发育决定因素 Repo 在成年果蝇中的重要作用。在这里，我们报告 Repo 表达在成年胶质细胞中持续需要转录调节神经递质回收的高度保守功能，无论是在雄性还是雌性中。Repo 的短暂缺失会显著缩短果蝇的寿命，引发运动缺陷，并增加对癫痫发作的敏感性，部分原因是谷氨酸/γ-氨基丁酸/谷氨酰胺循环受损。我们的发现强调了参与谷氨酸/γ-氨基丁酸/谷氨酰胺循环的基因的转录调控在控制神经元中神经递质水平及其行为输出中的关键作用。这里在果蝇中确定的机制说明了成年功能如何在转录水平上被调节，并提示涉及同一途径的基因的主动同步调节。神经递质回收的过程在人类癫痫和精神疾病中至关重要，因此我们的发现可能对理解转录调节在星形胶质细胞中对神经递质回收的作用在人类疾病中的重要性具有重要意义。神经胶质细胞是成年期神经元的重要支持细胞，并参与了许多神经疾病。控制成年胶质细胞的维持和调节的机制尚未完全阐明。通过在果蝇成年胶质细胞中的 miR 过表达筛选，我们确定了在成年胶质细胞中起关键作用的，它在胚胎发育过程中指导胶质细胞分化。Repo 水平通过转录调节来调节神经胶质细胞在谷氨酸/γ-氨基丁酸/谷氨酰胺循环中支持神经元的能力。这导致运动行为的显著异常，通过一种新的自动化范式进行评估。我们的工作表明转录调节在成年胶质细胞中的重要性，对于神经递质回收，这是几种人类神经疾病中的关键过程。
