Stabilizing Brain Function via Glial Epigenetic Signaling

摘要 动态平衡信号系统在单个突触、神经元、 以及稳定大脑功能和动物行为的神经回路。体内平衡调节缺陷导致 突触和神经网络不稳定，这与多种慢性神经疾病有关，例如 癫痫、自闭症和阿尔茨海默病。神经胶质细胞是控制神经许多不同方面的关键分子。 发育和突触功能，并日益与神经发育和神经退行性变联系在一起 病理学。然而，对于神经胶质信号是否以及如何参与调节，我们几乎一无所知。 突触前神经递质在突触动态平衡中的释放。我们对果蝇的初步数据表明 当神经系统受损时，神经胶质信号的损害完全破坏突触前的稳态 受到急性或长期突触扰动的挑战。我们证明了神经胶质细胞对慢性抑制的反应 通过调节组蛋白乙酰化代码来影响突触后谷氨酸受体的敏感性。通过一种基因 在果蝇的筛选中，我们确定了在胶质细胞中具有诱导和持续作用的特异性基因 突触前动态平衡的表达。我们的初步数据强调了表观遗传学的重要性 稳定突触功能的机制介导的神经胶质信号。我们建议填补这一机制空白 了解神经胶质信号在稳定大脑功能中的作用。我们将系统地研究这些互动是如何 神经胶质细胞和神经元之间的关系通过利用广泛的遗传， 分子、细胞、电生理、成像和生物信息学方法。我们将进一步延长我们的 对小鼠海马区培养的研究以检测星形胶质细胞表达的表观遗传调节因子如何调节 突触前钙内流、神经递质囊泡池大小和神经递质释放。了解 神经胶质细胞衍生分子在稳定神经系统对抗慢性有害刺激中的作用 有利于开发突触所致神经功能障碍的新疗法和潜在疗法 不稳定。

Abstract Homeostatic signaling systems operate as protective mechanisms at the level of individual synapses, neurons, and neural circuits to stabilize brain function and animal behavior. Defective homeostatic regulation causes synapse and neural network instability, which is associated with multiple chronic neural disorders, such as epilepsy, autism and Alzheimer's Disease. Glia are key players that control many different aspects of neural development and synaptic function and are increasingly linked to neurodevelopmental and neurodegenerative pathology. However, virtually nothing is known about whether and how glial signaling is involved in modulating presynaptic neurotransmitter release in synaptic homeostasis. Our preliminary data in Drosophila suggest that impairment of glial signaling completely abolishes presynaptic homeostasis when the nervous system is challenged by acute or long-term synaptic perturbations. We demonstrate that glia respond to chronic inhibition of postsynaptic glutamate receptor sensitivity by modulating their histone acetylation codes. Through a genetic screen in Drosophila, we identified genes that function specifically in glia for the induction and sustained expression of presynaptic homeostasis. Our preliminary data emphasize the importance of epigenetic mechanism-mediated glial signaling in stabilizing synaptic function. We propose to fill the mechanistic gap of understanding the glial signaling in stabilizing the brain function. We will systematically study how the interactions between glia and neuron affect synaptic transmission and synapse stability by using a wide array of genetic, molecular, cellular, electrophysiological, imaging and bioinformatic approaches. We will further extend our studies to mouse hippocampal cultures to examine how astrocyte-expressed epigenetic regulators modulate presynaptic calcium influx, neurotransmitter vesicle pool size and neurotransmitter release. Understanding the function of glial-derived molecules in stabilizing the nervous system confronting chronic harmful stimuli will benefit the development of new treatments and potential therapeutics for neural disorders caused by synapse instability.