Stabilizing Brain Function via Glial Epigenetic Signaling

摘要 稳态信号系统在个体突触、神经元、 和神经回路来稳定大脑功能和动物行为。体内平衡调节缺陷的原因 突触和神经网络不稳定，与多种慢性神经疾病相关，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参与者 发育和突触功能，并且与神经发育和神经退行性病变的联系越来越紧密 病理学。然而，对于神经胶质信号是否以及如何参与调节几乎一无所知。 突触稳态中突触前神经递质的释放。我们在果蝇中的初步数据表明 当神经系统处于正常状态时，神经胶质信号传导受损会完全破坏突触前稳态 受到急性或长期突触扰动的挑战。我们证明神经胶质细胞对慢性抑制有反应 通过调节组蛋白乙酰化代码来改变突触后谷氨酸受体的敏感性。通过遗传 在果蝇筛选中，我们鉴定了在神经胶质细胞中特异性发挥作用的基因，用于诱导和持续 突触前稳态的表达。我们的初步数据强调了表观遗传的重要性 机制介导的神经胶质信号传导稳定突触功能。我们建议填补以下机制的空白 了解稳定大脑功能的神经胶质信号传导。我们将系统地研究如何相互作用 神经胶质细胞和神经元之间通过使用广泛的遗传因素影响突触传递和突触稳定性， 分子、细胞、电生理学、成像和生物信息方法。我们将进一步拓展我们的 对小鼠海马培养物进行研究，以检查星形胶质细胞表达的表观遗传调节因子如何调节 突触前钙流入、神经递质囊泡池大小和神经递质释放。了解 神经胶质衍生分子在稳定神经系统面对慢性有害刺激方面的功能 有助于开发针对突触引起的神经疾病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.