Astrocyte branchlet dysfunction as an early step in brain disorders

描述（由申请人提供）：神经生物学的一个中心目标是了解大脑如何形成、存储、检索和编码信息，以及这些操作在疾病中是如何出错的。这项应用的重点是星形胶质细胞，它与整个大脑的神经元密切接触。长久以来，星形胶质细胞被认为只是大脑的黏合剂，但现在星形胶质细胞正逐渐成为神经元功能的重要调节者。解读星形胶质细胞在大脑中的作用被认为是神经科学中主要的开放性问题之一。这项先锋奖申请旨在测试一种新的假设，即大脑疾病的早期阶段涉及星形胶质细胞非常精细的末端功能障碍，称为小枝，已知与突触有关。在这种情况下，我们将功能障碍定义为小枝从突触退出或小枝信号改变，包括对突触的营养支持。这些功能障碍会改变星形胶质细胞已建立的功能，包括神经递质清除、突触调节和维持。这反过来又会改变突触传递的时间，导致兴奋性毒性，并可能引发突触移除。通过关注纹状体微电路，我们将验证一个假设，即小枝代表了迄今为止被忽视的神经和精神疾病的机制，可以用于新的治疗方法。

DESCRIPTION (provided by applicant): A central goal of neurobiology is to understand how the brain forms, stores, retrieves and encodes information and how these operations go awry in disease. The focus of this application is astrocytes, which make intimate contacts with neurons throughout the brain. Long considered simply the brain's glue, astrocytes are emerging as important regulators of neuronal function. Deciphering the roles of astrocytes in the brain is considered one of the major open questions in neuroscience. This Pioneer Award application seeks to test the novel hypothesis that an early step in brain disorders involves dysfunction of the very fine termini of astrocytes called branchlets that are known to abut synapses. In this context, we define dysfunction as branchlet withdrawal from synapses or altered branchlet signaling, including trophic support, to synapses. These dysfunctions would alter established astrocyte functions including neurotransmitter clearance, synapse regulation and maintenance. This in turn would alter the timing of synaptic transmission, contribute to excitotoxicity and perhaps trigger synapse removal. By focusing on the striatal microcircuitry, we will test the hypothesis that branchlets represents a hitherto overlooked mechanism in neurological and psychiatric disorders that could be exploited for novel therapeutics.