Trans-Synaptic Signaling during Neuromuscular Development

描述（由申请人提供）：在这项资助中，我们有潜力连接两个研究领域：神经系统中的先天免疫信号和突触传递的稳态控制。先天免疫系统在所有动物中都是进化保守的。最近的研究表明，先天免疫信号参与神经发育、可塑性和疾病。这项先前的工作包括补体级联中C1q组分在突触消除过程中的功能，Toll受体在学习和记忆中的功能，以及NFkB/Rel转录因子在学习相关可塑性中的功能的证据。在这项资助中，我们确定了先天免疫信号在神经系统中的新作用。具体来说，我们表明先天免疫受体（PGRP-LC）和下游先天免疫信号级联（IMD信号级联）是稳态突触可塑性所必需的。该受体似乎在突触前神经末梢起作用，诱导两种下游效应：1)突触前神经递质释放的局部稳态调节和2)依赖转录的稳态可塑性维持。我们的实验将在分子和基因细节上探索这种可能性。我们的发现可能与我们理解神经功能如何在整个发育过程中、在衰老过程中以及在疾病背景下稳定的广泛相关。更具体地说，体内平衡可塑性受损被认为会导致多种神经系统疾病，包括癫痫、自闭症谱系障碍和焦虑。我们的初步数据和拟议的实验也可能记录了一种从未在神经系统中研究过的先天免疫信号系统的新功能。因此，我们的数据可能在几个层面上具有重要意义，对我们理解和治疗各种神经系统疾病具有启示意义。

DESCRIPTION (provided by applicant): In this grant, we have the potential to bridge two fields of investigation: innate immune signaling in the nervous system and the homeostatic control of synaptic transmission. The innate immune system is evolutionarily conserved in all animals. Recent work has revealed that innate immune signaling participates in neural development, plasticity and disease. This previous work includes evidence for the function of the C1q component of the complement cascade during synapse elimination, the function of Toll receptors in learning and memory, and the function of NFkB/Rel transcription factors in learning- related plasticity. In this grant, we identify a novel role for innate immune signaling in the nervous system. Specifically, we show that an innate immune receptor (PGRP-LC) and the downstream innate immune signaling cascade (the IMD signaling cascade) are required for homeostatic synaptic plasticity. The receptor appears to function at the presynaptic nerve terminal to induce two downstream effects: 1) the local homeostatic modulation of presynaptic neurotransmitter release and 2) the transcription-dependent maintenance of homeostatic plasticity. Our experiments will explore this possibility in molecular and genetic detail. Our findings may be broadly relevant for our understanding how neural function is stabilized throughout development, during aging and in the context of disease. More specifically, impaired homeostatic plasticity is believed to contribute to diverse neurological diseases including epilepsy, autism spectrum disorders, and anxiety. Our preliminary data and proposed experiments may also document a novel function for an innate immune signaling system that has never before been studied in the nervous system. Thus, our data may be significant at several levels, with implications for our understanding and treatment of diverse neurological diseases. PUBLIC HEALTH RELEVANCE: In this grant, we have the potential to bridge two fields of investigation: innate immune signaling and the homeostatic control of neural function. The innate immune system is evolutionarily conserved in all animals. We have discovered that an innate immune receptor, never before studied in the nervous system of any organism, and the downstream signaling system, are necessary for the homeostatic stabilization of neural function. Impaired homeostatic stabilization of neural function is widely believed to be involved in neurological disorders that range from autism-spectrum disorders to epilepsy. As such, our insights and experiments could have broad clinical relevance.