Trans-Synaptic Signaling during Neuromuscular Development

描述(申请人提供)：在这笔赠款中，我们有可能连接两个研究领域：神经系统中的先天免疫信号和突触传递的动态平衡控制。所有动物的先天免疫系统在进化上都是保守的。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。以前的工作包括补体C1q组分在突触消除过程中的作用，Toll受体在学习和记忆中的作用，以及NFkB/Rel转录因子在学习相关可塑性中的作用。在这项资助中，我们确定了先天免疫信号在神经系统中的一个新角色。具体地说，我们发现先天免疫受体(PGRP-LC)和下游的先天免疫信号级联(IMD信号级联)对于动态平衡突触的可塑性是必需的。该受体在突触前神经末梢发挥作用，产生两种下游效应：1)局部内稳态调节突触前神经递质的释放；2)依赖转录维持内稳态可塑性。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是如何在发育、衰老和疾病背景下稳定的广泛相关的。更具体地说，体内平衡可塑性受损被认为是导致包括癫痫、自闭症谱系障碍和焦虑在内的各种神经疾病的原因。我们的初步数据和拟议的实验也可能证明一种先天免疫信号系统的新功能，这是以前从未在神经系统中研究过的。因此，我们的数据可能在几个层面上具有重要意义，对于我们对各种神经疾病的理解和治疗具有重要意义。 公共卫生相关性：在这笔赠款中，我们有可能将两个研究领域联系起来：先天免疫信号和神经功能的动态平衡控制。所有动物的先天免疫系统在进化上都是保守的。我们发现，一种在任何生物体的神经系统中从未被研究过的先天免疫受体及其下游信号系统，对于神经功能的动态平衡稳定是必要的。神经功能的动态平衡稳定受损被广泛认为与从自闭症谱系障碍到癫痫等一系列神经疾病有关。因此，我们的见解和实验可能具有广泛的临床意义。

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.