Synaptic Control of Glutamate Homeostasis

稳态信号系统是生物调节的重要形式， 神经系统中稳定的信息传递。这些基本机制的运作， 维持突触强度和谷氨酸水平等特性在稳定的生理 范围.尽管深入的研究一直集中在了解兴奋性突触 是稳态调节，以稳定突触强度，远不知道这些如何 神经键调节以控制谷氨酸的释放。过量的谷氨酸释放会导致多种 神经系统的疾病和功能障碍，导致癫痫发作，兴奋性中毒， 神经变性在这里，我们提出了一个谷氨酸稳态，控制 利用果蝇神经肌肉接头作为独特而强大的模型研究突触前功能 系统在这个谷氨酸能突触处，突触前过量的谷氨酸分泌诱导了一个神经元突触。 神经递质释放的稳态抑制，一种称为突触前的适应， 稳态抑郁症（PHD）。这一过程与在一个实验中观察到的类似现象相似。 包括哺乳动物的中央突触。我们假设 谷氨酸被突触前谷氨酸受体感知并激活自分泌信号传导 系统稳态抑制突触囊泡释放。为了测试这个模型，我们将使用 系统电生理学筛选以测试果蝇中谷氨酸受体在PHD中的作用。 接下来，我们将利用细胞生物学、异源表达、药理学和 创新的功能成像技术，以确定机制，通过过度 谷氨酸发出突触前囊泡释放精确减少的信号。最后，我们将评估如何 突触、神经元和神经胶质使用几种方法适应慢性谷氨酸盐不平衡， 包括我们开发的细胞特异性翻译分析技术以及一种新的 谷氨酸指示剂的生成。这些实验将共同推进我们对 在赋予突触稳态调节谷氨酸释放能力的机制中， 并将识别神经系统中谷氨酸失衡的适应不良反应。最后， 这些知识将为治疗策略提供信息， 谷氨酸失衡，包括癫痫，脆性X综合征和神经变性。

Homeostatic signaling systems are crucial forms of biological regulation that permit flexible yet stable information transfer in the nervous system. These fundamental mechanisms operate to maintain such properties as synaptic strength and glutamate levels within stable physiological ranges. Although intensive research has been focused on understanding how excitatory synapses are homeostatically modulated to stabilize synaptic strength, far less is known about how these synapses adjust to control glutamate release itself. Excess glutamate release can lead to a variety of diseases and dysfunctions in the nervous system, contributing to seizures, excitotoxity, and neurodegeneration. Here, we propose to characterize a glutamate homeostat that controls presynaptic function using the Drosophila neuromuscular junction as a unique and powerful model system. At this glutamatergic synapse, excess presynaptic glutamate secretion induces a homeostatic inhibition of neurotransmitter release, an adaptation referred to as presynaptic homeostatic depression (PHD). This process parallels a similar phenomenon observed in a variety of other organisms, including mammalian central synapses. We hypothesize that excess glutamate is sensed by a presynaptic glutamate receptor and activates an autocrine signaling system to homeostatically depress synaptic vesicle release. To test this model, we will use a systematic electrophysiology screen to test glutamate receptors in Drosophila for roles in PHD. Next, we will leverage a combination of cell biology, heterologous expression, pharmacology, and innovative functional imaging techniques to determine the mechanisms through which excess glutamate signals a precise reduction in presynaptic vesicle release. Finally, we will assess how synapses, neurons, and glia adapt to chronic glutamate imbalance using several approaches, including a cell-specific translational profiling technology we have developed as well as a new generation of glutamate indicators. Together, these experiments will advance our understanding of the mechanisms that endow synapses with the ability homeostatically tune glutamate release, and will identify maladaptive responses to glutamate imbalance in the nervous system. Ultimately, this knowledge will inform therapeutic strategies towards counteracting diseases associated with glutamate imbalance, including epilepsy, fragile X syndrome and neurodegeneration.