Toll and kinase-less Trk receptors in concert drive a novel mechanism of structural synaptic plasticity.

随着神经元、神经突和突触的产生和消除，神经系统在一生中不断变化。大脑结构的可塑性使我们能够学习和适应变化，破坏性的变化保持结构的稳态和完整性，使我们能够进一步适应。这种神经元重塑可能与大脑功能的结构相关。因此，揭示结构可塑性/体内平衡和神经元活动之间的关系是理解大脑如何工作的一个途径。结构可塑性和体内平衡之间的平衡对大脑健康也是至关重要的，这种平衡的破坏会导致脑肿瘤、神经变性、运动和精神疾病。相反，增加大脑的可塑性是解决脑部疾病的关键策略。脑部疾病是欧洲最大的疾病负担，其费用是癌症和心脏病加起来的两倍多。大多数脑部疾病——从焦虑和抑郁，到癫痫、自闭症、神经退行性疾病，如阿尔茨海默病和帕金森病，以及神经炎症——都涉及神经营养因子（NTs）和/或toll样受体（TLRs）的问题。NTs是关键的可塑性因子，通过Trk受体和酪氨酸激酶下游信号传导促进神经元存活、连通性、突触形成、学习和长期记忆。然而，矛盾的是，成人大脑中最丰富的Trk亚型缺乏酪氨酸激酶，但它们的神经元功能尚不清楚。tlr最为人所知的是潜在的先天免疫。tlr也存在于所有神经元中，但其神经元功能在很大程度上是未知的，其在大脑中的配体也是未知的。总之，调节神经系统结构可塑性和内稳态的分子机制尚不清楚。发现增强大脑可塑性的新机制是神经科学的迫切目标。我们最近在果蝇的中枢神经系统（CNS）中发现了nt、无激酶Trk和Toll受体之间先前未预料到的关系。果蝇中没有全长Trks，相反，由kekkon （kek）基因编码的Trk同源物缺乏酪氨酸激酶。因此，果蝇为研究截断的Trk受体在体内的功能提供了一个绝佳的机会。果蝇是体内功能遗传分析最强大的模式生物，提供了从神经回路到突触分辨率和行为的研究。我们发现果蝇神经营养因子（DNTs）结合Toll受体调节神经元数量、连通性和行为，并结合Keks促进突触结构可塑性，如突触按键形成和轴突乔木复杂性。我们怀疑它们也一起起作用。我们假设突触前和突触后细胞之间的反馈回路，包括DNT2和Kek-Toll受体复合物的突触后翻译，调节突触功能并促进神经元的结构变化，以响应神经元活动。我们将在果蝇幼虫的谷氨酸能神经肌肉连接处（NMJ）验证这一假设：(1)确定Kek-6的作用机制，验证我们已经确定的候选物质。(2)研究Keks和toll的交互方式，并解析Kek-Toll代码。由于有多个Keks和toll，不同的对可能是神经元类型的特征，或者是树突和轴突对神经元活动的不同反应。(3)我们将选择2-3对Kek-Toll及其下游因子，测试它们是否以及如何调节神经元突触功能和结构变化以响应神经元活动。结果将是鉴定一种新的，意想不到的神经系统结构可塑性的分子机制。即使不是所有的细节都是在人类进化中保守的，我们的框架将提供令人信服和深刻的预测，以在啮齿动物中进行测试，有利于了解人类中枢神经系统，在健康和疾病方面。

The nervous system changes throughout life, as neurons, neurites and synapses are generated and eliminated. Structural brain plasticity enables us to learn and adapt to change, and destructive change maintains structural homeostasis and integrity, enabling further adaptation. Such neuronal remodelling could be structural correlates of brain function. Thus, unravelling the relationship between structural plasticity/homeostasis and neuronal activity is a gateway to understanding how the brain works. The balance between structural plasticity and homeostasis is also essential for brain health, and its breakdown leads to brain tumours, neurodegeneration, motor and psychiatric disorders. Conversely, increasing brain plasticity is a key strategy to tackle brain disease. Brain disease constitutes the greatest disease burden in Europe, costing over double of cancer and cardiac diseases put together. Most brain diseases - from anxiety and depression, to epilepsy, autism, neurodegeneration, e.g. Alzheimer's and Parkinson's diseases, and neuroinflammation - involve problems with the neurotrophins (NTs) and/or Toll-Like-Receptors (TLRs). NTs are key plasticity factors, and promote neuronal survival, connectivity, synaptic formation, learning and long-term memory, through Trk receptors and tyrosine kinase signaling downstream. However, paradoxically, the most abundant Trk isoforms in the human adult brain lack the tyrosine kinase, but their neuronal functions are unknown. TLRs are best known for underlying innate immunity. TLRs are also found in all neurons, however their neuronal functions are largely unknown, and their ligands in the brain are also unknown. Altogether, the molecular mechanisms regulating nervous system structural plasticity and homeostasis are little understood. Discovering novel mechanisms to enhance brain plasticity is an urgent neuroscience goal.We recently discovered a previously unforeseen relationship between NTs, kinase-less Trk and Toll receptors in the central nervous system (CNS) of the fruit-fly, Drosophila. There are no full-length Trks in Drosophila, and instead, Trk homologues encoded by the kekkon (kek) genes lack the tyrosine kinase. Thus, Drosophila offers a golden opportunity to investigate the functions of truncated Trk receptors in vivo. The fruit-fly is the most powerful model organism for functional genetic analysis in vivo, offering from neural circuit to synaptic resolution and behaviour.We discovered that Drosophila neurotrophins (DNTs) bind Toll receptors to regulate neuronal number, connectivity and behaviour, and bind Keks to promote structural synaptic plasticity, e.g. synaptic bouton formation and axonal arbor complexity. We suspect they also function together. We hypothesize that a feedback loop between pre- and post-synaptic cells, involving post-synaptic translation of DNT2 and a Kek-Toll receptor complex, modulates synaptic function and promotes structural changes in neurons in response to neuronal activity. We will test this hypothesis at the glutamatergic neuromuscular junction (NMJ) of the Drosophila larva by: (1) Determining the mechanism of Kek-6 action, validating candidates we have identified. (2) Working out how Keks and Tolls interact, and resolving the Kek-Toll code. As there are multiple Keks and Tolls, distinct pairs could be characteristic of neuronal type, or of distinct responses to neuronal activity by dendrites and axons. (3) We will select 2-3 Kek-Toll pairs with their downstream factors, to test whether and how they modulate synaptic function and structural changes in neurons in response to neuronal activity.The outcome will be the identification of a novel, unanticipated molecular mechanism for nervous system structural plasticity. Even if not all details were to be evolutionarily conserved in humans, our framework will provide compelling and incisive predictions to test in rodents, for the benefit of understanding the human CNS, in health and disease.