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

神经系统会随着神经元、突起和突触的产生和消除而在整个生命过程中发生变化。结构大脑可塑性使我们能够学习和适应变化，破坏性变化保持结构的动态平衡和完整性，使进一步的适应成为可能。这种神经元重构可能是大脑功能的结构性关联。因此，解开结构可塑性/动态平衡和神经元活动之间的关系是理解大脑如何工作的门户。结构可塑性和动态平衡之间的平衡对大脑健康也是至关重要的，它的崩溃会导致脑瘤、神经退化、运动和精神障碍。相反，增加大脑的可塑性是应对大脑疾病的关键策略。脑部疾病构成了欧洲最大的疾病负担，其成本是癌症和心脏疾病总和的两倍多。大多数大脑疾病--从焦虑和抑郁，到癫痫、自闭症、神经退行性变，如阿尔茨海默氏症和帕金森氏症，以及神经炎症--都与神经营养因子(NTS)和/或Toll样受体(TLRs)有关。NTs是关键的可塑性因子，通过Trk受体和下游酪氨酸激酶信号通路促进神经元存活、连接、突触形成、学习和长期记忆。然而，矛盾的是，人类成年大脑中含量最丰富的Trk亚型缺乏酪氨酸激酶，但它们的神经功能尚不清楚。TLR最为人所知的是潜在的先天免疫力。在所有神经元中也发现了TLRs，但它们的神经功能在很大程度上是未知的，它们在大脑中的配体也是未知的。总而言之，调节神经系统结构可塑性和内稳态的分子机制还知之甚少。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NTS、无激酶Trk和Toll受体之间的先前未预见的关系。果蝇中没有全长Trk，相反，由kekkon(Kek)基因编码的Trk同源物缺乏酪氨酸激酶。因此，果蝇为研究截短的Trk受体在体内的功能提供了一个黄金机会。果蝇是体内最强大的功能遗传学分析的模式生物，提供从神经回路到突触分辨和行为的信息。我们发现，果蝇神经营养因子(DroSingila Neurotroins，DNTs)与Toll受体结合，调节神经元的数量、连通性和行为，并与Keks结合，促进结构突触的可塑性，如突触突触的形成和轴突乔木的复杂性。我们怀疑它们也一起发挥作用。我们假设，突触前和突触后细胞之间的反馈环，包括DNT2和Kek-Toll受体复合体的突触后翻译，调节突触功能，并促进神经元结构的变化，以响应神经元的活动。我们将在果蝇幼虫的谷氨酸能神经肌肉接头(NMJ)上验证这一假说：(1)确定KEK-6的作用机制，验证我们已经确定的候选基因。(2)找出KEK和TALL的相互作用，并解析KEK-Toll代码。由于有多个KEK和Toll，不同的KEK和Toll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个KEK-Toll及其下游因子，以测试它们是否以及如何调节神经元的突触功能和结构变化，以响应神经元的活动。结果将确定神经系统结构可塑性的一种新的、意想不到的分子机制。即使不是所有的细节在进化上在人类身上都是保守的，我们的框架也将提供令人信服和精辟的预测，用于在啮齿动物身上进行测试，以利于理解人类中枢神经系统的健康和疾病。

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.