Mechanisms underlying short-term synaptic plasticity and synapse formation between identified neurons

动物的所有神经系统功能，从简单的反射到复杂的运动模式，以及学习和记忆，都依赖于被称为神经元的脑细胞网络之间的突触连接。神经元通过被称为突触的高度专业化的结构相互通信，正是这种在早期发育过程中突触连接的精确协调形成了出生后所有大脑功能的基础。因此，了解突触特异性最初是如何实现的，以及神经元通信是如何在整个生命过程中建立和调节的，这对于我们理解所有的大脑功能是至关重要的。然而，主要由于脊椎动物大脑的复杂性(数百亿个细胞，甚至更多的胶质细胞)，在选定的突触前和突触后神经元组之间直接和同时记录往往很难可靠地实现。因此，我们对哺乳动物脑细胞的基本相互作用的了解在很大程度上仍然是未知的。因此，在我们的实验室里，我们选择了开发一个无脊椎动物模型，在这个模型中，我们定义了突触形成和突触可塑性的机制，其分辨率在其他地方是无法达到的。我们利用这个模型来定义突触连接的基本机制，并展示了营养因子如何通过活性依赖机制激活人类肿瘤抑制基因MEN1，进而控制突触后神经元中烟碱型乙酰胆碱受体的表达。我们现在希望在这个模型系统中破译MEN1功能的细胞和分子机制。利用现代分子和生物医学工程技术，我们的实验室是世界上第一个开发出真正的仿生混合(通过芯片实现神经元刺激和记录)的实验室。这些新的脑芯片记录技术大大增强了我们同时并在更长时间内询问多个神经元的能力。接触这些最先进的电生理技术也帮助我们在生物医学工程的跨学科领域培养了未来一代高素质的个人。我们现在的短期目标是使用这些技术首先破译突触连接的机制，而从长远来看，我们希望进一步开发这些技术，使大脑控制的假体设备能够用于人类应用。我们相信，我们对大脑研究的生物医学工程方法不仅将创造新的知识，还将帮助我们创造“加拿大制造”的技术，这将为我们的经济做出重大贡献。

All nervous system functions in animals, ranging from simple reflexes to complex motor patterns and learning and memory rely upon synaptic connectivity between networks of brain cells – termed neurons. Neurons communicate with each other through highly specialized structures called synapses, and it is this precise orchestration of synaptic connectivity during early development that forms the basis for all brain functions after birth. Understanding how synapse-specificity is achieved in the first instance, and how neuronal communications are established and modulated throughout life, is therefore central to our understanding of all brain function. However, due primarily to the complexity of the vertebrate brain (tens of billions of cells and even larger numbers of glia), direct and simultaneous recordings between select groups of pre-and postsynaptic neurons are often difficult to achieve reliably. As such, our knowledge regarding fundamental inter-workings of the mammalian brain cells remain largely unknown. In our lab, we have thus opted to develop an invertebrate model, where we have defined mechanisms of synapse formation and synaptic plasticity at a resolution that is unattainable elsewhere. We have exploited this model to define fundamental mechanisms of synaptic connectivity, and have demonstrated how trophic factors activate a human tumor suppressor MEN1 gene through activity dependent mechanisms, which in turn control the expression of nicotinic acetylcholine receptors in the postsynaptic neurons. We now wish to decipher cellular and molecular mechanisms underlying MEN1 function in this model system. Using modern molecular and biomedical engineering techniques, our lab was the first in the world to develop a true bionic hybrid (neuronal stimulation and recordings achieved through the chip). These novel brain-chip recording technologies have significantly enhanced our ability to interrogate multiple neurons concurrently and over an extended time period. An exposure to these state of the art electrophysiological techniques has also helped us train the future generation of highly qualified individual in the interdisciplinary field of biomedical engineering. Our short-term goals now are to use these techniques to first decipher mechanisms of synaptic connectivity, whereas in the longer-term, we wish to develop these technologies further to enable brain-controlled prosthetic devices for human applications. We believe that our biomedical engineering approach to brain research will not only create new knowledge but also help create “made in Canada” technology, which will contribute significantly to our economy.