Development, maintenance, and human-specific evolution of cortical circuits

摘要 在过去的二十年里，我的实验室一直专注于鉴定新的分子和细胞 的发展、维持（项目1）和人类特异性进化（项目2）的基本机制 皮层回路在项目1中，我们建议研究调节细胞功能的新型分子效应物的作用。 神经元中最丰富的两种细胞器：内质网和线粒体。我们发现 这两种细胞器在轴突和树突中在形态和功能上非常不同。更 最近，我们发现了一种新的拴系蛋白Pdzd 8，它介导了这两种蛋白之间的特殊联系。 细胞器内质网-线粒体接触（ERMCs）作为一种独特的生物化学和生理学信号正在出现 我们发现，在锥体神经元的树突中，ERMC在大多数细胞中起着关键作用， 调节突触诱发的Ca 2+动力学（Hirabayashi等，Science 2017）。我们现在建议使用 一系列新技术来确定Pdzd 8依赖性ER-线粒体偶联对树突状细胞的作用， 整合，突触可塑性及其对CA 1 PN中特征选择性出现的影响。 自2010年以来，我们还启动了一个新的范式，为最具挑战性的问题之一提供见解 《神经科学》：“是什么让人类大脑独一无二？”特别是，我们的工作解决了 人类皮层回路的独特性在突触水平上具有分子和生理决定因素。在 项目2，我们建议继续我们为解决这个问题而实施的新模式， 人类特异性基因重复（HSGDs）作为回路发育的潜在遗传修饰剂的作用， 功能这种HSGD作为突触发育的人类特异性修饰剂的第一个例子， 皮层回路结构来自我们对SRGAP 2A及其人类特异性paraminosSRGAP 2C的研究。 小鼠皮质锥体神经元中SRGAP 2C表达的人源化表型模拟部分缺失的 SRGAP 2A的功能，并导致出现表征人类皮层回路的表型特征， E和I突触成熟期延长，两种类型突触的密度增加。我们最 最近的结果表明，SRGAP 2C特异性地增加了皮质-皮质突触的形成， 层2/3 PN，增加感觉编码的可靠性，并改善行为表现的任务，包括 感觉辨别（施密特等人bioRxiv（2020）; Nature in press）。我们建议探讨其他方面， SRGAP 2A的功能以及SRGAP 2C的人源化如何调节它们，包括它们在小胶质细胞中的作用 在成年人的皮层回路中，两者都在突触可塑性中表达。我们还将扩展这个范例 其他人类特有的基因复制作为皮层回路发育的潜在修饰剂，限制了我们的研究范围。 在小鼠和人类皮层中成熟和成熟的有丝分裂后神经元中表达的其他4个基因。我们 项目将以前所未有的相关性解决基因，电路结构， 在人类皮层回路进化的框架中的回路功能和行为。

ABSTRACT Over the past two decades, my laboratory has focused on the identification of novel molecular and cellular mechanisms underlying the development, maintenance (Project 1) and human-specific evolution (Project 2) of cortical circuits. In Project 1, we propose to study the role of novel molecular effectors regulating the function of the two most abundant organelles in neurons: the endoplasmic reticulum and mitochondria. We discovered that these two organelles are morphologically and functionally very different in axons and dendrites. Even more recently, we identified a novel tethering protein Pdzd8 mediating specialized contacts between these two organelles. ER-mitochondria contacts (ERMCs) are emerging as unique biochemical and physiological signaling platforms in most cells and we discovered that in dendrites of pyramidal neurons, ERMCs play critical roles in regulating synaptically-evoked Ca2+ dynamics (Hirabayashi et al., Science 2017). We are now proposing to use an array of new techniques to determine the role of Pdzd8-dependent ER-mitochondria coupling on dendritic integration, synaptic plasticity and their impact on the emergence of feature selectivity in CA1 PNs. Since 2010, we have also initiated a new paradigm to provide insights into one of the most challenging questions in Neuroscience: ‘what makes the human brain unique?’. In particular, our work tackled whether or not the uniqueness of the human cortical circuits has molecular and physiological determinants at the synaptic level. In Project 2, we propose to continue the new paradigm we implemented starting to tackle this question, by studying the role of human-specific gene duplications (HSGDs) as potential genetic modifiers of circuit development and function. The first example of such an HSGD acting as a human-specific modifier of synaptic development and cortical circuit architecture came from our study on SRGAP2A and its human-specific paralog SRGAP2C. Humanization of SRGAP2C expression in mouse cortical pyramidal neurons phenocopies a partial loss of function of SRGAP2A and leads to the emergence of phenotypic traits characterizing human cortical circuits, protracted period of E and I synaptic maturation and increased density of both types of synapses. Our most recent results demonstrate that SRGAP2C increases specifically the formation of cortico-cortical synapses onto layer 2/3 PNs, increased reliability of sensory coding and improved behavioral performance in tasks involving sensory discrimination (Schmidt et al. bioRxiv (2020); Nature in press). We propose to explore other aspects of SRGAP2A functions and how humanization of SRGAP2C modulates them, including their role in microglial cells where both are expressed and in synaptic plasticity within adult cortical circuits. We will also extend this paradigm to other human-specific gene duplications as potential modifiers of cortical circuit development, limiting our scope to 4 other genes expressed in maturing and adult postmitotic neurons in the mouse and human cortex. Our projects will tackle with unprecedented relevance the relationship between genes, circuit architecture, circuit function and behavior in the framework of human cortical circuit evolution.