Dense Analysis of Cortical Circuit Dysfunction in the MECP2-duplication Syndrome of Autism

关于自闭症的皮质回路功能障碍，已经提出了多种假说，包括：兴奋到 抑制(E/I)失衡，连接过度或过低，沿皮质柱异常处理， 感觉编码的可变性增加，“规范的”皮质计算失败，等等。尽管如此，我们 目前缺乏对大脑皮层回路如何在感觉处理过程中发生故障的详细机制了解 自闭症。这一关键的知识赤字需要得到纠正。确定神经回路功能障碍的共同主题 自闭症将产生新的干预目标，可能为恢复功能打开新的窗口。 甲基CpG结合蛋白-2(MECP2)复制综合征是由MECP2基因复制引起的，导致 对100%外显的男性进行性智力残疾和自闭症。这就是雷特的“镜像” 综合征，由MECP2功能丧失引起。突触可塑性异常和E/I失衡是 与MECP2障碍和自闭症有关，已知会影响皮质功能。值得注意的是，我们和 其他研究表明，MECP2综合征患者的视觉功能异常。视皮层，一种典型的“低水平” 感觉区，使其本身成为研究皮质感觉处理的最佳选择。在这里，我们上马了一个全面的 通过研究视觉皮质，努力了解MECP2-重复综合症的感觉处理是如何失败的。 最近的进展将使我们第一次能够在单个细胞分辨率下密集地绘制功能属性和 MECP2中皮层计算的基本模块之一--皮质柱的连接体--复制 自闭症小鼠模型(目标1)。这之后将详细的电生理连通性分析 用于探测潜在机制的皮质回路(目标2)。所获得的数据将与深度学习结合使用 创建复杂的皮质回路神经现实模型的技术，这将允许详细的，在 Computo，“询问功能障碍的机制和如何改善它(目标#3)。已制定的假设 然后“在计算机中”可以进行光遗传学测试，从而关闭环路。 期望：1)获得此模型中早期感觉处理如何失败的第一张全面图片 自闭症。2)确定反映神经元间连接异常的特定子网络连接缺陷，并 E/I平衡，3)构建了一个皮质微电路的神经现实模型，该模型可以用来揭示 计算“功能障碍的机制，并探索如何干预以修复它。最后，我们会 建立一个系统的框架，在这个框架内对自闭症的皮质处理和功能障碍进行分类。在 未来，更多的自闭症模型将被纳入这个文件夹，进行分类和系统研究。

Multiple hypotheses have been put forward regarding cortical circuit dysfunction in autism, including: excitation to inhibition (E/I) imbalance, hyper- or hypo- connectivity profiles, abnormal processing along the cortical column, increased variability of sensory encoding, failure of “canonical” cortical computations, and others. Nevertheless, we currently lack a detailed mechanistic understanding of how cortical circuits malfunction during sensory processing in autism. This critical knowledge deficit needs to be corrected. Identifying common themes of neural circuit dysfunction in autism would yield new targets for intervention, potentially opening new windows for restoring function. Methyl-CpG-binding-protein-2 (MECP2) duplication syndrome is caused by duplication of the MECP2 gene, leading to progressive intellectual disability and autism in males with 100% penetrance. It is the “mirror image” of Rett syndrome, caused by loss of MECP2 function. Abnormal synaptic plasticity and E/I imbalance have been causally implicated in both MECP2-disorders and autism in general and are known to affect cortical function. Notably, we and others have shown that visual function is abnormal in MECP2-syndromes. Visual cortex, a prototypical “low level” sensory area, renders itself optimally for studying cortical sensory processing. Here, we mount a comprehensive effort to understand how sensory processing fails in MECP2-duplication syndrome, by studying the visual cortex. Recent advances will allow us for the first time to map densely, at single cell resolution, the functional properties and connectome of a cortical column, one of the fundamental modules of cortical computation, in the MECP2-duplication mouse model of autism (aim #1). This will be followed by a detailed electro-physiological connectivity analysis of the cortical circuit to probe underlying mechanisms (aim #2). Data obtained will be used in conjunction with deep learning techniques to create a sophisticated neuro-realistic model of the cortical circuit, which will allow a detailed, “in computo,” interrogation of the mechanism of dysfunction and how to ameliorate it (aim #3). Hypotheses formulated “in computo” can then be tested optogenetically, closing the loop. Expectations: 1) Obtain the first comprehensive picture of how early sensory processing fails in this model of autism. 2) Identify specific sub-network connectivity defects reflecting abnormal interneuronal connectivity and E/I balance, 3) Construct a neuro-realistic model of the cortical microcircuit, which can be used to uncover “in computo” the mechanism of dysfunction and to probe how one might intervene to repair it. Finally, we will 4) develop a systematic framework, within which to categorize cortical processing and dysfunction in autism. In the future, additional models of autism will be brought into this fold to be categorized and systematically studied.