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

自闭症 MECP2 重复综合征皮质回路功能障碍的密集分析

• 批准号: 10322152
• 负责人: Stelios Manolis Smirnakis
• 金额: $ 69.09万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10322152
• 关键词: Adult; Affect; Anatomy; Animals; Area; Behavior; Behavioral; Cell Communication; Cells; Collaborations; Cortical Column; Data; Defect; Disease; Disease Progression; Electrophysiology (science); Equilibrium; Etiology; Failure; Functional disorder; Future; Genes; Genetic; Image; Intellectual functioning disability; Interneurons; Intervention; Investigation; Knowledge; Laboratories; Lead; Link; Literature; Maps; MeCP2 Duplication Syndrome; Methods; Methyl-CpG-Binding Protein 2; Modeling; Mus; Neurons; Pattern; Penetrance; Performance; Physiological; Physiology; Population; Probability; Property; Reporting; Resolution; Retina; Rett Syndrome; Sensory; Slice; Stimulus; Synaptic plasticity; Syndrome; Techniques; Testing; Time; Vision; Visual Cortex; area V1; area striata; autism spectrum disorder; behavioral phenotyping; cell type; connectome; cortex mapping; deep learning; design; excitatory neuron; expectation; functional restoration; improved functioning; in silico; in vivo; inhibitory neuron; machine learning method; male; mouse model; neural circuit; neural patterning; optogenetics; patch clamp; repaired; therapeutic target; two-photon; visual processing

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.

关于自闭症的皮质回路功能障碍，人们提出了多种假设，包括： 抑制 (E/I) 失衡、连接性过高或过低、沿皮质柱的异常处理、 感觉编码的可变性增加、“规范”皮质计算的失败等等。 目前对感觉处理过程中皮层电路如何发生故障缺乏详细的机制理解 自闭症的这一关键知识缺陷需要得到纠正。 自闭症的治疗将产生新的干预目标，有可能为恢复功能打开新的窗口。 甲基 CpG 结合蛋白 2 (MECP2) 重复综合征是由 MECP2 基因重复引起的，导致 男性进行性智力障碍和自闭症的外显率达 100%，这是雷特的“镜像”。 MECP2 功能丧失导致的综合征，突触可塑性异常和 E/I 失衡是其因果关系。 与 MECP2 障碍和一般自闭症有关，并且已知会影响皮质功能。 其他人表明 MECP2 综合征的视觉功能异常，这是典型的“低水平”。 感觉区域，使其成为研究皮质感觉处理的最佳选择。在这里，我们安装了一个全面的系统。 通过研究视觉皮层，努力了解 MECP2 复制综合征中感觉处理如何失败。 最近的进展将使我们第一次能够以单细胞分辨率密集地绘制功能特性和 MECP2复制中皮质柱的连接组，皮质计算的基本模块之一 自闭症小鼠模型（目标#1）随后将进行详细的电生理连接分析。 探测潜在机制的皮层电路（目标#2）将与深度学习结合使用。 技术来创建一个复杂的神经现实模型的皮质回路，这将允许详细的，“在 computo”，询问功能障碍的机制以及如何改善它（目标#3）。 然后可以对“in computo”进行光遗传学测试，从而形成闭环。 期望：1）获得关于早期感觉处理在这个模型中如何失败的第一个全面的图片 2）识别反映异常的神经元连接的特定子网络连接缺陷和 E/I 平衡，3) 构建皮质微电路的神经现实模型，可用于揭示“ 计算机”功能障碍的机制，并探讨如何干预修复它最后，我们将 4)。 开发一个系统框架，在该框架内对自闭症的皮质处理和功能障碍进行分类。 未来，更多的自闭症模型将被纳入这一范围进行分类和系统研究。