| 论文题目: | MECP2 Duplication Causes Aberrant GABA Pathways, Circuits and Behaviors in Transgenic Monkeys: Neural Mappings to Patients with AutismMapping from Transgenic Monkeys to Autism Patients |
| 作者: | Cai DC, Wang Z, Bo T, Yan S, Liu Y, Liu Z, Zeljic K, Chen X, Zhan Y, Xu X, Du Y, Wang Y, Cang J, Wang GZ, Zhang J, Sun Q, Qiu Z, Ge S, Ye Z, Wang Z |
| 联系作者: | zheng.wang@ion.ac.cn |
| 发表年度: | 2020 |
| DOI: | doi: 10.1523/JNEUROSCI.2727-19.2020 |
| 摘要: | MECP2 gain- and loss-of-function in genetically-engineered monkeys recapitulates typical phenotypes in autism, yet where MECP2 mutation affects the monkey brain and whether/how it relates to autism pathology remains unknown. Here we report a combination of gene-circuit-behavior analyses including MECP2 co-expression network, locomotive and cognitive behaviors, EEG and fMRI in five MECP2overexpressed (Macaca fascicularis; 3 female) and twenty wild-type (Macaca fascicularis; 11 female) monkeys. Whole-genome expression analysis revealed MECP2 co-expressed genes significantly enriched in GABA-related signaling pathways, whereby reduced beta synchronization within fronto-parieto-occipital networks was associated with abnormal locomotive behaviors. Meanwhile, MECP2-induced hyper-connectivity in prefrontal and cingulate networks accounted for regressive deficits in reversal learning tasks. Furthermore, we stratified a cohort of 49 autisms and 72 controls out of 1112 subjects using functional connectivity patterns, and identified similar dysconnectivity profiles as in monkeys. By establishing a circuit-based construct link between genetically-defined models and stratified patients, these results pave new avenues to deconstruct clinical heterogeneity and advance accurate diagnosis in psychiatric disorders.Significance StatementAutism spectrum disorder (ASD) is a complex disorder with co-occurring symptoms caused by multiple genetic variations and brain circuit abnormalities. To dissect the gene-circuit-behavior causal chain underlying ASD, animal models are established by manipulating causative genes such as MECP2 However, it is unknown whether such models have captured any circuit-level pathology in ASD patients as demonstrated by human brain imaging studies. Here, we use transgenic macaques to examine the causal effect of MECP2 overexpression on gene co-expression, brain circuits and behaviors. For the first time, we demonstrate that the circuit abnormalities linked to MECP2 and autism-like traits in the monkeys can be mapped to a homogeneous ASD subgroup, thereby offering a new strategy to deconstruct clinical heterogeneity in ASD |
| 刊物名称: | Journal of Neuroscience |
| 论文出处: | https://www.jneurosci.org/content/early/2020/04/13/JNEUROSCI.2727-19.2020.long |
| 影响因子: | 6.074(2018年) |
