MECP2 Duplication Causes Aberrant GABA Pathways, Circuits and Behaviors in Transgenic Monkeys: Neural Mappings to Patients with Autism
| Autor: | Jie Zhang, Yafeng Zhan, Qiang Sun, Xiu Xu, Zhaowen Liu, Shengyao Yan, Yasong Du, Shengjin Ge, Kristina Zeljic, Yilin Liu, Dan-Chao Cai, Jing Cang, Zheng Wang, Tingting Bo, Yingwei Wang, Guang-Zhong Wang, Zilong Qiu, Zhiwei Wang, Zheng Ye, Xiaoyu Chen |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Connectomics medicine.diagnostic_test General Neuroscience Cognitive flexibility Cognition Biology Electroencephalography medicine.disease Macaque Phenotype MECP2 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Neuroimaging Autism spectrum disorder biology.animal Gene duplication mental disorders medicine Autism Neuroscience 030217 neurology & neurosurgery Research Articles |
| Zdroj: | J Neurosci |
| Popis: | MECP2gain-of-function and loss-of-function in genetically engineered monkeys recapitulates typical phenotypes in patients with autism, yet whereMECP2mutation affects the monkey brain and whether/how it relates to autism pathology remain unknown. Here we report a combination of gene–circuit–behavior analyses includingMECP2coexpression network, locomotive and cognitive behaviors, and EEG and fMRI findings in 5MECP2overexpressed monkeys (Macaca fascicularis; 3 females) and 20 wild-type monkeys (Macaca fascicularis; 11 females). Whole-genome expression analysis revealedMECP2coexpressed genes significantly enriched in GABA-related signaling pathways, whereby reduced β-synchronization within fronto-parieto-occipital networks was associated with abnormal locomotive behaviors. Meanwhile,MECP2-induced hyperconnectivity in prefrontal and cingulate networks accounted for regressive deficits in reversal learning tasks. Furthermore, we stratified a cohort of 49 patients with autism and 72 healthy controls of 1112 subjects using functional connectivity patterns, and identified dysconnectivity profiles similar to those 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 asMECP2. 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 ofMECP2overexpression on gene coexpression, brain circuits, and behaviors. For the first time, we demonstrate that the circuit abnormalities linked toMECP2and 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. |
| Databáze: | OpenAIRE |
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