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MECP2 Duplication Causes Aberrant GABA Pathways, Circuits and Behaviors in Transgenic Monkeys: Neural Mappings to
Dan-Chao Cai1, Zhiwei Wang1,2, Tingting Bo1,2
1Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, State Key Laboratory of Neuroscience, CAS Key Laboratory of Primate Neurobiology, Chinese Academy of Sciences, Shanghai 200031, People's Republic of China.
Abstract:
MECP2 gain-of-function and loss-of-function in genetically engineered monkeys recapitulates typical phenotypes in patients with autism, yet where MECP2 mutation affects the monkey brain and whether/how it relates to autism pathology remain unknown. Here we report a combination of gene-circuit-behavior analyses including MECP2 coexpression network, locomotive and cognitive behaviors, and EEG and fMRI findings in 5 MECP2 overexpressed monkeys (Macaca fascicularis; 3 females) and 20 wild-type monkeys (Macaca fascicularis; 11 females). Whole-genome expression analysis revealed MECP2 coexpressed 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 STATEMENT Autism 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 coexpression, 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.
Insights
Genetically engineered monkeys with MECP2 gene alterations show autism-like brain and behavior changes. These findings link specific brain circuit abnormalities in monkeys to a subgroup of autism spectrum disorder (ASD) patients.
Area of Science:
- Neuroscience
- Genetics
- Behavioral Science
Background:
- Autism spectrum disorder (ASD) involves complex genetic and brain circuit abnormalities.
- The role of MECP2 gene mutations in ASD pathogenesis and associated brain alterations remains unclear.
- Understanding gene-circuit-behavior links is crucial for dissecting ASD heterogeneity.
Purpose of the Study:
- To investigate the impact of MECP2 gene overexpression on brain circuitry and behavior in macaques.
- To determine if MECP2-induced circuit abnormalities in macaques mirror those found in human ASD patients.
- To establish a circuit-based link between genetic models and stratified ASD populations.
Main Methods:
- Gene-circuit-behavior analysis in MECP2-overexpressed macaques (Macaca fascicularis).
- Whole-genome expression analysis to identify MECP2 coexpressed genes and pathways.
- Locomotive and cognitive behavior assessments, EEG, and fMRI to study brain function.
- Functional connectivity analysis to stratify ASD patients and compare with macaque findings.
Main Results:
- MECP2 coexpressed genes were enriched in GABA-related signaling pathways.
- Reduced beta-synchronization in fronto-parieto-occipital networks correlated with abnormal locomotive behaviors.
- MECP2-induced hyperconnectivity in prefrontal and cingulate networks was linked to deficits in reversal learning.
- Identified dysconnectivity profiles in a subgroup of ASD patients that resemble those in MECP2-overexpressed macaques.
Conclusions:
- MECP2 overexpression in macaques recapitulates specific neurobiological and behavioral aspects of ASD.
- The study establishes a circuit-level connection between MECP2 gene manipulation and a homogeneous ASD subgroup.
- This research provides a novel strategy for deconstructing clinical heterogeneity and improving diagnosis in psychiatric disorders like ASD.
