MECP2 duplication causes aberrant GABA pathways, circuits and behaviors in transgenic monkeys: neural mappings to patients with autismMapping from transgenic monkeys to autism patients

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 MECP2 overexpressed (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 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 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.