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

in genetically-engineered monkeys demonstrably recapitulate typical phenotypes in patients, yet where mutation affects the monkey brain and whether/how it relates to autism pathology remains unknown. Using expression profiles of 13,888 genes in 182 macaque neocortical samples, we first show that coexpressed genes are enriched in GABA-related signaling pathways. We then perform analyses on multiple phenotypic levels including locomotive and cognitive behavior, resting-state electroencephalography and fMRI in overexpressed and wild-type macaque monkeys. Behaviorally, transgenic monkeys exhibit hyperactive and repetitive locomotion, greater separation anxiety response, and less flexibility in rule switching. Moreover, decreased neural synchronization at beta frequency (12-30 Hz) is associated with greater locomotion after peer separation. Further analysis of fMRI-derived connectomics reveals widespread hyper- and hypo-connectivity, where hyper-connectivity prominently involving prefrontal and cingulate networks accounts for deficits in cognitive flexibility. To map -related aberrant circuits of monkeys to the pathological circuits of autistic patients, individuals in a large public neuroimaging database of autism were clustered using community detection on functional connectivity patterns. In a stratified cohort of 49 autisms and 72 controls, the dysfunctional connectivity profile particularly in prefrontal and temporal networks is highly correlated with that of transgenic monkeys, as is further responsible for the severity of social communicative deficits in patients. Through establishing a circuit-based construct link between transgenic animal models and stratified clinical patients, the present findings with explicable biological causes are potentially amenable to translation for accurate diagnosis and evaluation of future treatments in autism-related disorders.