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Although CRISPR/Cas9-mediated gene editing is widely applied to mimic human disorders,whether acute manipulation of disease-causing genes in the brain leads to behavioral abnormalities in non-human primates remains to be determined.Here we induced genetic mutations in MECP2,a critical gene linked to Rett syndrome (RTI) and autism spectrum disorders (ASD),in the hippocampus (DG and CA1-4) of adolescent rhesus monkeys (Macaca mulatta) in vivo via adeno-associated virus (AAV)-delivered Staphylococcus aureus Cas9 with small guide RNAs (sgRNAs) targeting MECP2.In comparison to monkeys injected with AAV-SaCas9 alone (n =4),numerous autistic-like behavioral abnormalities were identified in the AAV-SaCas9-sgMECP2-injected monkeys (n =7),including social interaction deficits,abnormal sleep patterns,insensitivity to aversive stimuli,abnormal hand motions,and defective social reward behaviors.Furthermore,some aspects of ASD and RTT,such as stereotypic behaviors,did not appear in the MECP2 gene-edited monkeys,suggesting that different brain areas likely contribute to distinct ASD symptoms.This study showed that acute manipulation of disease-causing genes via in vivo gene editing directly led to behavioral changes in adolescent primates,paving the way for the rapid generation of genetically engineered non-human primate models for neurobiological studies and therapeutic development.