Longitudinal Characterization of Giant ANK2-Depleted Monkeys Suggests Neurodevelopmental-Disorder-Like Phenotypes

The ANK2 gene mutations are marked risk factors for autism spectrum disorder, one of the neurodevelopmental disorders (NDDs) that often extends into adulthood and has a complex etiology involving genetic and environmental factors. ANK2 encodes 2 major isoforms, AnkB-220 (220-kDa isoform of ankyrin-B) and giant AnkB-440. We previously generated a targeted knockout (KO) of giant AnkB-440 in 2 cynomolgus and 2 rhesus monkeys. While no autism-spectrum-disorder-like phenotypes were observed during infancy, we found marked brain volume loss. In this study, we conducted a longitudinal multimodal study in these giant ANK2 KO monkeys during adolescent and young adulthood. Behavioral results from these giant ANK2 KO monkeys revealed increased locomotor activity, deficient cognition (including working memory, cognitive flexibility, and operant lever-press learning), and impaired emotional regulation and social interaction. Furthermore, the giant ANK2 KO monkeys exhibited persistent structural and functional brain abnormalities, up-regulation of brain triglyceride and glycerophospholipids, and peripheral blood transcriptome signatures of immune dysregulation, which may be related to their behavioral alternations. These observations suggest that giant ANK2 depletion in non-human primates phenocopies aspects of behavioral, neural, and molecular features characteristic of NDDs. This study provides an in-depth exploratory longitudinal characterization of giant ANK2 functions in primate brains, which may contribute to translational research on NDDs.