Increased level of RAB39B leads to neuronal dysfunction and behavioural changes in mice.

Scientists studied a gene called RAB39B that's linked to intellectual disability when there are extra copies. They increased this gene in mice brains and found it caused memory problems, social difficulties, and repetitive behaviors similar to autism. The gene changes affected how brain cells develop and communicate. This helps explain why some children with extra copies of this gene region have learning and behavioral challenges.

This preclinical study investigated the effects of RAB39B gene overexpression in mice, relevant to X-linked intellectual disability caused by Xq28 duplications. Researchers injected AAVs to overexpresse RAB39B in neonatal mouse brains and assessed outcomes at 2 months. Results showed impaired recognition and working memory, autism-like behaviors (social novelty deficits and repetitive grooming in females), reduced dendritic arborization, and decreased synaptic transmission. The study also found altered autophagy without changes in synaptic protein levels or distribution.

These findings suggest RAB39B overexpression disrupts normal neuronal development, leading to synaptic dysfunction and behavioral abnormalities that model aspects of intellectual disability.

This preclinical research identifies RAB39B as a potential therapeutic target for X-linked intellectual disability involving Xq28 duplications. The findings suggest interventions targeting RAB39B function, autophagy pathways, or synaptic dysfunction could be explored, though human studies are needed to validate clinical relevance.

Animal model study with unclear sample sizes and methodological details. Female-specific effects noted but not fully explained. Limited assessment timepoint (2 months). Unclear how findings translate to human X-linked intellectual disability conditions.

Duplications of the Xq28 region are a common cause of X-linked intellectual disability (XLID). The RAB39B gene locates in Xq28 and has been implicated in disease pathogenesis. However, whether increased dosage of RAB39B leads to cognitive impairment and synaptic dysfunction remains elusive. Herein, we overexpressed RAB39B in mouse brain by injecting AAVs into bilateral ventricles of neonatal animals.

We found that at 2 months of age, neuronal overexpression of RAB39B impaired the recognition memory and the short-term working memory in mice and resulted in certain autism-like behaviours, including social novelty defect and repetitive grooming behaviour in female mice. Moreover, overexpression of RAB39B decreased dendritic arborization of primary neurons in vitro and reduced synaptic transmission in female mice. Neuronal overexpression of RAB39B also altered autophagy without affecting levels and PSD distribution of synaptic proteins. Our results demonstrate that overexpression of RAB39B compromises normal neuronal development, thereby resulting in dysfunctional synaptic transmission and certain intellectual disability and behavioural abnormalities in mice.

These findings identify a molecular mechanism underlying XLID with increased copy numbers of Xq28 and provide potential strategies for disease intervention.