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Increased level of RAB39B leads to neuronal dysfunction and behavioural changes in mice
Zijie Wang1,2, Mengxi Niu1, Naizhen Zheng1
1Center for Brain Sciences, the First Affiliated Hospital of Xiamen University, Institute of Neuroscience, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, School of Medicine, Xiamen University, Xiamen, China.
Abstract:
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.
Insights
Increased RAB39B gene dosage in mice impairs memory and causes autism-like behaviors. This study reveals a mechanism for X-linked intellectual disability (XLID) linked to Xq28 duplications.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Xq28 duplications are a common cause of X-linked intellectual disability (XLID).
- The RAB39B gene, located in Xq28, is implicated in XLID pathogenesis.
- The precise role of RAB39B gene dosage in cognitive function and synaptic health is unclear.
Purpose of the Study:
- To investigate the impact of RAB39B gene overexpression on cognitive function, behavior, and synaptic transmission in mice.
- To elucidate the molecular mechanisms underlying XLID associated with Xq28 duplications.
Main Methods:
- Adeno-associated viruses (AAVs) were used to overexpress RAB39B in the brains of neonatal mice.
- Cognitive functions (recognition and working memory) and autism-like behaviors were assessed.
- In vitro primary neuron cultures and in vivo synaptic transmission studies were performed.
Main Results:
- Neuronal RAB39B overexpression led to impaired recognition and short-term working memory in mice.
- Autism-like behaviors, including social novelty deficits and repetitive grooming, were observed, particularly in female mice.
- RAB39B overexpression reduced dendritic arborization and synaptic transmission, and altered autophagy, without affecting key synaptic protein levels.
Conclusions:
- Overexpression of RAB39B disrupts normal neuronal development, leading to synaptic dysfunction, intellectual disability, and behavioral abnormalities in mice.
- These findings highlight a molecular mechanism for XLID associated with Xq28 duplications.
- The study suggests potential therapeutic targets for XLID.
