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

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.