Neuron-specific overexpression of human vasoactive intestinal peptide receptor 2 in mice causes cognitive dysfunction...

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Microduplications of the VIPR2 gene are associated with schizophrenia.
• The specific role of vasoactive intestinal peptide receptor 2 (VPAC2) overexpression in neuronal function and its link to schizophrenia are not fully understood.

Purpose of the Study:

• To investigate the effects of human VPAC2 overexpression in neurons on cognitive behaviors and prefrontal cortex dendritic morphology in mice.
• To elucidate the molecular mechanisms underlying VPAC2-associated neurodevelopmental alterations.

Main Methods:

• Generated transgenic mice with neuron-specific VPAC2 overexpression using Tau-Cre and a tetracycline-inducible system.
• Assessed cognitive function using the novel object recognition test.
• Analyzed prefrontal cortex dendritic morphology and gene expression via immunohistochemistry, Western blot, RNA sequencing, and quantitative PCR.

Main Results:

• VPAC2 overexpression in neurons led to impaired performance in the novel object recognition test.
• Significant reductions in brain weight and prefrontal cortex pyramidal neuron dendritic complexity were observed.
• RNA sequencing indicated VPAC2 overexpression affects pathways regulating stem cell pluripotency, cell cycle, and actin cytoskeleton, with increased expression of the dendritic morphogenesis gene X-linked lymphocyte-regulated 3B.

Conclusions:

• Neuronal VPAC2 overexpression detrimentally impacts brain development, leading to impaired neural circuitry and cognitive deficits.
• These findings highlight VPAC2's role in neurodevelopment and suggest its dysregulation contributes to schizophrenia pathophysiology.