Neuron-specific overexpression of human vasoactive intestinal peptide receptor 2 in mice causes cognitive dysfunction and abnormal dendritic morphology in the prefrontal cortex

Accumulating evidence suggests that microduplications of the VIPR2 gene are strongly associated with schizophrenia. VIPR2 encodes vasoactive intestinal peptide receptor 2 (VPAC2). However, cell-type-specific actions of VPAC2 overexpression with respect to schizophrenia remain unclear. Therefore, we aimed to determine the effects of human VPAC2 overexpression in neurons on cognition-related behaviors and prefrontal cortex dendritic morphology in mice. We crossed a Tau-Cre mouse line, which targets neuronal recombinase activity, with a newly generated double transgenic mouse line containing tetracycline-responsive element-human VPAC2-IRES-mCherry and ROSA:LNL:tTA. Immunohistochemical and Western blot analyses revealed that VPAC2 was overexpressed in neurons throughout the brain. Mice that overexpressed VPAC2 showed impaired performance in the novel object recognition test. Furthermore, VPAC2-overexpressing mice exhibited significant reductions in brain weight and the length, branch number, and complexity of arborization of prefrontal cortex pyramidal neuron dendrites. RNA sequencing analysis revealed that VPAC2 overexpression may affect signaling pathways involved in regulating stem cell pluripotency, cell cycle, and actin cytoskeleton. Quantitative PCR analysis also confirmed increased expression of the X-linked lymphocyte-regulated 3B gene, which regulates dendritic morphogenesis and spine assembly. These results suggest that VPAC2 overexpression in neurons has a detrimental effect on brain development, which leads to impaired neural circuitry and cognitive function.