Abstract
Objective: Clinical studies have shown that microduplications at 7q36.3, containing VIPR2, confer significant risk for schizophrenia. VIPR2 gene encodes the VPAC2 receptor for vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP). Lymphocytes from patients with these mutations exhibited higher VIPR2 gene expression and VIP responsiveness, but mechanisms by which overactive VPAC2 signaling may lead to these psychiatric disorders are unknown. Here we aimed to determine if the VIPR2-linkage to mental health disorders might be due to overactive VPAC2 receptor signaling during postnatal brain development by daily administration of the highly-selective VPAC2 receptor agonist Ro 25–1553 from postnatal day 1 (P1) to P14 in mice.
Results: Western blot analyses on P21 revealed significant reductions of synaptophysin and PSD-95 in the prefrontal cortex, but not in the hippocampus, in Ro 25-1553-treated mice. Furthermore, Golgi staining in adult brain revealed alterations in dendritic morphology of prefrontal cortical neurons in Ro 25-1553-treated mice. The same postnatally-restricted treatment resulted in a disruption in prepulse inhibition of the acoustic startle and cognitive impairment in the novel object recognition task in adult mice. No effects were observed in locomotor activity, sociability in the three-chamber social interaction test, or fear conditioning or extinction. In addition, Ro 25–1553 and VIP, but not PACAP, caused reductions in total numbers and length of neuronal dendrites and length of axon in mouse primary cultured cortical neurons.
Conclusions: These results suggest that overactivation of the VPAC2 receptor in the postnatal mouse leads to a reduction in synaptic proteins and alterations in dendritic morphology in the prefrontal cortex and cognitive impairments. These findings imply that the VIPR2-linkage to mental health disorders may be due in part to overactive VPAC2 receptor signaling during a critical time of neuronal maturation.