Abstract
Clinical studies have shown that microduplications at 7q36.3, containing VIPR2, confer significant risk for schizophrenia and autism spectrum disorder (ASD). 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-induced cAMP responsiveness, but mechanisms by which overactive VPAC2 signaling may lead to these psychiatric disorders are unknown. We have previously found that repeated administration of a selective VPAC2 receptor agonist Ro25-1553 in the mouse during early postnatal development caused synaptic alterations in the prefrontal cortex and sensorimotor gating deficits. In this study, we aimed to clarify the effects of VPAC2 receptor activation on neurite outgrowth in cultured primary mouse cortical neurons. Ro25-1553 and VIP caused reductions in total numbers and lengths of both neuronal dendrites and axons, while PACAP38 facilitated elongation of dendrites, but not axons. These effects of Ro25-1553 and VIP were blocked by a VPAC2 receptor antagonist PG99-465 and abolished in VPAC2 receptor-deficient mice. Additionally, Ro25-1553-induced decreases in axon and dendritic outgrowth in wild-type mice were blocked by a protein kinase A (PKA) inhibitor H89, but not by a PKC inhibitor GF109203X or a mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor U0126. PACAP38- induced facilitation of dendritic outgrowth was blocked by U0126. These results suggest that activation of the VPAC2 receptor impairs neurite outgrowth and decreases branching of cortical neurons by a PKA-dependent mechanism. These findings also imply that the VIPR2-linkage to mental health disorders may be due in part to deficits in neuronal maturation induced by VPAC2 receptor overactivation.
Highlights
Accumulating evidence indicates that a number of rare copy number variants (CNVs), including both deletions and duplications, have been strongly associated with schizophrenia and neurodevelopmental disorders such as autism spectrum disorder (ASD) (Sullivan et al, 2012; Foley et al, 2017; Deshpande and Weiss, 2018; Vicari et al, 2019)
The present study confirmed that PAC1, VPAC1, and VPAC2 receptors are expressed in primary cultured mouse cortical neurons as observed in vivo mouse cortex
We demonstrated that low concentrations (1–100 nM) of vasoactive intestinal peptide (VIP) and the VPAC2 receptor agonist Ro251553 reduced axon and dendritic outgrowth of cortical neural precursors measured at 3, 7, and 14 days in vitro (DIV)
Summary
Accumulating evidence indicates that a number of rare copy number variants (CNVs), including both deletions and duplications, have been strongly associated with schizophrenia and neurodevelopmental disorders such as autism spectrum disorder (ASD) (Sullivan et al, 2012; Foley et al, 2017; Deshpande and Weiss, 2018; Vicari et al, 2019). The blood concentration of VIP, but not PACAP, was higher in children with ASD compared to healthy control subjects (Nelson et al, 2001). These suggest that overactivation of the VPAC2 receptor signaling is involved in the etiology of schizophrenia and ASD. VPAC2 receptor knockout mice have abnormal dendritic morphology of the prefrontal cortex neurons, but not basolateral amygdala neurons (Ago et al, 2017) These findings suggest that the VPAC2 receptor plays an important role in the regulation of the dendritic morphology and overactivation of the VPAC2 receptor might impair neural development in the brain
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