Activation of the VPAC2 Receptor Impairs Axon Outgrowth and Decreases Dendritic Arborization in Mouse Cortical Neurons by a PKA-Dependent Mechanism

• DOI: 10.3389/fnins.2020.00521
• Publication Date: 2020-06-04T04:47:20Z
• Authors: Shuto Takeuchi; Takuya Kawanai; Ryosuke Yamauchi; Lu Chen; Tatsunori Miyaoka; Mei Yamada; Satoshi Asano; Atsuko Hayata-Takano; Takanobu Nakazawa; Koji Yano; Naotaka Horiguchi; Shinsaku Nakagawa; Kazuhiro Takuma; James A. Waschek; Hitoshi Hashimoto; Yukio Ago
• Keywords: Neurite; Anisomycin

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 vasoactive intestinal peptide (VIP) pituitary adenylate cyclase-activating polypeptide (PACAP). Lymphocytes from patients with these mutations exhibited higher expression VIP-induced cAMP responsiveness, but mechanisms by which overactive signaling may lead to psychiatric disorders are unknown. We previously found repeated administration of a selective agonist Ro25-1553 in mouse during early postnatal development caused synaptic alterations prefrontal cortex sensorimotor gating deficits. In this study, we aimed clarify effects activation on neurite outgrowth cultured primary cortical neurons. VIP reductions total numbers lengths both neuronal dendrites axons, while PACAP38 facilitated elongation dendrites, not axons. These were blocked antagonist PG99-465 abolished receptor-deficient mice. Additionally, Ro25-1553-induced decreases axon dendritic wild-type mice protein kinase A (PKA) inhibitor H89, PKC GF109203X or mitogen-activated (MAPK) (MEK) U0126. PACAP38- induced facilitation was results suggest impairs branching neurons PKA-dependent mechanism. findings also imply VIPR2-linkage mental health be due part deficits maturation overactivation.