Comprehensive behavioral analysis of pituitary adenylate cyclase-activating polypeptide (PACAP) knockout mice.

Satoko Hattori,Keiko Toyama,Akemichi Baba,Hitoshi Hashimoto,Norihito Shintani,Keizo Takao,Tsuyoshi Miyakawa,Koichi Tanda

doi:10.3389/fnbeh.2012.00058

Abstract

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide acting as a neurotransmitter, neuromodulator, or neurotrophic factor. PACAP is widely expressed throughout the brain and exerts its functions through the PACAP-specific receptor (PAC1). Recent studies reveal that genetic variants of the PACAP and PAC1 genes are associated with mental disorders, and several behavioral abnormalities of PACAP knockout (KO) mice are reported. However, an insufficient number of backcrosses was made using PACAP KO mice on the C57BL/6J background due to their postnatal mortality. To elucidate the effects of PACAP on neuropsychiatric function, the PACAP gene was knocked out in F1 hybrid mice (C57BL/6J × 129SvEv) for appropriate control of the genetic background. The PACAP KO mice were then subjected to a behavioral test battery. PACAP deficiency had no significant effects on neurological screen. As shown previously, the mice exhibited significantly increased locomotor activity in a novel environment and abnormal anxiety-like behavior, while no obvious differences between genotypes were shown in home cage (HC) activity. In contrast to previous reports, the PACAP KO mice showed normal prepulse inhibition (PPI) and slightly decreased depression-like behavior. Previous study demonstrates that the social interaction (SI) in a resident-intruder test was decreased in PACAP KO mice. On the other hand, we showed that PACAP KO mice exhibited increased SI in Crawley's three-chamber social approach test, although PACAP KO had no significant impact on SI in a HC. PACAP KO mice also exhibited mild performance deficit in working memory in an eight-arm radial maze (RM) and the T-maze (TM), while they did not show any significant abnormalities in the left-right discrimination task in the TM. These results suggest that PACAP has an important role in the regulation of locomotor activity, social behavior, anxiety-like behavior and, potentially, working memory.

Highlights

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a member of the vasoactive intestinal peptide (VIP)/ secretin/glucagon superfamily and is widely distributed throughout the central nervous system
Latency to fall off the RR tended to be longer in PACAP KO mice compared with wild-type mice (Figure 1A; genotype effect, F(1, 38) = 3.194, p = 0.0819; genotype × trial interaction effect, F(5, 190) = 0.952, p = 0.4485)
The lack of PACAP did not lead to significant abnormalities in overall health and appearance; PACAP KO mice demonstrated some significantly abnormal behaviors

Summary

Introduction

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a member of the vasoactive intestinal peptide (VIP)/ secretin/glucagon superfamily and is widely distributed throughout the central nervous system. PACAP is found in various peripheral organs (Vaudry et al, 2000), the endocrine glands, respiratory system, gastro-intestinal tract, and urogenital tract. PACAP exerts multiple activities as a neurotransmitter, neuromodulator, and neurotrophic factor via three receptors, the PACAP-specific PAC1 receptor, and the two PACAP/VIPindifferent VPAC1 and VPAC2 receptors (Arimura, 1998; Vaudry et al, 2000; Hashimoto et al, 2006). Genetic association studies have shown that genetic variants of the genes encoding PACAP or PAC1 are associated with schizophrenia (Hashimoto et al, 2007), major depressive disorder (Hashimoto et al, 2010), and post-traumatic stress disorder (PTSD) (Ressler et al, 2011). A few reports do not support the association of the PACAP gene with either schizophrenia or bipolar disorder

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