Pituitary adenylate cyclase-activating polypeptide deficient mice show length abnormalities of the axon initial segment

Misaki Iwahashi; Takeshi Yoshimura; Wakana Harigai; Kazuhiro Takuma; Hitoshi Hashimoto; Taiichi Katayama; Atsuko Hayata-Takano

doi:10.1016/j.jphs.2023.08.006

Pituitary adenylate cyclase-activating polypeptide deficient mice show length abnormalities of the axon initial segment

J Pharmacol Sci. 2023 Nov;153(3):175-182. doi: 10.1016/j.jphs.2023.08.006. Epub 2023 Aug 28.

Authors

Misaki Iwahashi¹, Takeshi Yoshimura², Wakana Harigai¹, Kazuhiro Takuma³, Hitoshi Hashimoto⁴, Taiichi Katayama¹, Atsuko Hayata-Takano⁵

Affiliations

¹ Department of Child Development and Molecular Brain Science, United Graduate School of Child Development, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
² Department of Child Development and Molecular Brain Science, United Graduate School of Child Development, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Electronic address: tyoshimu@ugscd.osaka-u.ac.jp.
³ Department of Pharmacology, Graduate School of Dentistry, Osaka University, 1-8 Yamadaoka, Suita, Osaka 565-0871, Japan; Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
⁴ Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan; Transdimensional Life Imaging Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, 2-1 Yamadaoka, Suita, Osaka, 565-0871, Japan; Division of Bioscience, Institute for Datability Science, Osaka University, 2-8 Yamadaoka, Suita, Osaka, 565-0871, Japan; Department of Molecular Pharmaceutical Science, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
⁵ Department of Pharmacology, Graduate School of Dentistry, Osaka University, 1-8 Yamadaoka, Suita, Osaka 565-0871, Japan; Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan. Electronic address: hayata.atsuko.dent@osaka-u.ac.jp.

PMID: 37770159
DOI: 10.1016/j.jphs.2023.08.006

Abstract

We previously found that pituitary adenylate cyclase-activating polypeptide (PACAP)-deficient (PACAP^-/-) mice exhibit dendritic spine morphology impairment and neurodevelopmental disorder (NDD)-like behaviors such as hyperactivity, increased novelty-seeking behavior, and deficient pre-pulse inhibition. Recent studies have indicated that rodent models of NDDs (e.g., attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder) show abnormalities in the axon initial segment (AIS). Here, we revealed that PACAP^-/- mice exhibited a longer AIS length in layer 2/3 pyramidal neurons of the primary somatosensory barrel field compared with wild-type control mice. Further, we previously showed that a single injection of atomoxetine, an ADHD drug, improved hyperactivity in PACAP^-/- mice. In this study, we found that repeated treatments of atomoxetine significantly improved AIS abnormality along with hyperactivity in PACAP^-/- mice. These results suggest that AIS abnormalities are associated with NDDs-like behaviors in PACAP^-/- mice. Thus, improvement in AIS abnormalities will be a novel drug therapy for NDDs.

Keywords: Atomoxetine (ATX); Attention-deficit/hyperactivity disorder (ADHD); Axon initial segment (AIS); Neurodevelopmental disorder (NDD); Pituitary adenylate cyclase-activating polypeptide (PACAP).