Iwahashi Misaki, Yoshimura Takeshi, Harigai Wakana, Takuma Kazuhiro, Hashimoto Hitoshi, Katayama Taiichi, Hayata-Takano Atsuko
Department of Child Development and Molecular Brain Science, United Graduate School of Child Development, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Department of Child Development and Molecular Brain Science, United Graduate School of Child Development, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
J Pharmacol Sci. 2023 Nov;153(3):175-182. doi: 10.1016/j.jphs.2023.08.006. Epub 2023 Aug 28.
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.
我们之前发现，垂体腺苷酸环化酶激活多肽（PACAP）缺陷型（PACAP）小鼠表现出树突棘形态受损以及类似神经发育障碍（NDD）的行为，如多动、新奇寻求行为增加和前脉冲抑制缺陷。最近的研究表明，NDDs（如注意力缺陷多动障碍（ADHD）和自闭症谱系障碍）的啮齿动物模型在轴突起始段（AIS）表现出异常。在此，我们发现与野生型对照小鼠相比，PACAP小鼠在初级躯体感觉桶状区第2/3层锥体神经元中AIS长度更长。此外，我们之前表明，单次注射ADHD药物托莫西汀可改善PACAP小鼠的多动症状。在本研究中，我们发现重复给予托莫西汀可显著改善PACAP小鼠的AIS异常以及多动症状。这些结果表明，AIS异常与PACAP小鼠中类似NDDs的行为有关。因此，改善AIS异常将成为一种治疗NDDs的新型药物疗法。
