TREATMENT FOR ATTENTION-DEFICIT HYPERACTIVITY DISORDER (ADHD) DRUG NORMALIZES AIS LENGTH ABNORMALITY ALONG WITH HYPERACTIVITY IN PITUITARY ADENYLATE CYCLASE-ACTIVATING POLYPEPTIDE (PACAP)-DEFICIENT MICE

Abstract Background Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder (NDD) with three characteristics: hyperactivity, inattention, and impulsivity. Although the number of patients with ADHD has increased in recent years, its pathology remains unclear. The axon initial segment (AIS) is a region of the proximal axon, which is responsible for information output by generating action potentials. Recent studies have shown that the structure of AIS can be altered based on the input to the neuronal circuit, and the alteration can impact neural activity. We have previously observed an abnormality of AIS length in rodent models of ADHD and autism spectrum disorder. However, the relationship between AIS length abnormality and pathology of NDDs is still unknown. Aims & Objectives In this study, we examined whether PACAP-deficient (PACAP–/–) mice, which display ADHD-like behaviors show AIS length abnormalities. Further, we examined the effects of atomoxetine (ATX), an ADHD drug, on the AIS length in PACAP–/– mice. Method Brain sections were prepared from both PACAP–/– and wild-type mice and immunohistochemically stained with anti-Ankyrin-G antibody to stain AIS, and then the three-dimensional length of each AIS was traced and measured using Imaris software. We administered ATX dose or saline to both mice for 2 weeks. After that, we conducted the open field test, and then by immunohistochemical staining of mouse brain sections with anti-Ankyrin-G antibody to stain the AIS. Results & Discussion PACAP–/– mice exhibited abnormal Ankyrin-G-stained AIS lengths in layer 2/3 neurons of the S1BF. In addition, repeated ATX treatment effectively normalized abnormal AIS length in PACAP–/– mice along with improvement of hyperactivity. These results suggest that AIS abnormalities are one of the phenotypes of ADHD. This study is the first piece of evidence to indicate drug-mediated improvement in AIS length in the brains of ADHD animal models. Our findings provide novel insight into the potential contribution of the AIS to the pathology of NDDs. References 1)Iwahashi et al., (2023) J Pharmacol Sci. 153(3):175-182.