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Gestational diabetes mellitus induces 5-HT system dysfunction and exacerbates an ASD-like phenotype in male offspring by inhibiting the Ahi1/B9D1/Shh axis.

Guangcheng Qin,Hongbing Ni,Wei Ren,Zhuyun Wang,Weiyan Yan,Kemeng Li,Xiaojing Lin,Wei Zhang,Xiaoyang Zhang,Jiayu Li,Yi Hou,Min Wu,Hua Zhang,Lixue Chen,Xiaoqiu Xiao

Published 2025 in Brain, behavior, and immunity

ABSTRACT

Gestational diabetes mellitus (GDM) is a significant risk factor for autism spectrum disorder (ASD) in offspring. Despite the growing interest in the hypothesis of 5-hydroxytryptamine (5-HT) system dysfunction, the underlying mechanisms remain unclear and require further investigation. In this study, a GDM model was established in mice by feeding them a high fat diet (HFD) and administering an intraperitoneal injection of streptozocin (STZ). Our findings indicated that GDM exposure induced ASD-like behaviors and disrupted 5-HT system function by decreasing the level of Abelson helper integration site 1 (Ahi1) in the dorsal raphe nucleus (DRN) of male offspring. Furthermore, GDM evoked neuroinflammation, accompanied by a notable increase in the concentrations of proinflammatory factors (TNF-α, IL-1βand IL-6). Additionally, Ahi1 knockdown in normal mice mediated by an injection of AAV-Ahi1 in the brain recapitulated ASD-like behaviors and 5-HT system dysfunction, but these effects were blocked by the overexpression of B9 domain-containing protein 1 (B9D1) or meptazinol-mediated pharmacological activation of Ahi1, which ameliorated ASD-like behaviors, neuroinflammation and reversed 5-HT system dysfunction in male offspring of mothers with GDM (GDM-Os). Furthermore, lipopolysaccharide (LPS) induced neuroinflammation inhibited Ahi1 induced 5-HT system dysfunctions in vitro. Based on these findings, the inhibitory effects of meptazinol on GDM-induced ASD-like behaviors could be attributed to the involvement of 5-HT system dysfunction mediated by the Ahi1/B9D1/Shh axis. These findings provide novel insights into the mechanism by which neuroinflammation associated with GDM causes ASD pathogenesis and may pave the way for the development of a new therapeutic strategies for ASD.

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