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

This animal study found that diabetes during pregnancy (gestational diabetes) increases the risk of autism-like behaviors in male offspring. The researchers discovered this happens through disruption of brain serotonin systems and increased brain inflammation. They identified specific molecular pathways involved and tested a medication called meptazinol that helped reduce autism-like behaviors in the study. While promising, this research was conducted in mice and needs human studies to confirm relevance.

This mouse study investigated how gestational diabetes mellitus (GDM) increases autism spectrum disorder (ASD) risk in male offspring. Researchers established a GDM model using high-fat diet and streptozocin injection, finding that GDM exposure led to ASD-like behaviors and disrupted serotonin (5-HT) system function. The mechanism involved decreased Ahi1 protein levels in the dorsal raphe nucleus and increased neuroinflammation. The study identified the Ahi1/B9D1/Shh molecular pathway as crucial for this process.

Importantly, meptazinol treatment ameliorated ASD-like behaviors and reversed serotonin dysfunction in offspring of mothers with GDM. The research provides novel insights into how maternal diabetes-related neuroinflammation may contribute to autism development and suggests potential therapeutic targets.

While promising, this animal research requires human validation before clinical application. The identified Ahi1/B9D1/Shh pathway and meptazinol's effects warrant further investigation as potential therapeutic targets. Findings support existing evidence linking maternal diabetes to autism risk and highlight serotonin system dysfunction as a key mechanism.

Study conducted only in mice, limiting direct applicability to humans. Sample size not reported. Long-term effects and safety of meptazinol treatment unclear. Sex-specific effects only examined in males. Mechanism validation in human studies needed.

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.