Gestational diabetes induces autistic-like behaviors in offspring by disrupting the GABAergic system

Xuan-Qi Liu ¹ Tian-Li Huang ¹ Shu-Yu Zhang ² Yu-Tong Huang ¹ Jia-Ying Mo ³ Yishang Yan ⁴ Yi-Ning Cao ¹ Yue-Ran Cai ¹ Jianzhong Sheng ^1* Hong Zhu ^5* He-Feng Huang ^1*

• ¹ The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Zhejiang university school of medicine, Hangzhou,Zhejiang, China
• ² The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
• ³ Department of Obstetrics and Gynecology, Assisted Reproduction Unit, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China
• ⁴ The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
• ⁵ Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China

Increasing evidence have shown that gestational diabetes mellitus (GDM) is associated with the risk of autism in offspring. However, the underlying mechanisms have not yet been fully elucidated. By establishing a gestational diabetes mouse model and conducting behavioral analyses in offspring, we found that GDM induces impaired social novelty and increased stereotypic behaviors in male offspring. Further, through c-Fos staining, we found hyperexcitability in the prefrontal cortex (PFC) of male offspring from the GDM group after social behavior stimulation. Using single-cell transcriptomics and metabolomics, we observed several alterations in the GABAergic system in the PFC of offspring from mothers with GDM. Notably, there was a decrease in the proportion of GABAergic neurons and a reduction in GABA levels. This decrease in GABA levels was linked to a reduced expression of GAD2, caused by DNA hypermethylation in the promoter region of the GAD2 gene, which is essential for GABA synthesis. These data suggest that GDM induces autistic-like behaviors, including reduced social novelty and increased stereotypic behaviors, in offspring by affecting the GABAergic system. These findings provide new insights into how GDM may influence neurodevelopment in offspring.