1963-LB: Prenatal Treatment of Glucagon-Like Peptide 1 Agonist Mitigates Cognitive Deficits in Offspring of Mothers with Diabetes by Modulating Placental Development Mediated by ADGRL3

Hyperglycemia during pregnancy is associated with increased neurobehavioral risks in offspring, even with insulin control. We hypothesized that prenatal administration of Glucagon-like peptide 1 (GLP-1) agonist to diabetic mothers could alleviate cognitive deficits in offspring. A pregestational diabetes model was made with 8-week-old C57BL/6J female mice using streptozotocin (STZ). Offspring were used for behavior test and the tissues underwent immunohistochemistry, single-cell RNA sequencing, and qRT-PCR analyses. In vitro studies utilized HTR8/SVneo cells for mass spectrometry and cAMP assays by shRNA mediated knocking down, and HEK293 cells for the SRE assay by ADGRL3 overexpression. Offspring of the dam with diabetes showed learning deficits and prenatal treatment of GLP-1 agonist starting mid-gestation mitigated the deficits. Immunohistochemical analysis found GLP-1 agonist in placental trophoblasts, without distribution in fetal brain. In placenta from STZ model, trophoblast invasion was inhibited, but improved by GLP-1 agonist treatment. qRT-PCR of human placental tissue mirrored mouse findings; genes related to trophoblast inveation were altered in placenta from mother with pregestational diabetes. In HTR8/SVneo cells that lacks GLP-1 receptor, another class B GPCRs, ADGRL3, was determined as a GLP-1 binding receptor in immunoprecipitation-mass spec analysis. Functional assays showed that ADGRL3 mediates GLP-1 signaling via G alpha s and G alpha q proteins. Altogether, our study demonstrates that prenatal GLP-1 RA treatment mitigates cognitive deficits of offspring from STZ-exposed dams by affecting ADGRL3 mediated GLP-1 signaling in placental trophoblasts. Disclosure M. Ito: None. K. Sugai: None. J. Sasaki: None. R. Suzuki: Speaker's Bureau; Novo Nordisk Pharma, Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Astellas Pharma Inc., Kowa Company, Ltd., MSD, Eli Lilly and Company, Mitsubishi Tanabe Pharma Corporation, Teijin Pharma Limited. Research Support; Sumitomo Dainippon Pharma Co., Ltd. M. Odawara: Speaker's Bureau; Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Novartis Pharmaceuticals Corporation, Eli Lilly and Company, Astellas Pharma Inc., Ono Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Daiichi Sankyo, Takeda Pharmaceutical Company Limited, Mitsubishi Tanabe Pharma Corporation, Boehringer-Ingelheim, MSD Life Science Foundation, AstraZeneca, Kowa Company, Ltd. Research Support; Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company. Other Relationship; Astellas Pharma Inc., Ono Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Daiichi Sankyo, Takeda Pharmaceutical Company Limited, Mitsubishi Tanabe Pharma Corporation, Boehringer-Ingelheim. M. Torii: None. K. Hashimoto-Torii: None. Funding National Institutes of Health (A12BC345678)