Early IGF-1 receptor inhibition in mice mimics preterm human brain disorders and reveals a therapeutic target

• DOI: 10.1126/sciadv.adk8123
• Publication Date: 2024-03-01T18:58:56Z
• Authors: Alberto Potenzieri; Sara Uccella; Deborah Preiti; Matteo Pisoni; Silvia Rosati; Chiara Lavarello; Martina Bartolucci; Doriana Debellis; Federico Catalano; Andrea Petretto; Lino Nobili; Tommaso Fellin; Valter Tucci; Luca A. Ramenghi; Annalisa Savardi; Laura Cancedda
• Keywords: Brain Diseases; Placenta; Infant, Newborn; United States; Receptor, IGF Type 1; Mice; 03 medical and health sciences; 0302 clinical medicine; Pregnancy; Humans; Animals; Female; Insulin-Like Growth Factor I; Child; Infant, Premature; Neuroscience

Besides recent advances in neonatal care, preterm newborns still develop sex-biased behavioral alterations. Preterms fail to receive placental insulin-like growth factor-1 (IGF-1), a major fetal growth hormone in utero, and low IGF-1 serum levels correlate with preterm poor neurodevelopmental outcomes. Here, we mimicked IGF-1 deficiency of preterm newborns in mice by perinatal administration of an IGF-1 receptor antagonist. This resulted in sex-biased brain microstructural, functional, and behavioral alterations, resembling those of ex-preterm children, which we characterized performing parallel mouse/human behavioral tests. Pharmacological enhancement of GABAergic tonic inhibition by the U.S. Food and Drug Administration–approved drug ganaxolone rescued functional/behavioral alterations in mice. Establishing an unprecedented mouse model of prematurity, our work dissects the mechanisms at the core of abnormal behaviors and identifies a readily translatable therapeutic strategy for preterm brain disorders.