Early IGF-1 receptor inhibition in mice mimics preterm human brain disorders and reveals a therapeutic target
Alberto Potenzieri, Sarà 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
Abstract
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.