Besides recent advances in neonatal care, preterm newborns still develop sex-biased behavioural 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 behavioural alterations, resembling those of ex-preterm children, which we characterized performing parallel mouse/human behavioural tests. Pharmacological enhancement of GABAergic tonic-inhibition by the FDA-approved drug ganaxolone rescued functional/behavioural alterations in mice. Establishing an unprecedented mouse model of prematurity, our work dissects the mechanisms at the core of abnormal behaviours and identifies a new, readily-translatable therapeutic strategy for preterm brain disorders.

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

POTENZIERI, ALBERTO
2024-02-28

Abstract

Besides recent advances in neonatal care, preterm newborns still develop sex-biased behavioural 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 behavioural alterations, resembling those of ex-preterm children, which we characterized performing parallel mouse/human behavioural tests. Pharmacological enhancement of GABAergic tonic-inhibition by the FDA-approved drug ganaxolone rescued functional/behavioural alterations in mice. Establishing an unprecedented mouse model of prematurity, our work dissects the mechanisms at the core of abnormal behaviours and identifies a new, readily-translatable therapeutic strategy for preterm brain disorders.
28-feb-2024
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Descrizione: PhD thesis Alberto Potenzieri
Tipologia: Tesi di dottorato
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11567/1162475
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