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Published on: November 20, 2015
Early IGF-1 receptor inhibition in mice mimics preterm human brain disorders and reveals a therapeutic target
Alberto Potenzieri1,2, Sara Uccella3,4,5, Deborah Preiti4,5
1Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy.
Insights
Preterm newborns often experience neurodevelopmental issues due to low insulin-like growth factor-1 (IGF-1). A new mouse model shows ganaxolone can reverse these sex-biased behavioral changes, offering a potential therapy for preterm brain disorders.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- Preterm birth is associated with sex-biased behavioral alterations and poor neurodevelopmental outcomes.
- Insulin-like growth factor-1 (IGF-1) is crucial for fetal development, and its deficiency in preterm infants correlates with adverse outcomes.
- Existing neonatal care has not fully addressed these sex-specific neurodevelopmental challenges in preterm infants.
Purpose of the Study:
- To establish a mouse model mimicking IGF-1 deficiency in preterm newborns.
- To investigate the sex-biased microstructural, functional, and behavioral alterations resulting from this deficiency.
- To identify a potential therapeutic strategy to correct these prematurity-induced brain abnormalities.
Main Methods:
- Perinatal administration of an IGF-1 receptor antagonist to mice to induce IGF-1 deficiency.
- Characterization of brain alterations using parallel mouse/human behavioral tests.
- Pharmacological intervention using ganaxolone to target GABAergic tonic inhibition.
Main Results:
- The mouse model exhibited sex-biased brain microstructural, functional, and behavioral alterations similar to ex-preterm children.
- These alterations were successfully rescued by ganaxolone, a drug enhancing GABAergic tonic inhibition.
- The study successfully dissected underlying mechanisms of abnormal behaviors in a prematurity model.
Conclusions:
- IGF-1 deficiency in preterm infants leads to sex-specific neurodevelopmental deficits.
- Ganaxolone represents a promising, translatable therapeutic approach for treating preterm brain disorders.
- This research provides a novel mouse model for studying prematurity and its long-term neurological consequences.
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.
