IGF1 peptide targets Rett Syndrome astrocytes to degrade IGF binding protein, rescue synaptogenesis and restore mitochondrial function

Astrocyte dysfunction is increasingly recognized as a contributor to neurodevelopmental disorders, yet precise mechanisms remain elusive. Here, we identify IGFBP2 as a key astrocyte-derived inhibitor of synaptogenesis in Rett syndrome. We show that an IGF1-derived peptide, IGF1(1-3), depletes IGFBP2 via proteasomal degradation. This restores IGF1 bioavailability and rescues synaptic function in a non-cell-autonomous manner. These findings provide a mechanistic explanation for the clinical efficacy of IGF1 peptide and its mimetics in Rett syndrome, and highlight astrocytes as rational therapeutic targets in neurodevelopmental and other disorders.