Prenatal (1-3)IGF-1 Treatment Is Ineffective and Behaviorally Detrimental in a Rat Model of Cortical Malformation

Malformations of cortical development (MCD), a major cause of early-onset epilepsy, arise from disruptions in fetal corticogenesis, suggesting that prenatal intervention may be required to alter their developmental trajectory. Insulin-like growth factor-1 (IGF-1) has been proposed as a potential therapeutic agent due to its roles in neuronal survival, synaptogenesis, and plasticity. However, whether prenatal or prolonged early-life IGF-1 exposure can modify the trajectory of malformed cortical circuits remains unknown.

Pregnant dams were exposed to MAM to induce cortical malformation, and fetal brain development was assessed at embryonic day 19 (E19) using in utero MRI. Offspring were assigned to receive prenatal and/or prolonged early postnatal administration of the truncated IGF-1 analog (1-3)IGF-1. Outcomes after IGF-1 treatment were evaluated across multiple domains, including brain morphology, body growth, seizure susceptibility, neurometabolic profiles (¹H-MRS), and behavioral performance (Y-maze, open field, fear conditioning).

Fetal MRI revealed significantly reduced brain size in MAM-exposed fetuses, indicating that structural abnormalities were already established prenatally. Neither prenatal nor prolonged postnatal (1-3)IGF-1 treatment improved whole-brain growth, neurometabolite levels, or susceptibility to N-methyl-D-aspartate-induced spasms. Moreover, long-term IGF-1 exposure led to adverse behavioral outcomes, including impaired spatial working memory in the Y-maze and increased freezing during conditioning, without affecting locomotor activity or fear recall. No beneficial effects were observed across any treatment paradigm.

Although IGF-1 has known neurotrophic properties, early and sustained exposure to the (1-3)IGF-1 analog did not ameliorate structural-, metabolic-, or seizure-related abnormalities and produced detrimental behavioral effects in this model of cortical malformation. These findings underscore the importance of developmental timing and molecular specificity when applying IGF-1-based interventions and caution against the assumption that earlier or prolonged treatment is necessarily beneficial in malformed cortical circuits.