Impaired Neuregulin 1 Processing is Associated with Synaptic and Behavioral Abnormalities in a Prenatal Valproic Acid...

Autism spectrum disorder (ASD) is characterized by deficits in social communication and restricted/repetitive behaviors, yet the molecular mechanisms by which prenatal environmental insults lead to circuit dysfunction remain incompletely understood. Neuregulin 1 (NRG1)-ErbB4 signaling is a key regulator of synaptic development and excitation-inhibition (E/I) balance, but whether altered NRG1 processing contributes to ASD-related phenotypes remains unclear. Here, using a prenatal valproic acid (VPA) rat model, we examined the relationship between NRG1 processing, synaptic integrity, and behavioral outcomes. Prenatal VPA exposure reduced cleaved NRG1 protein without altering Nrg1 transcript levels and was accompanied by decreased expression of the NRG1 sheddases ADAM10, ADAM17, and BACE1. These alterations were accompanied by attenuated ErbB4-AKT/ERK1/2 signaling, reduced synaptic scaffolding proteins, and impaired dendritic spine maturation in the hippocampus. Behaviorally, VPA-exposed offspring exhibited abnormalities across multiple ASD-relevant domains. Recombinant NRG1β1 administration during adolescence improved repetitive behaviors in both sexes, whereas deficits and rescue effects in social and sensorimotor domains were primarily observed in males. As robust social deficits were not evident in females, subsequent molecular and synaptic analyses were conducted in male hippocampus, where NRG1 restored ErbB4 signaling, synaptic organization, and spine maturity without affecting locomotor activity. Collectively, these findings indicate that altered NRG1 processing is associated with synaptic and behavioral abnormalities in the VPA model. Enhancement of NRG1-ErbB4 signaling modulates these phenotypes, supporting a functionally relevant role of this pathway in ASD-related neurodevelopmental alterations.