Disorders including schizophrenia, and atypical neurocognitive and behavioral disorders in humans, including speech delay, delusion severity, attention sustainability and scholastic disorganization. Furthermore, schizophrenia risk-associated genetic variation in NRG3 impacts human prefrontal cortical physiology during working memory. The same common risk variant in NRG3 is associated with elevated transcriptional levels of NRG3 in both adult and fetal prefrontal cortex. Additionally, in agreement with convergent evidence suggesting altered NRG3 expression is pathophysiologically relevant in normal brain function, NRG3 expression is elevated in the PFC of patients with schizophrenia, compared to unaffected individuals. While the evidence for involvement of NRG3 in neurodevelopmental and psychiatric disorders is mounting, little is known about its neurobiological role. NRG3 is a neurotrophic factor, a specific ligand for the receptor tyrosine kinase ErbB4 and a paralog of the growth factor NRG1, all of which are strong candidate risk genes for schizophrenia. Manipulation of NRG1 and ErbB4 in rodents leads to behavioral and neurophysiological phenotypes relevant to schizophrenia, consistent with their known roles in neuronal development, myelination and neurotransmitter function. Unlike NRG1, expression of NRG3 is limited to the CNS, where it is enriched during neurodevelopment. NRG3 promotes oligodendrocyte survival and is implicated in cortical plate development. CPI-613 Despite its structural similarities to NRG1 and disease associations, the neurobehavioral consequences of altered NRG3 signaling are unknown. Given recent data that demonstrate peripherally administered NRG1 peptides can cross the blood brain barrier of neonatal rodents and exert lifelong behavioral and neurochemical effects, and observation that NRG3 is pathologically elevated in the brains of patients with schizophrenia, we synthesized the bioactive NRG3 EGF peptide and investigated its ability to penetrate the neonatal murine BBB comparative to NRG1. Additionally, we assessed the impact of NRG3 overexposure during early neonatal development on a series of adult behaviors relevant to neurocognitive and neurodevelopmental disorders; testing the hypothesis that mice exposed to NRG3 during a critical neurodevelopmental window would show behavioral abnormalities later in life. Here, we present evidence that like NRG1, NRG3 can readily penetrate the BBB of neonatal mice and is bioactive, inducing activation of the ErbB4-Akt signaling pathway.