Bilirubin impairs neuritogenesis and synaptogenesis through NMDAR-CREB-BDNF signaling

Abstract Neonatal jaundice is one of the most common disorders in the first 2 weeks after birth. Moreover, unconjugated bilirubin (UCB) is neurotoxic and can cause neurological dysfunction, but the underlying mechanisms remain unclear. Neurogenesis, neuron growth and synaptogenesis is exuberant in early postnatal stage. In this study, the impact of bilirubin on neuritogenesis and synaptogenesis at the early postnatal stage was evaluated both in vitro and in vivo. Primary culture NSPCs were treated with bilirubin during differentiation, then the neurite length as well as synapse puncta were measured. In bilirubin encephalopathy (BE) animal model, DCX+ marked developing neurons were used to detect apitical length and dendritic arborization. According to the data, bilirubin significantly reduced neurite length and synapse density, as well as decreased apitical length and dendritic arborization. The NMDAR-CREB-BDNF signaling pathway changes in BE animal model were convoluted because to the intricate cell population constituted of hippocampus. While, UCB treatment reduced the expression of NMDAR subunit NR2B, pCREB, mBDNF and p-mTOR in NSPCs. In summary, it suggests that UCB causes chronic neurological impairment is related to the inhibition of NMDAR-CREB-BDNF signaling, which is associated with reduced neuritogenesis and synaptogenesis. This might inspire the creation development of novel pharmaceuticals and treatments.