Cyclosporin A impairs neurogenesis and cognitive abilities in brain development via the IFN--Shh-BDNF pathway

A wealth of evidence indicate that the peripheral immune activation alters brain development. However, it is still largely unclear whether and how peripheral immunosuppression affects neurodevelopment. Here, we found that the immunosuppressant cyclosporin A (CsA) decreased the number of BrdU+, BrdU+/DCX+, BrdU+/NeuN + cells in the hippocampus, impaired learning and memory and inhibited protein levels of the shh signaling pathway, including Shh, Smo and Gli1. However, the shh pathway receptor agonist SAG could block the impairment of cognitive ability and the decrease of hippocampal neurogenesis and brain-derived neurotrophic factor (BDNF) level induced by CsA. We also found that CsA decreased the level of interferon-gamma (IFN-gamma), while up-regulation of IFN-gamma altered the inhibitory effect of the shh signaling pathway and the decrease of BDNF induced by CsA. Collectively, these data indicate that peripheral CsA impairs neurogenesis and cognition in brain development through downregulating the IFN-gamma-Shh-BDNF pathway. The present study guides us to correctly apply immunomodulatory drugs in early life and suggests that the IFN-gamma-Shh-BDNF pathway may represent a novel protective target for neurodevelopment under the condition of immunosuppression.