Interferon-β impairs BDNF-induced neuronal signaling and differentiation.

The clinical use of type I interferon (IFN)-α and IFN-β is often accompanied by the appearance of neuropsychiatric side effects, including depression, psychosis and cognitive dysfunctions. The cellular and molecular mechanisms mediating the IFN neurotoxicity are not completely understood. In the present study, we investigated the effects of type I IFN on neuronal signaling and differentiation induced by brain-derived neurotrophic factor (BDNF), a neurotrophin involved in the regulation of neuronal survival and outgrowth. In differentiated SH-SY5Y human neuroblastoma cells, long- term exposure to IFN-α or IFN-β curtailed BDNF-induced activation of the PI3K survival pathway, as indicated by the reduced phoshorylation of the protein kinases Akt and GSK-3β. IFN treatment also reduced BDNF activation of PLCγ1 and ERK1/2, two signaling systems involved in the neurotrophin regulation of synaptic plasticity and neuritogenesis. Immunofluorescence analysis showed that IFN-β inhibited BDNF-induced neurite outgrowth in differentiated SH-SY5Y cells and mouse primary neurons. The IFN inhibition of BDNF responses was associated with a significant reduction in the expression levels of TrkB receptor protein and in BDNF-dependent TrkB autophosphorylation. These data demonstrate that in neuronal cells type I IFNs negatively regulate BDNF signaling and neurotrophic activity likely through inhibition of TrkB receptor expression and suggest that the alteration of BDNF signaling may contribute to the pathogenesis of neuropsychiatric side effects induced by IFN treatment.