Interferon-α Induces Neurotoxicity Through Activation of the Type I Receptor and the GluN2A Subunit of the NMDA Receptor

Elevated levels of interferon-alpha (IFN alpha) in the central nervous system (CNS) are linked to cognitive dysfunction in patients with inflammatory CNS diseases such as HIV-associated neurocognitive disorders (HAND). Increased CNS IFN alpha has also been found to be associated with cognitive dysfunction in a HAND mouse model. Here, we corroborate previous studies showing a dose-dependent decrease in dendritic branching and length caused by IFN alpha treatment and extend those studies. Because both direct and indirect mechanisms of IFN alpha-induced neurotoxicity are likely involved, the cell signaling pathway involving the IFN alpha receptor (IFNAR) was initially evaluated. Rat neuronal cultures exposed to IFN alpha demonstrate increased phosphorylation of STAT1 and increased interferon stimulating gene 15 (ISG15) expression, indicators of IFNAR engagement. However, specific blocking antibodies to the IFNAR were found to only partially protect neurons from IFN alpha-induced neurotoxicity. Additionally, inhibiting the GluN2A subunit of N-methyl-D-asparate receptor (NMDAR) was also found to be partially protective against IFN alpha-induced neurotoxicity compared with the GluN2B subunit. Neurotoxicity is evident in neurons extracted from IFNAR KO mice treated with IFN alpha as well, further indicating that IFNAR signaling is not required for IFN alpha neurotoxicity. The neurotoxic actions of IFN alpha are mediated through both the IFNAR as well as the GluN2A subunit of the NMDAR to reduce dendritic arborization in neurons. Complete protection from IFN alpha-induced neurotoxicity was demonstrated when both pathways were blocked. Blocking these pathways could lead to potential therapies for cognitive dysfunction during neuroinflammation and specifically lead to better treatments for HAND.