Interferon‐γ directly induces neurotoxicity through a neuron specific, calcium‐permeable complex of IFN‐γ receptor and AMPA GluRl receptor

Abstract

Interferon‐γ (IFN‐γ) is a proinflamma tory cytokine that plays a pivotal role in pathology of diseases in the central nervous system (CNS), such as multiple sclerosis. However, the direct effect of IFN‐γ on neuronal cells has yet to be elucidated. We show here that IFN‐γ directly induces neuronal dysfunction, which appears as dendritic bead formation in mouse cortical neurons and enhances glutamate neurotoxicity mediated via alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isox‐ azolepropionic (AMPA) receptors but not N ‐methyl‐D‐ aspartate receptors. In the CNS, IFN‐γ receptor forms a unique, neuron‐specific, calcium‐permeable receptor complex with AMPA receptor subunit GluRl. Through this receptor complex, IFN‐γ phosphorylates GluRl at serine 845 position by JAKT2/STAT1 pathway, in creases Ca 2+ influx and following nitric oxide production, and subsequently decreases ATP production, leading to the dendritic bead formation. These findings provide novel mechanisms of neuronal excitotoxicity, which may occur in both inflammatory and neurodegen erative diseases in the CNS.— Mizuno, T., Zhang, G., Takeuchi, H., Kawanokuchi, J., Wang, J., Sonobe, Y., Jin, S., Takada, N., Komatsu, Y., Suzumura, A. Inter feron‐γ directly induces neurotoxicity through a neu ron specific, calcium‐ permeable complex of IFN‐γ receptor and AMPA GluRl receptor. FASEB J. 22, 1797–1806 (2008)