Chemokine-Activated Glia Amplify Glutamate Signals

Abstract

Chemokines usually elicit chemotactic responses from immune cells. Bezzi et al. found that the neurotransmitter glutamate was released in hippocampal slices treated with the chemokine stromal-derived factor-1α (SDF-1α); however, the glutamate was released not from neurons, as expected, but from astrocytes. Glutamate release was blocked by treatment with antagonists to CXCR4 (the receptor to SDF-1α) or Ca2+ chelators, suggesting that SDF1-α induces Ca2+ influx-dependent release of glutamate from astrocytes. Bezzi et al. showed that activation of the tumor necrosis factor-α (TNF-α) receptor (TNFR), cyclooxygenase-2 (COX-2) activation, and production of prostaglandin E2 are required to cause glutamate release. The authors identified microglial cells as important secretors of SDF1-α-dependent TNF-α at the synapse. In fact, when both astrocytes and microglia were cultured together in the presence of SDF1-α, greatly increased amounts of glutamate and TNF-α were released from astrocytes, suggesting that synergy occurred. Bezzi et al. hypothesize that large amounts of secreted TNF-α and glutamate might lead to neurotoxic effects and apoptosis, under pathological conditions. Addition of gp120 glycoprotein from HIV (human immunodeficiency virus), which binds to and activates CXCR4, to cultures of astrocytes and microglia caused increased release of glutamate, and injection of gp120 into rat brains caused increased neuronal apoptosis. Thus, the authors may have identified a new mechanism for neurotransmitter release and propose a mechanism whereby secretion of TNF-α and glutamate might result in neuronal damage and apoptosis. Allen and Attwell provide analysis of the article in an accompanying News & Views.P. Bezzi, M. Domercq, L. Brambilla, R. Galli, D. Schols, E. De Clercq, A. Vescovi, G. Bagetta, G. Kollias, J. Meldolesi, A. Volterra, CXCR4-activated astrocyte glutamate release via TNFα: Amplification by microglia triggers neurotoxicity. Nature Neurosci. 4, 702-710 (2001). [Online Journal]N. J. Allen, D. Attwell, A chemokine-glutamate connection. Nature Neurosci. 4, 676-678 (2001). [Online Journal]