CXCR4-activated astrocyte glutamate release via TNFa: amplification by microglia triggers neurotoxicity

Astrocytes actively participate in synaptic integration by releasing transm itter (glutamate) via a calcium-regulated, exocytosis-like process. Here we show that this process follows activation of the receptor CXCR4 by the che mokine stromal cell-derived factor 1 (SDF-1). An extraordinary feature of t he ensuing signaling cascade is the rapid extracellular release of tumor ne crosis factor-alpha (TNF alpha). Autocrine/paracrine TNF alpha -dependent s ignaling leading to prostaglandin (PG) formation not only controls glutamat e release and astrocyte communication, but also causes their derangement wh en activated microglia cooperate to dramatically enhance release of the cyt okine in response to CXCR4 stimulation. We demonstrate that altered glial c ommunication has direct neuropathological consequences and that agents inte rfering with CXCR4-dependent astrocyte-microglia signaling prevent neuronal apoptosis induced by the HIV-1 coat glycoprotein, gp120(IIIB) Our results identify a new pathway for glia-glia and glia-neuron communication that is relevant to both normal brain function and neurodegenerative diseases.