Expression of CX(3)CR1 chemokine receptors on neurons and their role in neuronal survival

Recent in vitro and in vivo studies have shown that the chemokine fractalki ne is widely expressed in the brain and localized principally to neurons. C entral nervous system expression of CX(3)CR1, the only known receptor for f ractalkine, has been demonstrated exclusively on microglia and astrocytes. Thus, it has been proposed that fractalkine regulates cellular communicatio n between neurons (that produce fractalkine) and microglia (that express it s receptor). Here we show, for the first time, that hippocampal neurons als o express CX(3)CR1. Receptor activation by soluble fractalkine induces acti vation of the protein kinase Akt, a major component of prosurvival signalin g pathways, and nuclear translocation of NF-KB, a downstream effector of Ak t. Fractalkine protects hippocampal neurons from the neurotoxicity induced by the HIV-1 envelope protein gp120(IIIB), an effect blocked by anti-CX(3)C R1 antibodies, Experiments with two different inhibitors of the phosphatidy linositol 3-kinase, a key enzyme in the activation of Akt, and with a phosp holipid activator of Akt demonstrate that Akt activation is responsible for the neuroprotective effects of fractalkine. These data show that neuronal CX(3)CR1 receptors mediate the neurotrophic effects of fractalkine, suggest ing that fractalkine and its receptor are involved in a complex network of both paracrine and autocrine interactions between neurons and glia.