Role of CX3CL1 in synaptic activity and neuroprotection

The only member of the CX3C family of chemokines, fractalkine/CX3CL1, and its unique specific receptor CX3CR1, are expressed constitutively and at very high levels in the nervous system. While for other chemokine/chemokine receptor pairs constitutively expressed in the brain, like CXCL12/CXCR4, clear physiological roles have been assigned (Proc Natl Acad Sci USA 95:9448-9453, 1998; Nature 393:524-525, 1998; Proc Natl Acad Sci USA 99:7090-7095, 2002), knocking down CX3CL1 or CX3CR1 did not shed bright light on possible physiological functions of this monogamous pair in the nervous system (Mol Cell Biol 20:4106-4114; Mol Cell Biol 21:3159-3165). However, the strategic and abundant expression of CX3CL1 in neurons and of CX3CR1 in microglial cells has been suggestive, from the very beginning (Proc Natl Acad Sci USA 95:10896-10901; FEBS Lett 429:167-172), of a physical bridge or, in general, of a preferential communicating system between neurons and microglia. This view has now been confirmed by several in vitro and in vivo studies and there is a general agreement that at least part of the effects described for CX3CL1 on neurons is mediated by microglial cells. In particular, in this chapter, we will discuss how microglia intervenes in the effects of CX3CL1 on neurons in terms of (1) neuromodulation of synaptic activity; (2) neuroprotection from toxic insults; (3) modulation of pain sensation.