CX3CL1 protects neurons against excitotoxicity enhancing GLT-1 activity on astrocytes

• Astrocytes are required for the neuroprotective activity of CX3CL1.
• Inhibition of GLT-1 abolished CX3CL1-mediated neuroprotection.
• CX3CL1 increases GLT-1 activity on astrocytes.
• CX3CL1-induced modulation of GLT-1 on astrocytes requires A1R.

In this paper we show for the first time that: i) astrocytes are required for the neuroprotective activity of CX3CL1 against excitotoxicity; ii) inhibition of the glutamate transporter 1 (GLT-1) prejudices CX3CL1-mediated neuroprotection; iii) CX3CL1 increases GLT-1 activity on astrocytes. The modulation of GLT-1 activity induced by CX3CL1 on astrocytes requires the presence and the activity of A1 adenosine receptor (A1R), being blocked by the specific antagonist DPCPX and absent in A1R−/− astrocytes. These data introduce the astrocytes as active players in CX3CL1-mediated signaling between microglia and neurons, identifying GLT-1 as a key mediator of the neuroprotective activity of CX3CL1.