P2Y13receptors regulate microglial morphology,surveillance,and resting levels of interleukin 1 release

Kyrargyri V,Madry C,RifatA,Arancibia-Carcamo IL,Jones SP,Chan VTT,Xu Y,Robaye B,Attwell D

1.Department of Neuroscience,Physiology,&Pharmacology,University College London,London,UK 2.Department of Immunology,Laboratory of Molecular Genetics,Hellenic Pasteur Institute,Athens,Greece 3.Institute of Neurophysiology,Charité-Universitätsmedizin Berlin,Berlin,Germany 4.Faculté de Médecine,Université Libre de Bruxelles,Bruxelles,Belgium

Abstract Microglia sense their environment using an array of membrane receptors.While P2Y12receptors are known to play a key role in targeting directed motility of microglial processes to sites of damage where ATP/ADP is released,little is known about the role of P2Y13,which transcriptome data suggest is the second most expressed neurotransmitter receptor in microglia.We show that,in patch-clamp recordings in acute brain slices from mice lacking P2Y13receptors,the THIK-1 K+current density evoked by ADP activating P2Y12receptors was increased by～50%.This increase suggested that the P2Y12-dependent chemotaxis response should be potentiated;however,the time needed for P2Y12-mediated convergence of microglial processes onto an ADP-filled pipette or to a laser ablation was longer in the P2Y13KO.Anatomical analysis showed that the density of microglia was unchanged,but that they were less ramified with a shorter process length in the P2Y13KO.Thus,chemotactic processes had to grow further and so arrived later at the target,and brain surveillance was reduced by～30%in the knock-out.Blocking P2Y12receptors in brain slices from P2Y13KO mice did not affect surveillance,demonstrating that tonic activation of these high-affinity receptors is not needed for surveillance.Strikingly,baseline interleukin-1β release was increased fivefold while release evoked by LPS and ATP was not affected in the P2Y13KO,and microglia in intact P2Y13KO brains were not detectably activated.Thus,P2Y13receptors play a role different from that of their close relative P2Y12in regulating microglial morphology and function.

Key words ADP;ATP;P2Y12;P2Y13;purinergic signaling

（编译：杜一星）