Microglia sense their environment using an array of membrane receptors. While P2Y₁₂ receptors 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 P2Y₁₃ receptors, the THIK-1 K⁺ current density evoked by ADP activating P2Y₁₂ receptors 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 P2Y₁₃ KO. Anatomical analysis showed that the density of microglia was unchanged, but that they were less ramified with a shorter process length in the P2Y₁₃ KO. 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 P2Y₁₂ receptors in brain slices from P2Y₁₃ KO 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 P2Y₁₃ KO, and microglia in intact P2Y₁₃ KO brains were not detectably activated. Thus, P2Y₁₃ receptors play a role different from that of their close relative P2Y₁₂ in regulating microglial morphology and function.

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