P2Y(13) receptors regulate microglial morphology, surveillance, and resting levels of interleukin 1β release

Microglia sense their environment using an array of membrane receptors. While P2Y(12) 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 P2Y(13), 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 P2Y(13) receptors, the THIK‐1 K(+) current density evoked by ADP activating P2Y(12) receptors was increased by ~50%. This increase suggested that the P2Y(12)‐dependent chemotaxis response should be potentiated; however, the time needed for P2Y(12)‐mediated convergence of microglial processes onto an ADP‐filled pipette or to a laser ablation was longer in the P2Y(13) KO. Anatomical analysis showed that the density of microglia was unchanged, but that they were less ramified with a shorter process length in the P2Y(13) 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 P2Y(12) receptors in brain slices from P2Y(13) 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 P2Y(13) KO, and microglia in intact P2Y(13) KO brains were not detectably activated. Thus, P2Y(13) receptors play a role different from that of their close relative P2Y(12) in regulating microglial morphology and function.