P2Y₁₃ receptors regulate microglial morphology, surveillance, and resting levels of interleukin 1β release

Abstract

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.

Microglia-neuron communication at nodes of Ranvier depends on neuronal activity through potassium release and contributes to myelin repair

“…In order to address whether this pathway was required for microglia-node contact, we first inhibited the P2Y12R receptor specifically using PSB0739 (1 μM), a highly potent P2Y12 antagonist, and found that it is not required for microglia-node interaction (15.1 ± 1.2% of nodes contacted in control vs 15.5 ± 1.7% following treatment, Figure S4C-D). To further assess the potential role of the P2Y receptor family and exclude any compensatory mechanisms, we also inhibited P2Y13R, which participates in microglia dynamics control 39 , concomitantly to P2Y12R by using the MRS2211 inhibitor (50 μM). Again, there was no significant variation in the number of nodes contacted in control vs treated slices (15.1 ± 1.5% vs 14.3 ± 1.3% respectively, Figure S4E-F), confirming that P2Y12R and P2Y13R are not required for microglia-node interactions in physiological condition.…”

Loss of P2Y12 Has Behavioral Effects in the Adult Mouse

“…Additionally, the deletion of P2Y12 may result in compensatory changes in P2Y13 as it is similarly highly expressed in microglia and may have similar functions. However, the inverse deletion of P2Y13 does not result in altered P2Y12 expression nor compensatory functioning in the brain [ 31 ], suggesting that these two similar receptors are independently regulated.…”

How microglia sense and regulate neuronal activity

“…These receptors are preferentially activated by ATP and induce cation currents. Microglia also express four of the eight metabotropic P2Y receptors: P2Y1, P2Y6, P2Y12, and P2Y13 (Butovsky et al, 2014; Fukumoto et al, 2019; Koizumi et al, 2007; Kyrargyri et al, 2020). P2Y receptors have unique affinity profiles for different purine signals and are coupled to either Gq (P2Y1 and P2Y6) or Gi/o (P2Y12 and P2Y13) signaling cascades.…”