Microglial P2Y6 Calcium Signaling Promotes Phagocytosis and Shapes Neuroimmune Responses in Epileptogenesis

Authors

Anthony D Umpierre
Bohan Li
Katayoun Ayasoufi
Whitney L Simon
Shunyi Zhao
Manling Xie
Grace Thyen
Benjamin Hur
Jiaying Zheng
Yue Liang
Dale B Bosco
Mark A Maynes
Zhaofa Wu
Xinzhu Yu
Jaeyun Sung
Aaron J Johnson
Yulong Li
Long-Jun Wu

Publication Date

6-19-2024

Journal

Neuron

DOI

10.1016/j.neuron.2024.03.017

PMID

38614103

PMCID

PMC11189754

PubMedCentral® Posted Date

6-19-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Microglial calcium signaling is rare in a baseline state but strongly engaged during early epilepsy development. The mechanism(s) governing microglial calcium signaling are not known. By developing an in vivo uridine diphosphate (UDP) fluorescent sensor, GRABUDP1.0, we discovered that UDP release is a conserved response to seizures and excitotoxicity across brain regions. UDP can signal through the microglial-enriched P2Y6 receptor to increase calcium activity during epileptogenesis. P2Y6 calcium activity is associated with lysosome biogenesis and enhanced production of NF-κB-related cytokines. In the hippocampus, knockout of the P2Y6 receptor prevents microglia from fully engulfing neurons. Attenuating microglial calcium signaling through calcium extruder ("CalEx") expression recapitulates multiple features of P2Y6 knockout, including reduced lysosome biogenesis and phagocytic interactions. Ultimately, P2Y6 knockout mice retain more CA3 neurons and better cognitive task performance during epileptogenesis. Our results demonstrate that P2Y6 signaling impacts multiple aspects of myeloid cell immune function during epileptogenesis.

Keywords

Animals, Microglia, Mice, Phagocytosis, Receptors, Purinergic P2, Mice, Knockout, Calcium Signaling, Epilepsy, Uridine Diphosphate, Lysosomes, Neurons, Mice, Inbred C57BL, Male, Hippocampus, Neuroimmunomodulation, CalEx, GRAB sensor, P2Y6, UDP, calcium signaling, inflammation, microglia, phagocytosis, purine, seizures

Published Open-Access

yes

Recommended Citation

Umpierre, Anthony D; Li, Bohan; Ayasoufi, Katayoun; et al., "Microglial P2Y6 Calcium Signaling Promotes Phagocytosis and Shapes Neuroimmune Responses in Epileptogenesis" (2024). Faculty, Staff and Student Publications. 5181.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5181