Microglia sense and suppress epileptic neuronal hyperexcitability

Yang Hu; Yuanyuan Yao; Honggang Qi; Jiurong Yang; Canyu Zhang; Aifeng Zhang; Xiufang Liu; Chenchen Zhang; Guangming Gan; Xinjian Zhu

doi:10.1016/j.phrs.2023.106881

Microglia sense and suppress epileptic neuronal hyperexcitability

Pharmacol Res. 2023 Sep:195:106881. doi: 10.1016/j.phrs.2023.106881. Epub 2023 Aug 2.

Authors

Yang Hu¹, Yuanyuan Yao¹, Honggang Qi¹, Jiurong Yang¹, Canyu Zhang¹, Aifeng Zhang², Xiufang Liu³, Chenchen Zhang⁴, Guangming Gan⁵, Xinjian Zhu⁶

Affiliations

¹ Department of Pharmacology, Jiangsu Provincial Key Laboratory of Critical Care Medicine, Medical School of Southeast University, Nanjing, China.
² Department of Pathology, Medical School of Southeast University, Nanjing, China.
³ Department of Pathogenic Biology and Immunology, Medical School of Southeast University, Nanjing, China.
⁴ Transmission Electron Microscopy Center, Medical School of Southeast University, Nanjing, China.
⁵ Transmission Electron Microscopy Center, Medical School of Southeast University, Nanjing, China; Department of Genetics and Developmental Biology, Medical School of Southeast University, Nanjing, China.
⁶ Department of Pharmacology, Jiangsu Provincial Key Laboratory of Critical Care Medicine, Medical School of Southeast University, Nanjing, China. Electronic address: xinjianzhu@seu.edu.cn.

PMID: 37541638
DOI: 10.1016/j.phrs.2023.106881

Abstract

Microglia are the resident immune cells of the central nervous system, undertaking surveillance role and reacting to brain homeostasis and neurological diseases. Recent studies indicate that microglia modulate epilepsy-induced neuronal activities, however, the mechanisms underlying microglia-neuron communication in epilepsy are still unclear. Here we report that epileptic neuronal hyperexcitability activates microglia and drives microglial ATP/ADP hydrolyzing ectoenzyme CD39 (encoded by Entpd1) expression via recruiting the cAMP responsive element binding protein (CREB)-regulated transcription coactivator-1 (CRTC1) from cytoplasm to the nucleus and binding to CREB. Activated microglia in turn suppress epileptic neuronal hyperexcitability in a CD39 dependent manner. Disrupting microglial CREB/CRTC1 signaling, however, decreases CD39 expression and diminishes the inhibitory effect of microglia on epileptic neuronal hyperexcitability. Overall, our findings reveal CD39-dependent control of epileptic neuronal hyperexcitability by microglia is through an excitation-transcription coupling mechanism.

Keywords: AMP (PubChem CID: 6083); ATP (PubChem CID: 5957); Adenosine (PubChem CID: 60961); CD39; CREB; CRTC1; DPCPX (PubChem CID: 1329); Epilepsy; Microglia; Pilocarpine hydrochloride (PubChem CID: 5909).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Brain / metabolism
Epilepsy* / metabolism
Humans
Microglia*
Signal Transduction