Microglia sense and suppress epileptic neuronal hyperexcitability

• Published in: Pharmacological research Vol. 195; p. 106881
• Main Authors: Hu, Yang, Yao, Yuanyuan, Qi, Honggang, Yang, Jiurong, Zhang, Canyu, Zhang, Aifeng, Liu, Xiufang, Zhang, Chenchen, Gan, Guangming, Zhu, Xinjian
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.09.2023; Elsevier
• Subjects: CD39; CREB; CRTC1; Epilepsy; Microglia; ATP (PubChem CID: 5957); DG; CRTC1; Pilocarpine hydrochloride (PubChem CID: 5909); Epilepsy; PKA; AMP (PubChem CID: 6083); FACS; ADO; TLE; ECL; Microglia; DSB; SE; CREB; CHIP; scRNA-Seq; Adenosine (PubChem CID: 60961); AAV; GABA; CD39; Mg2; DPCPX (PubChem CID: 1329)
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1016/j.phrs.2023.106881

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. [Display omitted]