Department of Pharmacology, Jiangsu Provincial Key Laboratory of Critical Care Medicine, Medical School of Southeast University, Nanjing, China.
Department of Pathology, Medical School of Southeast University, Nanjing, China.
Pharmacol Res. 2023 Sep;195:106881. doi: 10.1016/j.phrs.2023.106881. Epub 2023 Aug 2.
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.
小胶质细胞是中枢神经系统的固有免疫细胞，承担着监视作用，并对大脑内环境稳定和神经疾病作出反应。最近的研究表明，小胶质细胞调节癫痫引起的神经元活动，但在癫痫中，小胶质细胞-神经元通讯的机制仍不清楚。在这里，我们报告癫痫神经元过度兴奋激活小胶质细胞，并通过将 cAMP 反应元件结合蛋白（CREB）-调节转录共激活因子-1（CRTC1）从细胞质募集到细胞核并与 CREB 结合，驱动小胶质细胞 ATP/ADP 水解酶外切酶 CD39（由 Entpd1 编码）的表达。激活的小胶质细胞反过来以 CD39 依赖的方式抑制癫痫神经元的过度兴奋。然而，破坏小胶质细胞的 CREB/CRTC1 信号会降低 CD39 的表达，并减弱小胶质细胞对癫痫神经元过度兴奋的抑制作用。总的来说，我们的研究结果揭示了小胶质细胞通过兴奋-转录偶联机制对癫痫神经元过度兴奋的 CD39 依赖性控制。
