Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854.
Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854
J Neurosci. 2014 Aug 6;34(32):10528-40. doi: 10.1523/JNEUROSCI.0416-14.2014.
Microglia are highly dynamic immune cells of the CNS and their dynamism is proposed to be regulated by neuronal activities. However, the mechanisms underlying neuronal regulation of microglial dynamism have not been determined. Here, we found an increased number of microglial primary processes in the hippocampus during KA-induced seizure activity. Consistently, global glutamate induced robust microglial process extension toward neurons in both brain slices and in the intact brain in vivo. The mechanism of the glutamate-induced microglial process extension involves the activation of neuronal NMDA receptors, calcium influx, subsequent ATP release, and microglial response through P2Y12 receptors. Seizure-induced increases in microglial process numbers were also dependent on NMDA receptor activation. Finally, we found that P2Y12 KO mice exhibited reduced seizure-induced increases in microglial process numbers and worsened KA-induced seizure behaviors. Our results elucidate the molecular mechanisms underlying microglia-neuron communication that may be potentially neuroprotective in the epileptic brain.
小胶质细胞是中枢神经系统中高度动态的免疫细胞，其动态性被认为是由神经元活动调节的。然而，神经元调节小胶质细胞动态性的机制尚未确定。在这里，我们发现在 KA 诱导的癫痫发作活动期间，海马体中小胶质细胞的初级突起数量增加。一致地，在脑切片和体内完整大脑中，全局谷氨酸诱导了强大的小胶质细胞突起向神经元延伸。谷氨酸诱导的小胶质细胞突起延伸的机制涉及神经元 NMDA 受体的激活、钙内流、随后的 ATP 释放以及通过 P2Y12 受体的小胶质细胞反应。癫痫发作诱导的小胶质细胞突起数量增加也依赖于 NMDA 受体的激活。最后，我们发现 P2Y12 KO 小鼠表现出癫痫发作诱导的小胶质细胞突起数量增加减少，以及 KA 诱导的癫痫发作行为恶化。我们的结果阐明了小胶质细胞-神经元通讯的分子机制，这在癫痫大脑中可能具有潜在的神经保护作用。
