Li Baoman, Sun Qian, Ding Fengfei, Xu Qiwu, Kang Ning, Xue Yang, Ladron-de-Guevara Antonio, Hirase Hajime, Weikop Pia, Gong Sheng, Smith Nathan, Nedergaard Maiken
Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA; Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang, China.
Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA.
Cell Metab. 2025 Jan 7;37(1):223-238.e5. doi: 10.1016/j.cmet.2024.10.011. Epub 2024 Oct 31.
The brain's ability to rapidly transition between sleep, quiet wakefulness, and states of high vigilance is remarkable. Cerebral norepinephrine (NE) plays a key role in promoting wakefulness, but how does the brain avoid neuronal hyperexcitability upon arousal? Here, we show that NE exposure results in the generation of free fatty acids (FFAs) within the plasma membrane from both astrocytes and neurons. In turn, FFAs dampen excitability by differentially modulating the activity of astrocytic and neuronal Na, K, ATPase. Direct application of FFA to the occipital cortex in awake, behaving mice dampened visual-evoked potentials (VEPs). Conversely, blocking FFA production via local application of a lipase inhibitor heightened VEP and triggered seizure-like activity. These results suggest that FFA release is a crucial step in NE signaling that safeguards against hyperexcitability. Targeting lipid-signaling pathways may offer a novel therapeutic approach for seizure prevention.
大脑在睡眠、安静觉醒和高度警觉状态之间快速转换的能力十分显著。脑去甲肾上腺素（NE）在促进觉醒方面起着关键作用，但大脑在唤醒时如何避免神经元过度兴奋呢？在这里，我们表明，NE暴露会导致星形胶质细胞和神经元的质膜内产生游离脂肪酸（FFA）。反过来，FFA通过差异性调节星形胶质细胞和神经元的钠钾ATP酶活性来抑制兴奋性。在清醒、活动的小鼠枕叶皮质直接应用FFA可抑制视觉诱发电位（VEP）。相反，通过局部应用脂肪酶抑制剂阻断FFA的产生会增强VEP并引发癫痫样活动。这些结果表明，FFA释放是NE信号传导中防止过度兴奋的关键步骤。靶向脂质信号通路可能为癫痫预防提供一种新的治疗方法。
