Hippocampal astrocytic neogenin regulating glutamate uptake, a critical pathway for preventing epileptic response
Dong Sun, Zhibing Tan, Xiangdong Sun, Zhipeng Liu, Wenbing Chen, Leena Milibari, Xiao Ren, Lingling Yao, Daehoon Lee, Chen Shen, Jin‐Xiu Pan, Zhi-Hui Huang, Lin Mei, Wen‐Cheng Xiong
Abstract
Significance Epilepsy, a neurological disorder, is caused by abnormal brain activity due to genetic variances or acquired brain injuries. However, the underlying molecular mechanisms remain elusive. We demonstrate that NEO1, a member of the deleted in colorectal cancer (DCC) family transmembrane proteins, is decreased in human hippocampi of patients with epilepsy. By using a combination of genetic, electrophysiological, biochemical, and molecular biological methods, we show that KO Neo1 in hippocampal astrocytes, but not in neurons, increased epileptiform spikes and seizure susceptibility in mice. Astrocyte-specific KO of Neo1 reduced inhibitory synaptic vesicles and GABAergic synaptic transmission in the hippocampus by impairing the GLAST-mediated glutamate–glutamine cycle. Together, this study reveals a function of NEO1 in hippocampal astrocytes to protect the brain from epilepsy.