Department of Emergency and Intensive Care Unit, The First Affiliated Hospital of Chongqing Medical University, 1 You Yi Road, Chongqing, 400016, China.
Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, 1 You Yi Road, Chongqing, 400016, China.
Mol Neurobiol. 2016 Jan;53(1):270-284. doi: 10.1007/s12035-014-8999-8. Epub 2014 Nov 27.
Abnormally synchronized synaptic transmission in the brain leads to epilepsy. Neuroligin-1 (NL1) is a synaptic cell adhesion molecule localized at excitatory synapses. NL1 modulates synaptic transmission and determines the properties of neuronal networks in the mammalian central nervous system. We showed that the expression of NL1 and its binding partner neurexin-1β was increased in temporal lobe epileptic foci in patients and lithium-pilocarpine-treated epileptic rats. We investigated electrophysiological and behavioral changes in epileptic rats after lentivirally mediated NL1 knockdown in the hippocampus to determine whether NL1 suppression prevented seizures and, if so, to explore the probable underlying mechanisms. Our behavioral studies revealed that NL1 knockdown in epileptic rats reduced seizure severity and increased seizure latency. Whole-cell patch-clamp recordings of CA1 pyramidal neurons in hippocampal slices from NL1 knockdown epileptic rats revealed a decrease in spontaneous action potential frequency and a decrease in miniature excitatory postsynaptic current (mEPSC) frequency but not amplitude. The amplitude of N-methyl-D-aspartate receptor (NMDAR)-dependent EPSCs was also selectively decreased. Notably, NL1 knockdown reduced total NMDAR1 expression and the surface/total ratio in the hippocampus of epileptic rats. Taken together, these data indicate that NL1 knockdown in epileptic rats may reduce the frequency and severity of seizures and suppress neuronal hyperexcitability via changes in postsynaptic NMDARs.
大脑中异常同步的突触传递会导致癫痫。神经黏附素-1（NL1）是一种定位于兴奋性突触的突触细胞黏附分子。NL1 调节突触传递，并决定哺乳动物中枢神经系统中神经元网络的特性。我们发现，NL1 及其结合伴侣神经连接素-1β的表达在患者的颞叶癫痫病灶和锂-匹罗卡品治疗的癫痫大鼠中增加。我们研究了在海马中通过慢病毒介导的 NL1 敲低后癫痫大鼠的电生理和行为变化，以确定 NL1 抑制是否可以预防癫痫发作，如果可以，那么探索可能的潜在机制。我们的行为研究表明，癫痫大鼠中 NL1 的敲低降低了癫痫发作的严重程度并增加了发作潜伏期。NL1 敲低癫痫大鼠海马脑片 CA1 锥体神经元的全细胞膜片钳记录显示自发性动作电位频率降低，以及微小兴奋性突触后电流（mEPSC）频率降低但幅度不变。N-甲基-D-天冬氨酸受体（NMDAR）依赖性 EPSC 的幅度也选择性降低。值得注意的是，NL1 敲低降低了癫痫大鼠海马中的总 NMDAR1 表达和表面/总比值。综上所述，这些数据表明，癫痫大鼠中 NL1 的敲低可能通过改变突触后 NMDAR 来降低癫痫发作的频率和严重程度，并抑制神经元过度兴奋。
