Tong Jia, Okutani Fumino, Murata Yoshihiro, Taniguchi Mutsuo, Namba Toshiharu, Wang Yu-Jie, Kaba Hideto
Department of Physiology, Kochi Medical School, Nankoku, Kochi 783-8505, Japan.
Department of Physiology, Kochi Medical School, Nankoku, Kochi 783-8505, Japan; Department of Occupational Health, Kochi Medical School, Nankoku, Kochi 783-8505, Japan.
Neuroscience. 2017 Mar 6;344:371-379. doi: 10.1016/j.neuroscience.2017.01.001. Epub 2017 Jan 11.
Tunicamycin (TM) induces endoplasmic reticulum (ER) stress and inhibits N-glycosylation in cells. ER stress is associated with neuronal death in neurodegenerative disorders, such as Parkinson's disease and Alzheimer's disease, and most patients complain of the impairment of olfactory recognition. Here we examined the effects of TM on aversive olfactory learning and the underlying synaptic plasticity in the main olfactory bulb (MOB). Behavioral experiments demonstrated that the intrabulbar infusion of TM disabled aversive olfactory learning without affecting short-term memory. Histological analyses revealed that TM infusion upregulated C/EBP homologous protein (CHOP), a marker of ER stress, in the mitral and granule cell layers of MOB. Electrophysiological data indicated that TM inhibited tetanus-induced long-term potentiation (LTP) at the dendrodendritic excitatory synapse from mitral to granule cells. A low dose of TM (250nM) abolished the late phase of LTP, and a high dose (1μM) inhibited the early and late phases of LTP. Further, high-dose, but not low-dose, TM reduced the paired-pulse facilitation ratio, suggesting that the inhibitory effects of TM on LTP are partially mediated through the presynaptic machinery. Thus, our results support the hypothesis that TM-induced ER stress impairs olfactory learning by inhibiting synaptic plasticity via presynaptic and postsynaptic mechanisms in MOB.
衣霉素（TM）可诱导内质网（ER）应激并抑制细胞中的N-糖基化。ER应激与神经退行性疾病（如帕金森病和阿尔茨海默病）中的神经元死亡有关，并且大多数患者抱怨嗅觉识别受损。在这里，我们研究了TM对主要嗅球（MOB）中厌恶嗅觉学习及潜在突触可塑性的影响。行为实验表明，球内注射TM会破坏厌恶嗅觉学习，而不影响短期记忆。组织学分析显示，注射TM会使MOB的二尖瓣和颗粒细胞层中ER应激的标志物C/EBP同源蛋白（CHOP）上调。电生理数据表明，TM抑制了从二尖瓣细胞到颗粒细胞的树突-树突兴奋性突触处的破伤风诱导的长时程增强（LTP）。低剂量的TM（250nM）消除了LTP的晚期阶段，高剂量（1μM）则抑制了LTP的早期和晚期阶段。此外，高剂量而非低剂量的TM降低了双脉冲易化率，这表明TM对LTP的抑制作用部分是通过突触前机制介导的。因此，我们的结果支持这样的假设，即TM诱导的ER应激通过抑制MOB中突触前和突触后机制的突触可塑性来损害嗅觉学习。
