PDF(Pubmed)
Abstract：
Obesity has been linked with the impairment of spatial memory and synaptic plasticity but the molecular mechanisms remained unidentified. Since glutamatergic transmission and NMDA receptor neural pathways in hippocampal dentate gyrus (DG) are essential in the learning and memory, we aimed to investigate glutamate (Glu) and NMDA receptor signaling of DG in spatial learning and memory in diet-induced obesity (DIO) rats. Spatial learning and memory were assessed via Morris water maze (MWM) test on control (Ctr) and DIO rats. Extracellular concentration of Glu in the DG was determined using in vivo microdialysis and HPLC. The protein expressions of NMDA receptor subunit 2B (NR2B), brain-derived neurotrophic factor (BDNF), the activation of calcium/calmodulin-dependent kinase II (CaMKII) and cAMP-response-element-binding protein (CREB) in the DG were observed by western blot. Spatial learning and memory were impaired in DIO rats compared to those of Ctr. NR2B expression was increased, while BDNF expression and CaMKII and CREB activation were decreased in DG of DIO rats. Extracellular concentration of Glu was increased in Ctr on the 3rd and 4th days of the MWM test, but significant further increment was observed in DIO rats. Microinjection of an NMDA antagonist (MK-801) into the DG reversed spatial learning and memory impairment. Such effects were accompanied by greater BDNF expression and CaMKII/CREB activation in the DG of DIO rats. In conclusion, the enhancement of Glu-NMDA receptor transmission in the hippocampal DG contributes to the impairment of spatial learning and memory in DIO rats, maybe via the modulation of CaMKII-CREB-BDNF signaling pathway.
摘要：
肥胖与空间记忆和突触可塑性的损害有关，但其分子机制仍未确定。由于海马齿状回（DG）中的谷氨酸能传递和NMDA受体神经通路在学习和记忆中至关重要，我们旨在研究谷氨酸（Glu）和DG的NMDA受体信号在饮食诱导的肥胖（DIO）大鼠空间学习和记忆中的作用。通过Morris水迷宫（MWM）测试对对照（Ctr）和DIO大鼠进行空间学习和记忆评估。使用体内微透析和HPLC测定DG中Glu的细胞外浓度。NMDA受体2B亚基(NR2B)的蛋白表达,脑源性神经营养因子(BDNF),通过蛋白质印迹观察到DG中钙/钙调蛋白依赖性激酶II（CaMKII）和cAMP反应元件结合蛋白（CREB）的激活。与Ctr相比，DIO大鼠的空间学习和记忆受损。NR2B表达增加，DIO大鼠DG中BDNF表达、CaMKII和CREB活性降低。在MWM试验的第3天和第4天，细胞外Glu浓度在Ctr中增加，但在DIO大鼠中观察到显着的进一步增加。将NMDA拮抗剂（MK-801）显微注射到DG中可逆转空间学习和记忆障碍。这种作用伴随着DIO大鼠DG中更高的BDNF表达和CaMKII/CREB激活。总之,海马DG中Glu-NMDA受体传递的增强有助于DIO大鼠空间学习和记忆的损害,可能通过调节CaMKII-CREB-BDNF信号通路。
