RAGE signaling is required for AMPA receptor dysfunction in the hippocampus of hyperglycemic mice
RAGE signaling is required for AMPA receptor dysfunction in the hippocampus of hyperglycemic mice
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DOI：
10.1016/j.physbeh.2020.113255
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发表时间：
2021-02-01
影响因子：
2.9
通讯作者：
Campanucci, Veronica A.
中科院分区：
文献类型：
--
作者：
Momeni, Zeinab;Bautista, Maricris;Campanucci, Veronica A.
长期以来，人类的糖尿病一直与认知功能障碍有关。在啮齿动物模型中，认知功能障碍可表现为海马区突触可塑性受损。特别关注的是晚期糖基化终末产物受体(RAGE)，它与多种糖尿病并发症有关，包括血管和周围神经异常的发展。在这项研究中，我们假设RAGE信号改变了谷氨酸受体的功能和表达，损害了海马区的突触传递。使用雄性小鼠的海马片，我们发现在链脲佐菌素(STZ)诱导的糖尿病后，长时程增强(LTP)和双脉冲易化(PPF)均呈剂量依赖性降低。一贯地，在雄性和雌性新生小鼠的海马区培养中，高糖引起AMPA-而不是NMDA-诱发电流的依赖于RAGE的减少，以及胞浆活性氧物种(ROS)的增加。当培养的细胞与高糖和RAGE拮抗剂FPS-ZM1共同处理时，AMPA诱发的电流没有变化。STZ诱导的高血糖野生型(WT)小鼠的海马区RAGE表达增加，同时AMPA GluA1亚单位的表达和磷酸化(Ser831和845)降低。我们发现这些变化与MAPK通路的激活有关，与pJNK/JNK比值和JNK激酶pMEK7的降低一致。由于没有观察到STZ诱导的高血糖RAGE-KO小鼠海马区调节蛋白的表达或磷酸化的变化，我们报告了高血糖WT小鼠海马区RAGE依赖的损伤，AMPA受体表达/功能降低和LTP缺陷。
Diabetes in humans has been associated for a long time with cognitive dysfunction. In rodent animal models, cognitive dysfunction can manifest as impaired hippocampal synaptic plasticity. Particular attention has been concentrated on the receptor for advanced glycation end products (RAGE), which is implicated in multiple diabetic complications involving the development of vascular and peripheral nerve abnormalities. In this study, we hypothesize that RAGE signaling alters glutamate receptor function and expression, impairing synaptic transmission in the hippocampus. Using preparations of hippocampal slices from male mice, we show a RAGE-dependent decrease in long-term potentiation (LTP) and an increase in paired-pulse facilitation (PPF) following streptozotocin (STZ)-induced diabetes. Consistently, in hippocampal cultures from male and female neonatal mice, high glucose caused a RAGE-dependent reduction of AMPA- but not NMDA-evoked currents, and an increase in cytosolic reactive oxygen species (ROS). Consistently, when cultures were co-treated with high glucose and the RAGE antagonist FPS-ZM1, AMPA-evoked currents were unchanged. Hippocampi from STZ-induced hyperglycemic wild type (WT) mice showed increased RAGE expression concomitant with a decrease of both expression and phosphorylation (Ser 831 and 845) of the AMPA GluA1 subunit. We found these changes correlated to activation of the MAPK pathway, consistent with decreased pJNK/JNK ratio and the JNK kinase, pMEK7. As no changes in expression or phosphorylation of regulatory proteins were observed in hippocampi from STZ-induced hyperglycemic RAGE-KO mice, we report a RAGE-dependent impairment in the hippocampi of hyperglycemic WT mice, with reduced AMPA receptor expression/function and LTP deficits.