Ripoli Cristian, Spinelli Matteo, Natale Francesca, Fusco Salvatore, Grassi Claudio
Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy.
Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
Front Cell Dev Biol. 2020 Aug 19;8:810. doi: 10.3389/fcell.2020.00810. eCollection 2020.
Glucose metabolism derangement is critically involved in the age-related memory loss but the underlying molecular mechanisms are still poorly understood. In a mouse model of type 1 diabetes we found memory impairment associated with inhibition of the transcription factor CREB and alteration of pre- and post-synaptic protein expression in the hippocampus. Accordingly, glucose excess negatively affected activity-dependent CREB phosphorylation and CREB-mediated mRNA expression of synaptic proteins in hippocampal primary neurons. Specifically, glucose excess inhibited the activity-dependent recruitment of CREB on the regulatory sequences of synaptotagmin (SYT) 2 and 4 promoters and the expression of SYT4 protein. As a result, high glucose affected both the frequency of miniature excitatory postsynaptic currents and NMDA receptor-mediated currents in autaptic hippocampal neuronal cultures. Collectively, our findings highlight novel mechanisms underlying hyperglycaemia-related memory loss, including CREB-dependent downregulation of synaptotagmin expression.
葡萄糖代谢紊乱与年龄相关的记忆丧失密切相关，但其潜在的分子机制仍知之甚少。在1型糖尿病小鼠模型中，我们发现记忆障碍与转录因子CREB的抑制以及海马体中突触前和突触后蛋白表达的改变有关。因此，葡萄糖过量对海马原代神经元中活性依赖的CREB磷酸化和CREB介导的突触蛋白mRNA表达产生负面影响。具体而言，葡萄糖过量抑制了活性依赖的CREB在突触结合蛋白（SYT）2和4启动子调控序列上的募集以及SYT4蛋白的表达。结果，高葡萄糖影响了自突触海马神经元培养物中微小兴奋性突触后电流的频率和NMDA受体介导的电流。总体而言，我们的研究结果突出了高血糖相关记忆丧失的新机制，包括CREB依赖的突触结合蛋白表达下调。
