The Role of Cytoplasmic Polyadenylation Element Binding Protein 2 in Regulating Neuronal mRNA Translation, Synaptic Plasticity and Memory

• Main Authors: Wen-Hsin Lu, 呂文心
• Other Authors: Yi-Shuian Huang
• Format: Others
• Language: en_US
• Published: 2017
• Online Access: http://ndltd.ncl.edu.tw/handle/gqvt6w

博士 === 國立陽明大學 === 生化暨分子生物研究所 === 106 === Activity-dependent synthesis of plasticity-related proteins is necessary to sustain long-lasting synaptic modifications and consolidate memory. Regulated mRNA translation contributes to synaptic plasticity, so we investigated the role of the translational regulator CPEB2 in learning and memory. Forebrain-restricted CPEB2-cKO mice exhibited impaired hippocampus-dependent memory in the contextual fear conditioning and Morris water maze tests. CPEB2-cKO hippocampi showed impaired LTP in the SC-CA1 pathway. Reduced surface but not total expression of AMPARs in CPEB2-KO neurons led us to identify that CPEB2 enhanced the translation of GRASP1 mRNA to facilitate recycling and maintain the surface level of AMPARs. Ectopic expression of CPEB2 or GRASP1 in CA1 areas of CPEB2-cKO mouse hippocampi rescued long-term potentiation and spatial memory in the water maze test, so CPEB2-regulated GRASP1 mRNA translation is pivotal for AMPAR recycling, long-term plasticity and memory. Using the RNA immunoprecipitation-coupled microarray assay to genome-wide screen CPEB2-bound mRNAs, we identified VGLUT2 mRNA is one of top candidates bound to CPEB2. CPEB2 activated translation of VGLUT2 mRNA. The VGLUT2 protein level, presynaptic glutamate release probability and LTP in the SC-CA1 pathway were reduced in neuron-specific CPEB2-cKO hippocampi. Thus, CPEB2 plays an important role in glutamatergic signaling by promoting GRASP1 and VGLUT2 expression to control AMPAR recycling at postsynapses and glutamate loading into vesicles at presynapses.