CPEB2 Activates GRASP1 mRNA Translation and Promotes AMPA Receptor Surface Expression, Long-Term Potentiation, and Memory

Summary: Activity-dependent synthesis of plasticity-related proteins is necessary to sustain long-lasting synaptic modifications and consolidate memory. We investigated the role of the translational regulator cytoplasmic polyadenylation element binding protein 2 (CPEB2) in learning and memory because regulated mRNA translation contributes to synaptic plasticity. Forebrain-restricted CPEB2 conditional knockout (cKO) mice exhibited impaired hippocampus-dependent memory in contextual fear conditioning and Morris water maze tests. CPEB2 cKO hippocampi showed impaired long-term potentiation in the Schaffer collateral-CA1 pathway. Reduced surface, but not total, expression of AMPA receptors (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 a water maze test. Thus, CPEB2-regulated GRASP1 mRNA translation is pivotal for AMPAR recycling, long-term plasticity, and memory. : Lu et al. report that forebrain-specific deletion of CPEB2 in mice impaired hippocampus-dependent synaptic plasticity and long-term memory. CPEB2 activated GRASP1 mRNA translation to support AMPA receptor recycling and surface expression. Ectopic expression of CPEB2 or GRASP1 in hippocampal CA1 neurons sufficiently rescued memory loss. Keywords: AMPAR trafficking, CPEB2, GRASP1, long-term potentiation, memory, translational contro