Ph.D. University of Texas Southwestern Medical Center at Dallas
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.
The ability for mammals to navigate and find the way home depends on hippocampal plasticity. Lu et al. show that CPEB2-activated GRASP1 mRNA translation is critical for surface AMPAR expression and spatial memory. Stone walkways, trees, flowers and leaves resemble hippocampus, pyramidal neurons, surface and total AMPARs, respectively. The CPEB2-knockout neuron with reduced GRASP1 and surface AMPARs (light brown trunk and few flowers) impairs the mouse’s memory to find home. The swimming trace inside the sun symbolizes the consolidated spatial memory in Morris water maze.
Artwork by Ya-Shu Chang (張雅舒).