101. LARGE, an AMPA receptor interactor, plays a large role in long-term memory formation by driving homeostatic scaling-down
- Author
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Kathryn A. Cunningham, Thomas A. Green, Kelly T. Dineley, Daniel Z. Lee, Seong-Wook Kim, Ho Min Kim, Bo-Young Lee, Hee-Sup Shin, Taesup Cho, Bo Am Seo, Hwa Young Lee, Myoung-Goo Kang, Se-Young Choi, and Joong-jae Lee
- Subjects
Gene knockdown ,Long-term memory ,Chemistry ,musculoskeletal, neural, and ocular physiology ,Glutamate receptor ,Long-term potentiation ,AMPA receptor ,Golgi apparatus ,symbols.namesake ,nervous system ,symbols ,Interactor ,Neuroscience ,Homeostasis - Abstract
Dynamic trafficking of AMPA-type glutamate receptor (AMPA-R) in neuronal cells is a key cellular mechanism for learning and memory in the brain, which is regulated by AMPA-R interacting proteins. LARGE, a protein associated with intellectual disability, was found to be a novel component of the AMPA-R protein complex in our proteomic study. Here, our functional study of LARGE showed that during homeostatic scaling-down, increased LARGE expression at the Golgi apparatus (Golgi) negatively controlled AMPA-R trafficking from the Golgi to the plasma membrane, leading to downregulated surface and synaptic AMPA-R targeting. In LARGE knockdown mice, long-term potentiation (LTP) was occluded by synaptic AMPA-R overloading, resulting in impaired long-term memory formation. These findings indicate that the fine-tuning of AMPA-R trafficking by LARGE at the Golgi is critical for memory stability in the brain. Our study thus provides novel insights into the pathophysiology of brain disorders associated with intellectual disability.
- Published
- 2017
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