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Stepan, Jens; Heinz, Daniel E.; Dethloff, Frederik; Bajaj, Thomas; Zellner, Andreas; Hafner, Kathrin; Wiechmann, Svenja; Mackert, Sarah; Mecdad, Yara; Rabenstein, Michael; Ebert, Tim; Martinelli, Silvia; Haeusl, Alexander S.; Poehlmann, Maximilian L.; Hermann, Anke; Ma, Xiao; Pavenstaedt, Hermann; Schmidt, Mathias V.; Philipsen, Alexandra; Turck, Chris W.; Deussing, Jan M.; Kuster, Bernhard; Wehr, Michael C.; Stein, Valentin; Kremerskothen, Joachim; Wotjak, Carsten T. and Gassen, Nils C. (2022): Hippo-released WWC1 facilitates AMPA receptor regulatory complexes for hippocampal learning. In: Cell Reports, Vol. 41, No. 10, 111766

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Learning and memory rely on changes in postsynaptic glutamergic a-amino-3-hydroxy-5-methyl-4-isoxazo-lepropionic acid (AMPA)-type receptor (AMPAR) number, spatial organization, and function. The Hippo pathway component WW and C2 domain-containing protein 1 (WWC1) regulates AMPAR surface expression and impacts on memory performance. However, synaptic binding partners of WWC1 and its hierarchical po-sition in AMPAR complexes are largely unclear. Using cell-surface proteomics in hippocampal tissue of Wwc1-deficient mice and by generating a hippocampus-specific interactome, we show that WWC1 is a major regulatory platform in AMPAR signaling networks. Under basal conditions, the Hippo pathway members WWC1 and large tumor-suppressor kinase (LATS) are associated, which might prevent WWC1 effects on synaptic proteins. Reduction of WWC1/LATS binding through a point mutation at WWC1 elevates the abundance of WWC1 in AMPAR complexes and improves hippocampal-dependent learning and memory. Thus, uncoupling of WWC1 from the Hippo pathway to AMPAR-regulatory complexes provides an innovative strategy to enhance synaptic transmission.

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