Hippo-released WWC1 facilitates AMPA receptor regulatory complexes for hippocampal learning
Jens Stepan, Daniel E. Heinz, Frederik Dethloff, Thomas Bajaj, Andreas Zellner, Kathrin Hafner, Svenja Wiechmann, Sarah Mackert, Yara Mecdad, Michael Rabenstein, Tim Ebert, Silvia Martinelli, Alexander S. Häusl, M. Pöhlmann, Anke Hermann, Xiao Ma, Hermann Pavenstädt, Mathias V. Schmidt, Alexandra Philipsen, Chris W. Turck, Jan M. Deussing, Bernhard Küster, Michael C. Wehr, Valentin Stein, Joachim Kremerskothen, Carsten T. Wotjak, Nils C. Gassen
Abstract
Learning and memory rely on changes in postsynaptic glutamergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic 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 position 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.