Hippo-Released WWC1 Primes Ampa Receptor Regulatory Complexes for Hippocampal Learning

Learning and memory rely on changes in postsynaptic AMPA-type glutamate receptor (AMPA receptor) number, spatial organization and function. The Hippo pathway component WWC1 regulates AMPA receptor surface expression and impacts on memory performance. However, synaptic binding partners of WWC1 and its hierarchical position in AMPA receptor complexes are largely unknown. 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 AMPA receptor signalling networks. Interaction of the Hippo pathway members WWC1 and LATS limited the impact of WWC1 on synaptic proteins. Truncation of WWC1/LATS-binding through a point mutation at WWC1 elevated the abundance of WWC1 in AMPA receptor complexes and improved hippocampal-dependent learning and memory. Thus, relocation of WWC1 from the Hippo-pathway to AMPA receptor regulatory complexes provides an innovative strategy for the treatment of cognitive impairments.