Hippo-released WWC1 facilitates AMPA receptor regulatory complexes for 
hippocampal learning

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, Max 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.; Gassen, Nils C.

doi:10.1016/j.celrep.2022.111766

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Hippo-released WWC1 facilitates AMPA receptor regulatory complexes for hippocampal learning

MPS-Authors

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Stepan, Jens
Dept. Genes and Environment, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons222127

Heinz, Daniel E.
RG Neuronal Plasticity, Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons97120

Dethloff, Frederik
Dept. Genes and Environment, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons160195

Zellner, Andreas
Dept. Genes and Environment, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80351

Hafner, Kathrin
Dept. Genes and Environment, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons263391

Ebert, Tim
RG Neuronal Plasticity, Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons222053

Martinelli, Silvia
Dept. Genes and Environment, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons135680

Haeusl, Alexander S
RG Stress Resilience, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons135519

Poehlmann, Max L.
RG Stress Resilience, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80514

Schmidt, Mathias V.
RG Stress Resilience, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80561

Turck, Chris W.
RG Proteomics and Biomarkers, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80301

Deussing, Jan M.
RG Molecular Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80598

Wotjak, Carsten T.
RG Neuronal Plasticity, Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80333

Gassen, Nils C.
Dept. Genes and Environment, Max Planck Institute of Psychiatry, Max Planck Society;

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Citation

Stepan, J., Heinz, D. E., Dethloff, F., Bajaj, T., Zellner, A., Hafner, K., et al. (2022). Hippo-released WWC1 facilitates AMPA receptor regulatory complexes for hippocampal learning. CELL REPORTS, 41(10): 111766. doi:10.1016/j.celrep.2022.111766.

Cite as: https://hdl.handle.net/21.11116/0000-000C-CF46-D

Abstract

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.