Fine control of protein stoichiometry at synapses underlies brain function and plasticity. How proteostasis is controlled independently for each type of synaptic protein in a synapse-specific and activity-dependent manner remains unclear. Here, we show that Susd4, a gene coding for a complement-related transmembrane protein, is expressed by many neuronal populations starting at the time of synapse formation. Constitutive loss-of-function of Susd4 in the mouse impairs motor coordination adaptation and learning, prevents long-term depression at cerebellar synapses, and leads to misregulation of activity-dependent AMPA receptor subunit GluA2 degradation. We identified several proteins with known roles in the regulation of AMPA receptor turnover, in particular ubiquitin ligases of the NEDD4 subfamily, as SUSD4 binding partners. Our findings shed light on the potential role of SUSD4 mutations in neurodevelopmental diseases.Agence Nationale de la Recherche ANR 9139SAMA90010901Agence Nationale de la Recherche ANR-15-CE37-0001-01ATIP-AVENIR RSE11005JSAEcole des Neurosciences de ParisFondation pour la Recherche Medicale DEQ20150331748Fondation pour la Recherche Medicale DEQ20140329514H2020 European Research Council SynID 724601Idex PSL ANR-10-IDEX-0001-02 PSL*Labex ANR-11-IDEX-0004-02Labex Memolife ANR-10-LABX-5
