Sushi domain-containing protein 4 controls synaptic plasticity and motor learning

Description

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.

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Agence Nationale de la Recherche ANR 9139SAMA90010901

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Agence Nationale de la Recherche ANR-15-CE37-0001-01

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ATIP-AVENIR RSE11005JSA

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Ecole des Neurosciences de Paris

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Fondation pour la Recherche Medicale DEQ20150331748

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Fondation pour la Recherche Medicale DEQ20140329514

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H2020 European Research Council SynID 724601

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Idex PSL ANR-10-IDEX-0001-02 PSL*

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Labex ANR-11-IDEX-0004-02

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Labex Memolife ANR-10-LABX-54

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