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

ABSTRACT: 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.

SUBMITTER: Gonzalez-Calvo I

PROVIDER: S-EPMC7972451 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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

González-Calvo Inés I Iyer Keerthana K Carquin Mélanie M Khayachi Anouar A Giuliani Fernando A FA Sigoillot Séverine M SM Vincent Jean J Séveno Martial M Veleanu Maxime M Tahraoui Sylvana S Albert Mélanie M Vigy Oana O Bosso-Lefèvre Célia C Nadjar Yann Y Dumoulin Andréa A Triller Antoine A Bessereau Jean-Louis JL Rondi-Reig Laure L Isope Philippe P Selimi Fekrije F

eLife 20210304

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 <i>Susd4</i>, 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 <i>Susd4</i> in the mouse impairs motor coordina ...[more]

PMID: 33661101

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Project description:Gilles de la Tourette syndrome is a neuropsychiatric disorder characterized by motor and phonic tics that can be considered motor responses to preceding inner urges. It has been shown that Tourette patients have inferior performance in some motor learning tasks and reduced synaptic plasticity induced by transcranial magnetic stimulation. However, it has not been investigated whether altered synaptic plasticity is directly linked to impaired motor skill acquisition in Tourette patients. In this study, cortical plasticity was assessed by measuring motor-evoked potentials before and after paired associative stimulation in 14 Tourette patients (13 male; age 18-39) and 15 healthy controls (12 male; age 18-33). Tic and urge severity were assessed using the Yale Global Tic Severity Scale and the Premonitory Urges for Tics Scale. Motor learning was assessed 45 minutes after inducing synaptic plasticity and 9 months later, using the rotary pursuit task. On average, long-term potentiation-like effects in response to the paired associative stimulation were present in healthy controls but not in patients. In Tourette patients, long-term potentiation-like effects were associated with more and long-term depression-like effects with less severe urges and tics. While motor learning did not differ between patients and healthy controls 45 minutes after inducing synaptic plasticity, the learning curve of the healthy controls started at a significantly higher level than the Tourette patients' 9 months later. Induced synaptic plasticity correlated positively with motor skills in healthy controls 9 months later. The present study confirms previously found long-term improvement in motor performance after paired associative stimulation in healthy controls but not in Tourette patients. Tourette patients did not show long-term potentiation in response to PAS and also showed reduced levels of motor skill consolidation after 9 months compared to healthy controls. Moreover, synaptic plasticity appears to be related to symptom severity.

Dataset Information

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

Publications

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

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