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

Area of Science:

• Neuroscience
• Molecular Biology
• Synaptic Plasticity

Background:

• Precise control of protein levels (proteostasis) at synapses is crucial for brain function and plasticity.
• Mechanisms for synapse-specific and activity-dependent regulation of synaptic protein proteostasis remain largely unknown.

Purpose of the Study:

• To investigate the role of the gene Susd4, encoding a complement-related transmembrane protein, in synaptic function and proteostasis.
• To elucidate the molecular mechanisms by which Susd4 influences synaptic plasticity and neuronal development.

Main Methods:

• Generated and analyzed constitutive loss-of-function Susd4 mouse models.
• Assessed motor coordination, learning, and cerebellar synaptic plasticity (long-term depression).
• Investigated the regulation of AMPA receptor subunit GluA2 degradation.
• Identified SUSD4 binding partners using biochemical approaches, including ubiquitin ligases.

Main Results:

• Constitutive loss of Susd4 in mice resulted in impaired motor coordination adaptation and learning.
• Susd4 deficiency prevented long-term depression at cerebellar synapses.
• Loss of Susd4 led to misregulation of activity-dependent degradation of the AMPA receptor subunit GluA2.
• SUSD4 was identified as a binding partner for NEDD4 subfamily ubiquitin ligases involved in AMPA receptor turnover.

Conclusions:

• Susd4 plays a critical role in maintaining synaptic proteostasis, particularly regulating AMPA receptor turnover.
• Susd4 is essential for cerebellar synaptic plasticity, motor learning, and coordination.
• Findings suggest that Susd4 mutations may contribute to neurodevelopmental diseases.