Calcium-dependent synaptic proteomics reveals EGFR signaling at active synapses

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Synapses are dynamic structures that change protein composition with neural activity.
• Activity-dependent processes are vital for synaptic maturation and neural circuit plasticity.
• Studying active synapses is difficult due to their transient and sparse nature, limiting proteomic analysis.

Purpose of the Study:

• To develop a method for selectively labeling proteins at active synapses.
• To identify novel proteins involved in activity-dependent synaptic remodeling.
• To elucidate the molecular mechanisms linking synaptic activity to synaptic maturation.

Main Methods:

• Developed a synapse-targeted calcium-dependent biotin ligase (synaptic Cal-ID) to label proteins at active synapses.
• Utilized synaptic Cal-ID to analyze the activity-dependent synaptic proteome in cultured neurons and mouse brains.
• Identified and characterized novel synaptic proteins using proteomic and molecular biology techniques.

Main Results:

• Identified two previously uncharacterized synaptic proteins, Anks1a and Ubash3b.
• Demonstrated that Anks1a and Ubash3b are rapidly recruited to active synapses.
• Showed that Anks1a and Ubash3b cooperatively enhance EGF receptor (EGFR) accumulation and signaling at synapses, supporting synaptic maturation.

Conclusions:

• Synaptic Cal-ID is an effective tool for studying activity-dependent synaptic proteomes.
• Activity-dependent EGFR signaling is a key mechanism linking synaptic activity to synaptic remodeling and maturation.
• Calcium-dependent activity rapidly reorganizes synaptic signaling machinery to regulate local synaptic function.