Photoactivated Protein Degrader for Optical Control of Synaptic Function

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Synaptic function relies on numerous proteins, crucial for neuronal circuits and brain functions.
• Precise manipulation of specific proteins in space and time is essential for understanding their roles.

Purpose of the Study:

• To develop and validate a novel photochemical strategy, PHOTACs, for precise, light-inducible protein degradation.
• To investigate the role of CaMKIIα in synaptic function using this new degradation technology.

Main Methods:

• Designed and synthesized PHOTACs, small molecules that trigger protein degradation upon light activation.
• Utilized a CaMKIIα- PHOTAC to optically degrade CaMKIIα in mouse brain tissue.
• Measured changes in synaptic function via field excitatory postsynaptic potential (fEPSP) after light-induced degradation.

Main Results:

• Demonstrated effective, spatially precise degradation of CaMKIIα in mouse hippocampus using CaMKIIα-PHOTAC.
• Observed rapid (within minutes) and significant decrease in synaptic function following light activation.
• Confirmed degradation was localized to within 25 μm of the illuminated surface.

Conclusions:

• PHOTACs offer a powerful tool for high-resolution spatiotemporal control of protein levels in biological systems.
• This method enables precise investigation of protein function in synaptic plasticity, long-term potentiation, and memory formation.
• The PHOTACs strategy is broadly applicable to studying other key proteins in neuroscience research.