A Photoactivated Protein Degrader for Optical Control of Synaptic Function.

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Synaptic function relies on hundreds of proteins, crucial for brain circuits and behavior.
• Precise manipulation of specific proteins at subcellular locations and times is essential for understanding their roles.
• Ca2+/calmodulin-dependent protein kinase II alpha (CaMKIIα) is vital for excitatory neuron synaptic function.

Approach:

• Developed PHOtochemically TArgeting Chimeras (PHOTACs) for precise, light-induced protein degradation.
• Designed and characterized a PHOTAC targeting CaMKIIα (CaMKIIα-PHOTAC).
• Validated the CaMKIIα-PHOTAC in mouse brain tissue, demonstrating spatial and temporal control.

Key Points:

• CaMKIIα-PHOTAC selectively degraded CaMKIIα within 25 μm of illuminated areas in the mouse hippocampus.
• Optical activation of CaMKIIα-PHOTAC rapidly impaired synaptic function within minutes.
• Measured synaptic function by observing the light-initiated attenuation of evoked field excitatory postsynaptic potential (fEPSP) responses.

Conclusions:

• PHOTACs offer a powerful tool for optically controlling protein levels with high spatial and temporal resolution.
• This methodology enables precise investigation of protein functions in synaptic plasticity and memory formation.
• The PHOTAC strategy is broadly applicable to studying other key proteins in neuronal function.