Phase separation in the multi-compartment organization of synapses

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Neuronal synapses, the communication junctions between neurons, feature intricate compartmentalization at micro- and nano-scales.
• These compartments, including presynaptic boutons and postsynaptic spines, possess distinct molecular organizations and functions.
• Understanding the mechanisms governing this fine-scale organization is crucial for comprehending synaptic function and plasticity.

Purpose of the Study:

• To review recent findings on how phase separation contributes to the formation and coexistence of molecular condensates within neuronal synapses.
• To elucidate the role of phase separation in organizing presynaptic and postsynaptic compartments.
• To highlight the functional implications of phase separation in synaptic transmission and plasticity.

Main Methods:

• This review synthesizes data from numerous recent studies.
• It focuses on research demonstrating the principles of multivalent protein-protein interactions.
• The review examines evidence for phase separation driving condensate formation in synaptic microdomains.

Main Results:

• Multivalent protein-protein interactions and subsequent phase separation are key mechanisms underlying synaptic compartmentalization.
• In postsynapses, phase separation enables the clustering of neurotransmitter receptors into specific nanodomains, influencing postsynaptic density regulation and plasticity.
• In presynapses, phase separation facilitates the organization of synaptic vesicles into distinct pools, impacting activity-induced neurotransmitter release.

Conclusions:

• Phase separation is a fundamental biophysical process critical for establishing and maintaining molecular organization within neuronal synapses.
• This mechanism allows for the formation of multiple, distinct molecular condensates, enabling specialized functions in both pre- and postsynaptic compartments.
• The regulation of synaptic function, including plasticity and neurotransmitter release, is intricately linked to phase separation-driven synaptic organization.