Molecular organization of central cholinergic synapses

Area of Science:

• Neuroscience
• Molecular Biology
• Developmental Biology

Background:

• Synaptic diversity and adaptation are crucial for central nervous system complexity.
• Nicotinic acetylcholine receptors (nAChRs) are widespread in metazoan brains, but their associated protein networks are poorly understood.
• Understanding nAChR molecular architecture is key to deciphering brain evolution.

Purpose of the Study:

• To generate subunit-specific proteomic maps of nAChR interactomes in developing and mature *Drosophila* brains.
• To investigate the developmental changes and plasticity of nAChR-associated protein networks.
• To identify key regulators of cholinergic synapse development and maintenance.

Main Methods:

• Utilized in vivo proximity labeling to map nAChR interactomes.
• Performed proteome profiling with genetic perturbations (e.g., subunit removal).
• Investigated the role of the Rho-GTPase regulator Still life (Sif).

Main Results:

• Revealed a developmental expansion and reconfiguration of the nAChR interactome in *Drosophila* brains.
• Demonstrated that removing nAChR subunits induces compensatory shifts in receptor subtypes, indicating synaptic plasticity.
• Identified Still life (Sif) as a critical organizer of cholinergic synapses, with its loss disrupting synaptic structure and composition.

Conclusions:

• Provided novel molecular insights into the development and plasticity of central cholinergic synapses.
• Advanced understanding of how synaptic identity is conserved and diverges across species.
• Highlighted the importance of nAChR interactome dynamics in synaptic function and evolution.