STABILIZATION OF THE AMPA RECEPTORS BY EXTRACELLULAR PROTEINS: NEURONAL PENTRAXINS

AMPA receptors (AMPARs) mediate most fast excitatory synaptic neurotransmission in the brain. Anchoring AMPARs to specific postsynaptic sites facing neurotransmitter release is crucial for efficient synaptic function. While the mechanisms governing AMPARs accumulation at synapses have been intensely investigated due to their central role in learning and memory, most studies have focused on interactions with intracellular scaffolds. In contrast, the contribution of extracellular interactions remains poorly understood. In the search for extracellular AMPARs interactors, synaptic neuronal pentraxins (NPs) emerged as key candidates. NPs are presynaptically secreted proteins which bind AMPARs and promote their accumulation and clustering at synapses. Despite their critical role in excitatory synapse regulation and emerging links to synaptic disease, the mechanisms by which NPs engage AMPARs to promote synaptic stabilization remain poorly understood. To address this, we investigated the molecular and structural basis of the AMPAR-NP complex formation by combining fluorescence microscopy along with single particle tracking experiments. During our study, we discovered that these proteins bind to all AMPAR subunits, with a preference for the GluA4 subunit. They need to oligomerize to function as AMPAR crosslinkers and may primarily act on fast-spiking parvalbumin interneurons, which are enriched in the GluA4 subunit and regulate the timing and synchronization of neural circuits.