RABPHILIN-3A AS A POSITIVE SYNAPTIC TAG LINKING NMDAR RETENTION TO SYNAPSE-TO-NUCLEUS SIGNALLING

Synaptic-retained NMDA receptor (NMDAR) complexes function as signalling hubs that couple neuronal activation to transcriptional regulation through synapse-to-nucleus communication. Within this framework, Rabphilin-3A (Rph3A), a synaptic protein that directly binds the GluN2A subunit of the NMDAR, has emerged as a candidate positive synaptic tag. Rph3A is selectively enriched at potentiated dendritic spines, where it is required for NMDAR synaptic retention, long-term potentiation (LTP), and spine formation, suggesting a crucial role in the selective stabilization of activated synapses.
The aim of this work is to elucidate how Rph3A functions within synaptic NMDAR complexes to coordinate synapse-to-nucleus signalling and soma-to-synapse feedback, thereby supporting input-specific structural plasticity. Using immunocytochemistry, molecular, and biochemical approaches in primary hippocampal rat neurons, we show how Rph3A plays a key role in coordinating synaptonuclear messengers triggered by NMDAR activation. These findings further support the hypothesis that Rph3A acts as a positive synaptic tag in glutamatergic neurons, linking local synaptic activity to long-range nuclear responses and synapse-specific plasticity.