THE N-TERMINAL GLUTAMATE RECEPTOR DOMAIN PROMOTES PRESYNAPTIC HOMEOSTATIC PLASTICITY

Synaptic transmission relies on precise molecular compartmentalization to enable fast, efficient, and plastic communication between neurons. Within individual synapses, pre- and postsynaptic proteins form nanoclusters that can align across the synaptic cleft to generate transsynaptic nanocolumns. We previously showed that acute glutamate receptor (GluR) impairment rapidly induces nanocolumn formation during presynaptic homeostatic plasticity (PHP) at the Drosophila NMJ, with postsynaptic GluR reorganization preceding presynaptic remodeling. However, the molecular mechanisms underlying GluR reorganization during PHP remain largely elusive. The extracellular N-terminal domain (NTD) of GluRs has been implicated in regulating receptor mobility. We therefore tested whether the GluR-NTD plays a role in GluR remodeling during PHP using STED microscopy at the Drosophila NMJ. Overexpression of a GluRIIC subunit lacking the NTD abolished postsynaptic GluR reorganization after pharmacological GluR perturbation, demonstrating that this domain is essential for receptor remodeling in response to homeostatic challenge. Presynaptic active zone remodeling was also disrupted, as evidenced by impaired Bruchpilot reorganization. Consistent with impaired structural plasticity, electrophysiological analysis revealed a failure to maintain action potential evoked excitatory postsynaptic currents following acute GluR blockade, indicating that GluR NTD-dependent GluR remodeling is required for PHP. Together, our findings implicate the GluR NTD in rapid synaptic nanoarchitecture remodeling and homeostatic release potentiation during PHP.