Nonionic signaling rapidly remodels postsynaptic DLG to induce retrograde homeostatic plasticity

Synapses must be resilient to the challenges they confront during development, experience, disease, and aging. A conserved form of adaptive plasticity, observed at the glutamatergic <i>Drosophila</i> neuromuscular junction (NMJ), is expressed following acute pharmacological blockade of postsynaptic glutamate receptors (GluRs). This challenge is counteracted by enhanced presynaptic neurotransmitter release to maintain stable synaptic strength. This retrograde form of homeostatic plasticity is termed presynaptic homeostatic potentiation (PHP). How retrograde PHP signaling is acutely induced in the postsynaptic compartment is unknown. Here, we demonstrate that acute PHP induction does not require reductions in ionic flow through GluRs. Rather, pharmacological blockade provokes nanoscale changes in GluR organization that propagates remodeling of the postsynaptic apparatus. These postsynaptic structural changes are necessary for the presynaptic remodeling that characterizes PHP, including enhanced active zone intensity. Next, using a CRISPR-based genetic screen, we identify Discs large (DLG), the fly homolog of mammalian PSD-95, as a key postsynaptic substrate selectively required for acute PHP signaling. Finally, we find that homeostatic remodeling of both pre- and postsynaptic compartments persists in the absence of synaptic activity. Together, we propose that acute pharmacological perturbation of GluRs triggers activity-independent conformational signaling that is propagated throughout the postsynaptic apparatus, transmitting retrograde information that rapidly induces PHP.