Competing presynaptic protein assemblies coordinate basal neurotransmission with homeostatic plasticity

Neural circuits establish a stable basal level of synaptic transmission that is maintained throughout life. When synaptic activity is perturbed, homeostatic mechanisms restore this set point, but how neurons reconcile long-term stability and rapid compensatory plasticity remains unclear. Here, we identify two competing presynaptic multimolecular complexes that control steady-state transmission and homeostatic potentiation and define the molecular switch that enables transitions between these functional states. At Drosophila neuromuscular junction, the transmembrane protein PlexinB (PlexB) and the auxiliary subunit Neto-α regulate both basal synaptic function and homeostatic plasticity. PlexB association with presynaptic KaiR1D/Neto-α receptor complexes modulates channel properties and fine-tunes neurotransmitter release, whereas PlexB signaling with Semaphorin2b (Sema2b) and Neto-α drives homeostatic potentiation. KaiR1D and Sema2b/PlexB compete for a limited pool of presynaptic Neto-α. Motor neurons switch from steady-state transmission to homeostatic potentiation by exchanging KaiR1D/Neto-α/PlexB complexes for Neto-α/PlexB/Sema2b. Critically, Neto-α must dissociate from KaiR1D-containing complexes to initiate the homeostatic response. Variants of Neto-α or KaiR1D that fail to dissociate support normal basal neurotransmission but abolish homeostatic plasticity. These findings demonstrate that dynamic reorganization of competing presynaptic protein assemblies enables neurons to preserve stable baseline transmission while mounting robust compensatory responses to perturbations. Given the widespread roles of presynaptic receptors and Semaphorin/Plexin signaling in synaptic regulation, this mechanism may represent a conserved strategy for balancing stability and plasticity in neural circuits.