Excess glutamate release triggers subunit-specific homeostatic receptor scaling

Abstract

ABSTRACTIonotropic glutamate receptors (GluRs) are targets for modulation in Hebbian and homeostatic synaptic plasticity and are remodeled by development, experience, and disease. Although much is known about activity-dependent mechanisms that regulate GluR composition and abundance, the role of glutamate itself in these processes is unclear. To determine how glutamate sculpts GluR receptive fields, we have manipulated synaptically released glutamate and generated precise CRISPR mutations in the two postsynaptic GluR subtypes at the Drosophila neuromuscular junction, GluRA and GluRB. We first demonstrate that GluRA and GluRB compete to establish postsynaptic receptive fields, and that proper GluR abundance and localization can be orchestrated in the absence of any synaptic glutamate release. However, excess glutamate release adaptively tunes postsynaptic GluR abundance, echoing GluR receptor scaling observed in mammalian systems. Unexpectedly, when GluRA vs GluRB competition is eliminated, excess glutamate homeostatically regulates GluRA abundance, while GluRB abundance is now insensitive to glutamate modulation. Finally, Ca2+ impermeable GluRA receptors are no longer sensitive to homeostatic regulation by glutamate. Thus, excess glutamate, GluR competition, and Ca2+ signaling collaborate to selectively target GluR subtypes for homeostatic regulation at postsynaptic compartments.