Distinct molecular pathways govern presynaptic homeostatic plasticity

Abstract

SummaryPresynaptic homeostatic plasticity (PHP) stabilizes synaptic transmission by counteracting impaired neurotransmitter receptor function through increased presynaptic release. PHP is thought to be triggered by impaired receptor function, and to involve a stereotypic signaling pathway. However, here we demonstrate that different receptor perturbations that similarly reduce synaptic activity result in vastly different responses at the Drosophila neuromuscular junction. While receptor inhibition by the glutamate receptor (GluR) antagonist γ-DGG is not compensated by PHP, the GluR inhibitors PhTx-433 and Gyki induce compensatory PHP. Intriguingly, PHP triggered by PhTx and Gyki involve separable signaling pathways, including inhibition of distinct GluR subtypes, differential modulation of the active-zone scaffold Bruchpilot, and short-term plasticity. Moreover, while PHP upon Gyki treatment does not require genes promoting PhTx-induced PHP, it involves presynaptic Protein Kinase D. Thus, synapses not only respond differentially to similar activity impairments, but achieve homeostatic compensation via distinct mechanisms, highlighting the diversity of homeostatic signaling.