Distinct molecular pathways govern presynaptic homeostatic plasticity

Cell Rep. 2021 Dec 14;37(11):110105. doi: 10.1016/j.celrep.2021.110105.


Presynaptic homeostatic plasticity (PHP) stabilizes synaptic transmission by counteracting impaired neurotransmitter receptor function through neurotransmitter release potentiation. 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 transmission result in different responses at the Drosophila neuromuscular junction. While receptor inhibition by the glutamate receptor (GluR) antagonist γ-D-glutamylglycine (γDGG) is not compensated by PHP, the GluR inhibitors Philanthotoxin-433 (PhTx) and Gyki-53655 (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.

Keywords: Drosophila neuromuscular junction; Protein Kinase D; glutamate receptors; homeostatic plasticity; neurotransmitter release; synaptic transmission.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster
  • Excitatory Postsynaptic Potentials
  • Homeostasis*
  • Neuromuscular Junction / physiology
  • Neuronal Plasticity*
  • Neurotransmitter Agents / metabolism*
  • Presynaptic Terminals / physiology*
  • Receptors, Glutamate / chemistry
  • Receptors, Glutamate / genetics
  • Receptors, Glutamate / metabolism
  • Signal Transduction
  • Synapses / physiology*
  • Synaptic Transmission*


  • Drosophila Proteins
  • Neurotransmitter Agents
  • Receptors, Glutamate