Acute Fasting Regulates Retrograde Synaptic Enhancement through a 4E-BP-Dependent Mechanism

Neuron. 2016 Dec 21;92(6):1204-1212. doi: 10.1016/j.neuron.2016.10.063. Epub 2016 Dec 1.

Abstract

While beneficial effects of fasting on organismal function and health are well appreciated, we know little about the molecular details of how fasting influences synaptic function and plasticity. Our genetic and electrophysiological experiments demonstrate that acute fasting blocks retrograde synaptic enhancement that is normally triggered as a result of reduction in postsynaptic receptor function at the Drosophila larval neuromuscular junction (NMJ). This negative regulation critically depends on transcriptional enhancement of eukaryotic initiation factor 4E binding protein (4E-BP) under the control of the transcription factor Forkhead box O (Foxo). Furthermore, our findings indicate that postsynaptic 4E-BP exerts a constitutive negative input, which is counteracted by a positive regulatory input from the Target of Rapamycin (TOR). This combinatorial retrograde signaling plays a key role in regulating synaptic strength. Our results provide a mechanistic insight into how cellular stress and nutritional scarcity could acutely influence synaptic homeostasis and functional stability in neural circuits.

Keywords: 4E-BP; Fasting; Homeostatic synaptic plasticity; Regulation of Neurotransmitter release; Retrograde signaling; mTOR; postsynaptic translation.

MeSH terms

  • Animals
  • Drosophila Proteins / genetics*
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster
  • Fasting / metabolism*
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Muscle, Skeletal / metabolism*
  • Mutation
  • Neuromuscular Junction / metabolism*
  • Neuronal Plasticity / genetics
  • Peptide Initiation Factors / genetics*
  • Peptide Initiation Factors / metabolism
  • Protein Biosynthesis
  • Receptors, Ionotropic Glutamate / genetics
  • Ribosomal Protein S6 Kinases / genetics
  • Synaptic Transmission
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Drosophila Proteins
  • FOXO protein, Drosophila
  • Forkhead Transcription Factors
  • Intracellular Signaling Peptides and Proteins
  • Peptide Initiation Factors
  • Receptors, Ionotropic Glutamate
  • Thor protein, Drosophila
  • glutamate receptor IIA, Drosophila
  • TOR Serine-Threonine Kinases
  • Ribosomal Protein S6 Kinases