title: Acute Fasting Regulates Retrograde Synaptic Enhancement through a 4E-BP-Dependent Mechanism.
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.
authors.affiliation: Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors.forename: Grant
authors.initials: G
authors.lastname: Kauwe
authors.affiliation: Buck Institute for Research on Aging, Novato, CA 94945, USA; Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Tsurudome
authors.affiliation: Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Jay
authors.initials: J
authors.lastname: Penney
authors.affiliation: Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors.forename: Megumi
authors.initials: M
authors.lastname: Mori
authors.affiliation: Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Gray
authors.affiliation: Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors.forename: Mario R
authors.initials: MR
authors.lastname: Calderon
authors.affiliation: Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Fatima
authors.initials: F
authors.lastname: Elazouzzi
authors.affiliation: Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Chicoine
authors.affiliation: Department of Biochemistry and Cancer Center, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
authors.affiliation: Buck Institute for Research on Aging, Novato, CA 94945, USA; Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada. Electronic address: phaghighi@buckinstitute.org.
authors.forename: A Pejmun
authors.initials: AP
authors.lastname: Haghighi
mesh_terms: D000818:Animals; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster; D005215:Fasting / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D009154:Mutation; D009469:Neuromuscular Junction / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000235:genetics; D010448:Peptide Initiation Factors / Q000235:genetics* / Q000378:metabolism; D014176:Protein Biosynthesis; D058468:Receptors, Ionotropic Glutamate / Q000235:genetics; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics; D009435:Synaptic Transmission; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; C477334:FOXO protein, Drosophila; D051858:Forkhead Transcription Factors; D047908:Intracellular Signaling Peptides and Proteins; D010448:Peptide Initiation Factors; D058468:Receptors, Ionotropic Glutamate; C410006:Thor protein, Drosophila; C000618220:glutamate receptor IIA, Drosophila; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases
keywords: 4E-BP; Fasting; Homeostatic synaptic plasticity; Regulation of Neurotransmitter release; Retrograde signaling; mTOR; postsynaptic translation