title: IGF-1 Receptor Differentially Regulates Spontaneous and Evoked Transmission via Mitochondria at Hippocampal Synapses.
abstract: The insulin-like growth factor-1 receptor (IGF-1R) signaling is a key regulator of lifespan, growth, and development. While reduced IGF-1R signaling delays aging and Alzheimer's disease progression, whether and how it regulates information processing at central synapses remains elusive. Here, we show that presynaptic IGF-1Rs are basally active, regulating synaptic vesicle release and short-term plasticity in excitatory hippocampal neurons. Acute IGF-1R blockade or transient knockdown suppresses spike-evoked synaptic transmission and presynaptic cytosolic Ca(2+) transients, while promoting spontaneous transmission and resting Ca(2+) level. This dual effect on transmitter release is mediated by mitochondria that attenuate Ca(2+) buffering in the absence of spikes and decrease ATP production during spiking activity. We conclude that the mitochondria, activated by IGF-1R signaling, constitute a critical regulator of information processing in hippocampal neurons by maintaining evoked-to-spontaneous transmission ratio, while constraining synaptic facilitation at high frequencies. Excessive IGF-1R tone may contribute to hippocampal hyperactivity associated with Alzheimer's disease.
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel; Sagol School of Neuroscience, Tel Aviv University, 69978 Tel Aviv, Israel.
authors.forename: Neta
authors.initials: N
authors.lastname: Gazit
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel.
authors.forename: Irena
authors.initials: I
authors.lastname: Vertkin
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel.
authors.forename: Ilana
authors.initials: I
authors.lastname: Shapira
authors.affiliation: Department of Neuro- and Sensory Physiology, Cluster of Excellence Nanoscale Microscopy and Molecular Physiology of the Brain, European Neuroscience Institute, University of Göttingen Medical Center, 37075 Göttingen, Germany; International Max Planck Research School Molecular Biology, 37077 Göttingen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Helm
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel.
authors.forename: Edden
authors.initials: E
authors.lastname: Slomowitz
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel.
authors.forename: Maayan
authors.initials: M
authors.lastname: Sheiba
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel; Sagol School of Neuroscience, Tel Aviv University, 69978 Tel Aviv, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Mor
authors.affiliation: Department of Neuro- and Sensory Physiology, Cluster of Excellence Nanoscale Microscopy and Molecular Physiology of the Brain, European Neuroscience Institute, University of Göttingen Medical Center, 37075 Göttingen, Germany.
authors.forename: Silvio
authors.initials: S
authors.lastname: Rizzoli
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel; Sagol School of Neuroscience, Tel Aviv University, 69978 Tel Aviv, Israel. Electronic address: islutsky@post.tau.ac.il.
authors.forename: Inna
authors.initials: I
authors.lastname: Slutsky
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology* / Q000502:physiology; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D051379:Mice; D055369:Miniature Postsynaptic Potentials / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000378:metabolism; D061251:Primary Cell Culture; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*; D013572:Synaptic Vesicles / Q000378:metabolism
chemical_list: D007334:Insulin-Like Growth Factor I; D000255:Adenosine Triphosphate; D017526:Receptor, IGF Type 1; D002118:Calcium