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Neuron. 2016 Feb 3;89(3):583-97. doi: 10.1016/j.neuron.2015.12.034. Epub 2016 Jan 21.

IGF-1 Receptor Differentially Regulates Spontaneous and Evoked Transmission via Mitochondria at Hippocampal Synapses.

Author information

1
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.
2
Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel.
3
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.
4
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.
5
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.

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.

PMID:
26804996
PMCID:
PMC4742535
DOI:
10.1016/j.neuron.2015.12.034
[Indexed for MEDLINE]
Free PMC Article

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