Gazit, NetaNetaGazitVertkin, IrenaIrenaVertkinShapira, IlanaIlanaShapiraHelm, MartinMartinHelmSlomowitz, EddenEddenSlomowitzSheiba, MaayanMaayanSheibaMor, YaelYaelMorRizzoli, SilvioSilvioRizzoliSlutsky, InnaInnaSlutsky2018-11-072018-11-072016https://resolver.sub.uni-goettingen.de/purl?gro-2/41418The 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 Ca2+ transients, while promoting spontaneous transmission and resting Ca2+ level. This dual effect on transmitter release is mediated by mitochondria that attenuate Ca2+ 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.CC BY-NC-ND 4.0https://creativecommons.org/licenses/by-nc-nd/4.0journal_article10.1016/j.neuron.2015.12.03426804996000373564900016https://resolver.sub.uni-goettingen.de/purl?gs-1/13240