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

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 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. [Display omitted] •Presynaptic IGF-1Rs are basally active in hippocampal neurons•IGF-1R tone enhances evoked transmission, while inhibiting spontaneous transmission•Mitochondrion is a differential regulator of synaptic transmission by IGF-1Rs•IGF-1R tone buffers resting Ca2+ and maintains ATP levels during spiking activity Gazit et al. demonstrate that presynaptic IGF-1R tone enhances evoked while suppressing spontaneous synaptic vesicle release in hippocampal neurons. Mitochondria, activated by IGF-1Rs, constitute a differential regulator of information processing by maintaining evoked-to-spontaneous transmission ratio, while constraining synaptic high-pass filtering.