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

Abstract

SummaryThe 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.Video Abstract

Stress-altered synaptic plasticity and DAMP signaling in the hippocampus-PFC axis; elucidating the significance of IGF-1/IGF-1R/CaMKIIα expression in neural changes associated with a prolonged exposure therapy

“…Furthermore, a blockade of IGF-1 reduced the activity of IGF-1R. This implied that a basal IGF-1R activity exist and is activated by intrinsic IGF-1 concentration during hippocampal synaptic function (Adams et al, 2000; Yamaguchi et al, 1990 as cited by Gazit et al, 2016). Since IGF-1R directly mediates the activity of synaptophysin, we investigated the significance of a change in IGF-1R on other presynaptic proteins involved in neurotransmitter synthesis and function.…”

“…Although our study addressed basic relationship between synaptophysin and IGF-1R expression (Fig. 3I–L), a recent study elaborately showed the role of hippocampal IGF-1R in real-time regulation of synaptic function and presynaptic vesicle release (Gazit et al, 2016). Their results demonstrate that pharmacological inhibition or a genetic knock down of IGF-1R reduced synaptophysin expression, and significantly reduced presynaptic activity.…”

Progressive Decrease of Mitochondrial Motility during Maturation of Cortical Axons In Vitro and In Vivo

“…To measure the functionality of mitochondria under these conditions, we imaged mitochondrial membrane potential via tetramethylrhodamine (TMRM, [14]) and mitochondrial matrix calcium dynamics during action potential (AP) evoked neurotransmitter release using a genetically-encoded, matrix-targeted calcium indicator GCaMP5G (mito-GCaMP5G) [15]. Mitochondrial membrane potential is generated via the proton gradient, resulting from oxidative phosphorylation along the electron transport chain (ETC), across the inner mitochondrial membrane (IMM) which gates ATP generation.…”

Mitochondrial Aspects of Synaptic Dysfunction in Alzheimer’s Disease

“…Mitochondria are the principal producers of cellular energy, and thus are crucial for neuronal function and survival. Mitochondrial ATP production sustains various essential functions at synapses such as: 1) maintaining ion gradients across the cellular membrane, which is required for axonal and synaptic membrane potentials [1]; 2) mobilizing synaptic vesicles from reserve pools to release sites [2]; 3) supporting synaptic vesicle release and recycling [3–5]; 4) supporting synaptic assembly and plasticity [6, 7]. …”