IGF-1 receptor regulates upward firing rate homeostasis via the mitochondrial calcium uniporter

Abstract

Regulation of firing rate homeostasis constitutes a fundamental property of central neural circuits. While intracellular Ca 2+ has long been hypothesized to be a feedback control signal, the molecular machinery enabling a network-wide homeostatic response remains largely unknown. We show that deletion of insulin-like growth factor-1 receptor (IGF-1R) limits firing rate homeostasis in response to inactivity, without altering the distribution of baseline firing rates. The deficient firing rate homeostatic response was due to disruption of both postsynaptic and intrinsic plasticity. At the cellular level, we detected a fraction of IGF-1Rs in mitochondria, colocalized with the mitochondrial calcium uniporter complex (MCUc). IGF-1R deletion suppressed transcription of the MCUc members and burst-evoked mitochondrial Ca 2+ (mitoCa 2+ ) by weakening mitochondria-to-cytosol Ca 2+ coupling. Overexpression of either mitochondria-targeted IGF-1R or MCUc in IGF-1R–deficient neurons was sufficient to rescue the deficits in burst-to-mitoCa 2+ coupling and firing rate homeostasis. Our findings indicate that mitochondrial IGF-1R is a key regulator of the integrated homeostatic response by tuning the reliability of burst transfer by MCUc. Based on these results, we propose that MCUc acts as a homeostatic Ca 2+ sensor. Faulty activation of MCUc may drive dysregulation of firing rate homeostasis in aging and in brain disorders associated with aberrant IGF-1R/MCUc signaling.

Mitochondrial calcium modulates odor-mediated behavioral plasticity inC. elegans

“…Taken together, we conclude that MCU-mediated calcium influx, as well as NLP-1 secretion, takes place at the end of odor conditioning, likely at the time of AWC calcium transient upon odor removal. This is consistent with the observations made so far in neurons that mitochondrial calcium increase occurs synchronously with cytoplasmic calcium increase 37 .…”

“…This suggests that mitochondrial calcium entry may act as a duration sensor for sensory stimulation. Simultaneous imaging of cytoplasmic and mitochondrial calcium in neurons show mitochondrial calcium influx occurs concurrently with cytoplasmic calcium increase 37 . Concurrent cytoplasmic and mitochondrial calcium elevation is the norm for most tissues, as there is a minimum threshold of surrounding calcium that needs to be reached for the MCU pore to open 38 .…”

“…Simultaneous imaging of cytoplasmic and mitochondrial calcium in neurons show mitochondrial calcium influx occurs concurrently with cytoplasmic calcium increase 37 .…”

The Role of Insulin-like Growth Factor I in Mechanisms of Resilience and Vulnerability to Sporadic Alzheimer’s Disease

“…Thus, IGF-I is involved in physiological synaptogenesis during development [56], in adult brains [57], and in synapse repletion after an insult [58]. Importantly, dendritic spines, a major site of cortical synapses, provide AD resilience [46], while IGF-I promotes dendritogenesis [59] and is intricately involved in synaptic physiology [60,61].…”

Opposite effects of acute and chronic IGF1 on rat dorsal root ganglion neuron excitability

“…IGF-1 binds with high affinity to the IGF-1 receptor (IGF-1R) and with lower affinity to the insulin receptor ( Hakuno and Takahashi, 2018 ). In the central nervous system (CNS), IGF-1R signaling regulates a variety of crucial functions including neurogenesis, axonal growth, brain development and aging, neural metabolism, as well as neuronal excitability, excitatory and inhibitory synaptic transmission or homeostatic plasticity ( Nilsson et al, 1988 ; Castro-Alamancos and Torres-Aleman, 1993 ; Kenyon et al, 1993 ; D’Ercole et al, 1996 ; Seto et al, 2002 ; Holzenberger et al, 2003 ; Tropea et al, 2006 ; Kenyon, 2010 ; Fernandez and Torres-Aleman, 2012 ; Maya-Vetencourt et al, 2012 ; Gazit et al, 2016 ; Noriega-Prieto et al, 2021 ; Katsenelson et al, 2022 ). In addition to their presence in the CNS, IGF-1 and IGF-IR are also expressed in the peripheral nervous system, notably in the sensory dorsal root ganglion (DRG) nociceptive neurons that convey pain modalities.…”