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

Maxim Katsenelson, Ilana Shapira, Eman Abbas, Kristina Jevdokimenko, Boaz Styr, Antonella Ruggiero, Saba Aïd, Eugenio F. Fornasiero, Martin Holzenberger, Silvio O. Rizzoli, Inna Slutsky

Research output: Contribution to journalArticlepeer-review

Abstract

Regulation of firing rate homeostasis constitutes a fundamental property of central neural circuits. While intracellular Ca2+ 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 Ca2+ (mitoCa2+) by weakening mitochondria-to-cytosol Ca2+ coupling. Overexpression of either mitochondria-targeted IGF-1R or MCUc in IGF-1R–deficient neurons was sufficient to rescue the deficits in burst-to-mitoCa2+ 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 Ca2+ 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.

Original languageEnglish
Article numbere2121040119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number33
DOIs
StatePublished - 16 Aug 2022

Keywords

  • IGF-1 receptor
  • MCU
  • firing rate homeostasis
  • homeostatic plasticity
  • mitochonria

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