IGF-1 receptor regulates upward firing rate homeostasis via the mitochondrial calcium uniporter.
Proc Natl Acad Sci U S A
; 119(33): e2121040119, 2022 08 16.
Article
em En
| MEDLINE
| ID: mdl-35943986
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.
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Base de dados:
MEDLINE
Assunto principal:
Canais de Cálcio
/
Cálcio
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Receptor IGF Tipo 1
Limite:
Animals
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article