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标题：IGF-1 receptor regulates upward firing rate homeostasis via the mitochondrial calcium uniporter
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作者：Maxim Katsenelson ; Ilana Shapira ; Eman Abbas 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：33
DOI：10.1073/pnas.2121040119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance An emerging hypothesis is that neuronal circuits homeostatically maintain a stable spike rate despite continuous environmental changes. This firing rate homeostasis is believed to confer resilience to neurodegeneration and cognitive decline. We show that insulin-like growth factor-1 receptor (IGF-1R) is necessary for homeostatic response of mean firing rate to inactivity, termed “upward firing rate homeostasis.” We show that its mechanism of action is to couple spike bursts with downstream mitochondrial Ca 2+ influx via the mitochondrial calcium uniporter complex (MCUc). We propose that MCUc is a homeostatic Ca 2+ sensor that triggers the integrated homeostatic response. Firing rate homeostasis may be the principal mechanism by which IGF-1R regulates aging and neurodevelopmental and neurodegenerative disorders. 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.
关键词：enfiring rate homeostasishomeostatic plasticitymitochonriaIGF-1 receptorMCU