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.

中文翻译：

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IGF-1 受体通过线粒体钙单向转运体调节向上放电率稳态

放电率稳态的调节构成了中枢神经回路的基本特性。虽然细胞内 Ca2+尽管长期以来一直被假设为反馈控制信号，但实现全网络稳态反应的分子机制在很大程度上仍然未知。我们表明，胰岛素样生长因子 1 受体 (IGF-1R) 的缺失限制了响应不活动的放电率稳态，而不改变基线放电率的分布。不足的放电率稳态反应是由于突触后和内在可塑性的破坏。在细胞水平上，我们在线粒体中检测到一部分 IGF-1R，与线粒体钙单向转运体复合物 (MCUc) 共定位。IGF-1R 缺失抑制了 MCUc 成员的转录和突发诱发的线粒体 Ca2+（线粒体钙2+) 通过削弱线粒体到胞质溶胶 Ca2+耦合。在 IGF-1R 缺陷神经元中过度表达线粒体靶向 IGF-1R 或 MCUc 足以挽救 burst-to-mitoCa 中的缺陷2+耦合和发射率稳态。我们的研究结果表明，线粒体 IGF-1R 通过调节 MCUc 突发转移的可靠性，是综合稳态反应的关键调节因子。基于这些结果，我们建议 MCUc 作为稳态 Ca2+传感器。MCUc 的错误激活可能导致衰老和与异常 IGF-1R/MCUc 信号相关的脑部疾病中的放电率稳态失调。