IGF-1 Receptor Differentially Regulates Spontaneous and Evoked Transmission via Mitochondria at Hippocampal Synapses.
IGF-1 Receptor Differentially Regulates Spontaneous and Evoked Transmission via Mitochondria at Hippocampal Synapses.
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DOI：
10.1016/j.neuron.2015.12.034
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发表时间：
2016-02-03
期刊：
影响因子：
16.2
通讯作者：
Slutsky I
中科院分区：
文献类型：
--
作者：
Gazit N;Vertkin I;Shapira I;Helm M;Slomowitz E;Sheiba M;Mor Y;Rizzoli S;Slutsky I
胰岛素样生长因子-1受体(IGF-1R)信号是寿命、生长和胚胎发育的关键调节因子。虽然IGF-1R信号的减少延缓了衰老和阿尔茨海默病的进展，但它是否以及如何调控中央突触的信息处理仍然难以捉摸。在这里，我们展示了突触前IGF-1Rs在基础上是活跃的，调节兴奋性海马神经元中突触小泡的释放和短期可塑性。急性IGF-1R阻断或短暂击倒抑制了尖峰刺激的突触传递和突触前胞浆钙瞬变，同时促进自发传递和静息钙水平。这种对递质释放的双重影响是由线粒体介导的，线粒体在没有尖峰的情况下减弱了钙的缓冲，并在尖峰活动期间减少了ATP的产生。我们的结论是，由IGF-1R信号激活的线粒体，通过维持诱发到自发的传递比率，在高频下限制突触促进，构成了海马神经元信息处理的关键调节因子。过量的IGF-1R可能导致与阿尔茨海默病相关的海马区过度活跃。突触前IGF-1R在海马神经元中基本是活跃的，IGF-1R能增强诱发传递，而抑制自发传递，线粒体是突触传递的差异性调节因子，IGF-1R能缓冲静息钙离子，并在尖峰活动期间维持ATP水平。证实突触前IGF-1R在海马神经元中增强诱发的同时抑制自发的突触小泡释放。线粒体被IGF-1RS激活，通过维持诱发到自发的传输率，同时限制突触的高通过滤，构成信息处理的差异化调节器。
The insulin-like growth factor-1 receptor (IGF-1R) signaling is a key regulator of lifespan, growth, and development. While reduced IGF-1R signaling delays aging and Alzheimer’s disease progression, whether and how it regulates information processing at central synapses remains elusive. Here, we show that presynaptic IGF-1Rs are basally active, regulating synaptic vesicle release and short-term plasticity in excitatory hippocampal neurons. Acute IGF-1R blockade or transient knockdown suppresses spike-evoked synaptic transmission and presynaptic cytosolic Ca2+ transients, while promoting spontaneous transmission and resting Ca2+ level. This dual effect on transmitter release is mediated by mitochondria that attenuate Ca2+ buffering in the absence of spikes and decrease ATP production during spiking activity. We conclude that the mitochondria, activated by IGF-1R signaling, constitute a critical regulator of information processing in hippocampal neurons by maintaining evoked-to-spontaneous transmission ratio, while constraining synaptic facilitation at high frequencies. Excessive IGF-1R tone may contribute to hippocampal hyperactivity associated with Alzheimer’s disease. Presynaptic IGF-1Rs are basally active in hippocampal neurons IGF-1R tone enhances evoked transmission, while inhibiting spontaneous transmission Mitochondrion is a differential regulator of synaptic transmission by IGF-1Rs IGF-1R tone buffers resting Ca2+ and maintains ATP levels during spiking activity Gazit et al. demonstrate that presynaptic IGF-1R tone enhances evoked while suppressing spontaneous synaptic vesicle release in hippocampal neurons. Mitochondria, activated by IGF-1Rs, constitute a differential regulator of information processing by maintaining evoked-to-spontaneous transmission ratio, while constraining synaptic high-pass filtering.