Developmental shift to mitochondrial respiration for energetic support of sustained transmission during maturation at the calyx of Held.
Developmental shift to mitochondrial respiration for energetic support of sustained transmission during maturation at the calyx of Held.
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DOI：
10.1152/jn.00333.2021
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发表时间：
2021-10-01
影响因子：
2.5
通讯作者：
Renden RB
中科院分区：
文献类型：
--
作者：
Lujan BJ;Singh M;Singh A;Renden RB
在突触前活动之后，大量的能量被消耗以再生电极化并维持神经递质的有效释放和再循环。线粒体是神经元能量的主要供应者，通过氧化磷酸化产生ATP。然而，在突触活动期间，突触前末梢对来自胞质糖酵解而不是线粒体呼吸的能量的具体利用仍然不清楚且有争议。我们使用小鼠中专门用于高频传输的突触，Held的萼，来测试用于在短活动爆发（<1 s）和持续神经传递（30-150 s）期间维持能量的能量来源。我们解剖突触前糖酵解与线粒体呼吸的作用，通过急性和选择性地阻断这些ATP生成途径的突触准备线粒体和突触囊泡是多产的，在接近生理条件下。令人惊讶的是，如果糖酵解或线粒体ATP的产生是完整的，在重复的短脉冲活动期间的传输不受影响。在听力开始之前的年轻动物切片中，突触尚未完全特化，糖酵解和线粒体ATP的产生都需要支持持续的高频神经传递。在成熟的突触中，持续的传递完全依赖于线粒体ATP的产生，而不是糖酵解。在这两个年龄段，我们观察到，动作电位传播开始失败之前，在突触囊泡回收缺陷。我们的数据描述了一个特定的代谢特征，以支持高频信息传输在成熟的花萼举行，在出生后的突触成熟糖酵解依赖于单羧酸作为燃料来源。新&值得注意的是，我们剖析了突触前糖酵解与线粒体呼吸在支持高频神经传递中的作用，通过急性阻断这些ATP产生途径在突触处调谐为高频传递。我们发现，当只有一个通路被抑制时，产生故障需要大量的能量消耗。动作电位传播在受损的突触囊泡再循环之前丢失。突触传递完全依赖于成熟突触中的氧化磷酸化，表明突触前糖酵解可能是ATP维持的关键。
A considerable amount of energy is expended following presynaptic activity to regenerate electrical polarization and maintain efficient release and recycling of neurotransmitter. Mitochondria are the major suppliers of neuronal energy, generating ATP via oxidative phosphorylation. However, the specific utilization of energy from cytosolic glycolysis rather than mitochondrial respiration at the presynaptic terminal during synaptic activity remains unclear and controversial. We use a synapse specialized for high-frequency transmission in mice, the calyx of Held, to test the sources of energy used to maintain energy during short activity bursts (<1 s) and sustained neurotransmission (30–150 s). We dissect the role of presynaptic glycolysis versus mitochondrial respiration by acutely and selectively blocking these ATP-generating pathways in a synaptic preparation where mitochondria and synaptic vesicles are prolific, under near-physiological conditions. Surprisingly, if either glycolysis or mitochondrial ATP production is intact, transmission during repetitive short bursts of activity is not affected. In slices from young animals before the onset of hearing, where the synapse is not yet fully specialized, both glycolytic and mitochondrial ATP production are required to support sustained, high-frequency neurotransmission. In mature synapses, sustained transmission relies exclusively on mitochondrial ATP production supported by bath lactate, but not glycolysis. At both ages, we observe that action potential propagation begins to fail before defects in synaptic vesicle recycling. Our data describe a specific metabolic profile to support high-frequency information transmission at the mature calyx of Held, shifting during postnatal synaptic maturation from glycolysis to rely on monocarboxylates as a fuel source. NEW & NOTEWORTHY We dissect the role of presynaptic glycolysis versus mitochondrial respiration in supporting high-frequency neurotransmission, by acutely blocking these ATP-generating pathways at a synapse tuned for high-frequency transmission. We find that massive energy expenditure is required to generate failure when only one pathway is inhibited. Action potential propagation is lost before impaired synaptic vesicle recycling. Synaptic transmission is exclusively dependent on oxidative phosphorylation in mature synapses, indicating presynaptic glycolysis may be dispensable for ATP maintenance.
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