Glucose and lactate as metabolic constraints on presynaptic transmission at an excitatory synapse.
Glucose and lactate as metabolic constraints on presynaptic transmission at an excitatory synapse.
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葡萄糖和乳酸作为兴奋性突触突触前传递的代谢限制。
DOI：
10.1113/jp275107
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Lucas SJ
中科院分区：
文献类型：
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作者：
Lucas SJ
关键点突触有高能量需求，在激烈的活动中会增加。我们发现，突触前末梢可以利用细胞外葡萄糖或乳酸产生能量来维持突触传递。减少能量底物会诱导代谢应激：突触前ATP耗竭通过减少功能性突触囊泡释放位点的数量和减缓囊泡池的补充来损害突触传递，代谢功能在许多病理状况（例如中风、创伤性脑损伤和神经变性）中受到损害。突触传递是如何受到代谢压力的限制，特别是在激烈的大脑活动的知识，将提供见解，以改善认知以下病理insults.AbstractThe突触有很高的能量需求，增加在激烈的活动。突触前ATP的产生依赖于底物的可用性，并且在活动期间使用量会增加，这反过来又会影响递质的释放和信息传递。我们研究了发射器释放在小鼠杯举行突触使用葡萄糖或乳酸（10，1或0毫米）作为细胞外基质，同时诱导代谢应激。高频刺激（HFS）和恢复范式诱发了在电压钳下监测的EPSC序列。虽然突触后细胞内ATP稳定的扩散从贴片吸管，消耗葡萄糖增加EPSC抑郁症在HFS和受损的后续恢复。这些数据的计算建模表明，在代谢应激过程中，功能性释放位点的数量减少，囊泡池补充减慢，释放概率变化不大。直接消耗突触前末端ATP以类似于葡萄糖消耗的方式损害递质释放。在不存在葡萄糖的情况下，突触前终末代谢可利用aCSF中的乳酸，这可通过抑制单羧酸转运蛋白（MCT）来阻断。MCT抑制剂显著抑制低葡萄糖下的传输，这意味着乳酸是突触前底物。此外，在细胞外葡萄糖缺乏的情况下，糖原分解的阻断加速了突触传递的失败，这与局部星形胶质细胞补充乳酸的供应一致。我们的结论是，葡萄糖和乳酸都支持突触前代谢，并且由于高强度放电而加剧的有限可用性限制了突触前ATP，当ATP水平较低时，由于囊泡再循环减慢，通过功能性突触前释放位点的减少阻碍了传输。
Key pointsSynapses have high energy demands which increase during intense activity. We show that presynaptic terminals can utilise extracellular glucose or lactate to generate energy to maintain synaptic transmission.Reducing energy substrates induces a metabolic stress: presynaptic ATP depletion impaired synaptic transmission through a reduction in the number of functional synaptic vesicle release sites and a slowing of vesicle pool replenishment, without a consistent change in release probability.Metabolic function is compromised in many pathological conditions (e.g. stroke, traumatic brain injury and neurodegeneration). Knowledge of how synaptic transmission is constrained by metabolic stress, especially during intense brain activity, will provide insights to improve cognition following pathological insults.AbstractThe synapse has high energy demands, which increase during intense activity. Presynaptic ATP production depends on substrate availability and usage will increase during activity, which in turn could influence transmitter release and information transmission. We investigated transmitter release at the mouse calyx of Held synapse using glucose or lactate (10, 1 or 0 mm) as the extracellular substrates while inducing metabolic stress. High‐frequency stimulation (HFS) and recovery paradigms evoked trains of EPSCs monitored under voltage‐clamp. Whilst postsynaptic intracellular ATP was stabilised by diffusion from the patch pipette, depletion of glucose increased EPSC depression during HFS and impaired subsequent recovery. Computational modelling of these data demonstrated a reduction in the number of functional release sites and slowed vesicle pool replenishment during metabolic stress, with little change in release probability. Directly depleting presynaptic terminal ATP impaired transmitter release in an analogous manner to glucose depletion. In the absence of glucose, presynaptic terminal metabolism could utilise lactate from the aCSF and this was blocked by inhibition of monocarboxylate transporters (MCTs). MCT inhibitors significantly suppressed transmission in low glucose, implying that lactate is a presynaptic substrate. Additionally, block of glycogenolysis accelerated synaptic transmission failure in the absence of extracellular glucose, consistent with supplemental supply of lactate by local astrocytes. We conclude that both glucose and lactate support presynaptic metabolism and that limited availability, exacerbated by high‐intensity firing, constrains presynaptic ATP, impeding transmission through a reduction in functional presynaptic release sites as vesicle recycling slows when ATP levels are low.