Acid-Sensing Ion Channels Activated by Evoked Released Protons Modulate Synaptic Transmission at the Mouse Calyx of Held Synapse
Acid-Sensing Ion Channels Activated by Evoked Released Protons Modulate Synaptic Transmission at the Mouse Calyx of Held Synapse
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DOI：
10.1523/jneurosci.2566-16.2017
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发表时间：
2017-03-08
影响因子：
5.3
通讯作者：
Uchitel, Osvaldo D.
中科院分区：
文献类型：
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作者：
Gonzalez-Inchauspe, Carlota;Urbano, Francisco J.;Uchitel, Osvaldo D.
酸感离子通道（asic）调节突触活动，在神经退行性疾病中发挥重要作用。我们发现这些通道可以在中枢神经系统听觉系统梯形体内侧核（MNTB）的神经元中被激活。细胞外pH值的降低可诱导野生型小鼠突触后MNTB神经元瞬时向内ASIC电流（I(ASIC)s）。psalmotoxin-1 （PcTx1）对IASICs的抑制作用以及ASIC-1a亚基（ASIC1a(-/-)）敲除小鼠中这些电流的缺失表明，同源ASIC-1a介导了MNTB神经元中的这些电流。此外，我们在突触传递过程中检测到asic1a依赖性电流，这表明突触间隙的酸化是由于突触囊泡中神经递质和H（+）的共同释放。这些电流能够在没有谷氨酸能电流的情况下激发动作电位。这些同源ASIC-1as的一个显著特征是它们对Ca2+的渗透性。外源性H（+）激活MNTB神经元中的ASIC-1a诱导细胞内Ca2+的增加。此外，在高频刺激（HFS）突触前神经末梢时，突触后asic -1a的激活导致MNTB神经元细胞内Ca2+的pctx1敏感增加，这是独立于谷氨酸受体的，在ASIC1a（-/-）小鼠的神经元中不存在。在HFS期间，突触传递中功能性asic的缺乏导致谷氨酸能epsc的短期抑制增强。这些结果有力地支持了质子作为神经递质的假设，并证明突触前释放的质子通过激活Held-MNTB突触花萼上的ASIC-1as来调节突触传递。
Acid-sensing ion channels (ASICs) regulate synaptic activities and play important roles in neurodegenerative diseases. We found that these channels can be activated in neurons of the medial nucleus of the trapezoid body (MNTB) of the auditory system in the CNS. A drop in extracellular pH induces transient inward ASIC currents (I(ASIC)s) in postsynaptic MNTB neurons from wild-type mice. The inhibition of IASICs by psalmotoxin-1 (PcTx1) and the absence of these currents in knock-out mice for ASIC-1a subunit (ASIC1a(-/-)) suggest that homomeric ASIC-1as are mediating these currents in MNTB neurons. Furthermore, we detect ASIC1a-dependent currents during synaptic transmission, suggesting an acidification of the synaptic cleft due to the corelease of neurotransmitter and H (+) from synaptic vesicles. These currents are capable of eliciting action potentials in the absence of glutamatergic currents. A significant characteristic of these homomeric ASIC-1as is their permeability to Ca2+. Activation of ASIC-1a in MNTB neurons by exogenous H (+) induces an increase in intracellular Ca2+. Furthermore, the activation of postsynaptic ASIC-1as during high-frequency stimulation (HFS) of the presynaptic nerve terminal leads to a PcTx1-sensitive increase in intracellular Ca2+ in MNTB neurons, which is independent of glutamate receptors and is absent in neurons from ASIC1a(-/-) mice. During HFS, the lack of functional ASICs in synaptic transmission results in an enhanced short- term depression of glutamatergic EPSCs. These results strongly support the hypothesis of protons as neurotransmitters and demonstrate that presynaptic released protons modulate synaptic transmission by activating ASIC-1as at the calyx of Held-MNTB synapse.