Ethanol affects NMDA receptor signaling at climbing fiber-Purkinje cell synapses in mice and impairs cerebellar LTD
Ethanol affects NMDA receptor signaling at climbing fiber-Purkinje cell synapses in mice and impairs cerebellar LTD
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DOI：
10.1152/jn.00350.2012
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发表时间：
2013-03-01
影响因子：
2.5
通讯作者：
Hansel, Christian
中科院分区：
文献类型：
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作者：
He, Qionger;Titley, Heather;Hansel, Christian
[10]何Q，蒂特利H，Grasselli G，Piochon C，Hansel C.乙醇影响小鼠中攀爬纤维-浦肯野细胞突触处的NMDA受体信号传导并损害小脑LTD. J Neurophysiol 109：1333-1342，2013。首次发表于2012年12月5日; doi：10.1152/jn.00350.2012.乙醇深刻影响小脑回路功能和运动控制。最近的研究表明，功能性N-甲基-D-天冬氨酸（NMDA）受体在成年小脑的爬纤维（CF）到浦肯野细胞突触的突触后表达。使用全细胞膜片钳记录从小鼠小脑切片，我们研究了乙醇是否可以影响NMDA受体信号在成熟的浦肯野细胞。通过水浴应用α-氨基-3-羟基-5-甲基-4-异恶唑丙酸酯（AMPA）受体拮抗剂2，3-二羟基-6-硝基-7-氨磺酰基苯并[f]喹喔啉（NBQX）分离NMDA受体介导的电流。剩余的D-2-氨基-5-膦酰基戊酸（D-APV）敏感的电流降低乙醇浓度低至10 mM。在50 mM乙醇的浓度，D-APV敏感的CF-兴奋性突触后电流的封锁显着更强。乙醇也改变了波形的CF-诱发的复杂的尖峰，减少后去极化。当NMDA受体在乙醇洗入前被D-APV阻断时，未观察到这种作用。与CF突触传递相反，平行纤维（PF）突触输入不受乙醇的影响。最后，乙醇（10 mM）受损的长期抑郁症（LTD）在PF浦肯野细胞突触诱导对照条件下配对PF和CF活动。然而，由成对的PF刺激与去极化电压阶跃（替代CF激活）诱导的LTD不被乙醇阻断。这些观察结果表明，小脑回路功能和可塑性的敏感性，低浓度的乙醇可能是由乙醇介导的损害NMDA受体信号转导CF突触小脑浦肯野细胞。
He Q, Titley H, Grasselli G, Piochon C, Hansel C. Ethanol affects NMDA receptor signaling at climbing fiber-Purkinje cell synapses in mice and impairs cerebellar LTD. J Neurophysiol 109: 1333-1342, 2013. First published December 5, 2012; doi: 10.1152/jn.00350.2012.Ethanol profoundly influences cerebellar circuit function and motor control. It has recently been demonstrated that functional N-methyl-D-aspartate (NMDA) receptors are postsynaptically expressed at climbing fiber (CF) to Purkinje cell synapses in the adult cerebellum. Using whole cell patch-clamp recordings from mouse cerebellar slices, we examined whether ethanol can affect NMDA receptor signaling in mature Purkinje cells. NMDA receptor-mediated currents were isolated by bath application of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzol[f]quinoxaline (NBQX). The remaining D-2-amino-5-phosphonovaleric acid (D-APV)-sensitive current was reduced by ethanol at concentrations as low as 10 mM. At a concentration of 50 mM ethanol, the blockade of D-APV-sensitive CF-excitatory postsynaptic currents was significantly stronger. Ethanol also altered the waveform of CF-evoked complex spikes by reducing the afterdepolarization. This effect was not seen when NMDA receptors were blocked by D-APV before ethanol wash-in. In contrast to CF synaptic transmission, parallel fiber (PF) synaptic inputs were not affected by ethanol. Finally, ethanol (10 mM) impaired long-term depression (LTD) at PF to Purkinje cell synapses as induced under control conditions by paired PF and CF activity. However, LTD induced by pairing PF stimulation with depolarizing voltage steps (substituting for CF activation) was not blocked by ethanol. These observations suggest that the sensitivity of cerebellar circuit function and plasticity to low concentrations of ethanol may be caused by an ethanol-mediated impairment of NMDA receptor signaling at CF synapses onto cerebellar Purkinje cells.