DuBois Dustin W, Trzeciakowski Jerome P, Parrish Alan R, Frye Gerald D
Department of Neuroscience and Experimental Therapeutics, College of Medicine (ms 1114), Texas A & M System Health Science Center, College Station, TX 77843-1114, USA.
Brain Res. 2006 May 17;1089(1):101-15. doi: 10.1016/j.brainres.2006.03.023. Epub 2006 Apr 21.
Binge-like ethanol treatment of septal neurons blunts GABAAR-mediated miniature postsynaptic currents (mPSCs), suggesting it arrests synaptic development. Ethanol may disrupt postsynaptic maturation by blunting feedback signaling through immature GABAARs. Here, the impact of ethanol on the sensitivity of mPSCs to zolpidem, zinc and 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha-OH-DHP) was tested. The decay phase of mPSCs showed concentration-dependent potentiation by zolpidem (0.03-100 microM), which was substantially blunted after ethanol exposure. Since zolpidem potentiation exhibited a substantial age-dependent increase in untreated neurons, this finding supported the idea that ethanol arrests synaptic development. GABAAR alpha1 subunit protein also increased with age in untreated neurons, paralleling enhanced sensitivity to zolpidem. Surprisingly, alpha1 levels were not reduced by binge ethanol even though mPSCs were relatively zolpidem-insensitive. Zinc (3-30 microM) decreased mPSC parameters in a concentration- and age-related manner with older untreated cells showing less inhibition. However, there was no increase in mPSC zinc sensitivity after binge ethanol as would be expected if a general arrest of synaptic maturation had occurred. 3alpha-OH-DHP (3-1000 nM) induced concentration-dependent potentiation of mPSC decay. Although potentiation was age-independent, binge ethanol treatment exaggerated sensitivity to this neurosteroid. Finally, chronic picrotoxin pretreatment (100 microM) intended to mimic GABAAR inhibition from ethanol pretreatment did not significantly change mPSC modulation by zolpidem, zinc or 3alpha-OH-DHP. These results suggest that binge ethanol treatment selectively arrests a subset of processes important for maturation of postsynaptic GABAA Rs. However, it is unlikely that ethanol causes a broad arrest of postsynaptic development through a direct inhibition of GABAAR signaling.
对隔区神经元进行类似暴饮暴食的乙醇处理会减弱GABAA受体介导的微小突触后电流（mPSC），这表明它会阻碍突触发育。乙醇可能通过减弱未成熟GABAA受体的反馈信号来破坏突触后成熟。在此，测试了乙醇对mPSC对唑吡坦、锌和3α-羟基-5α-孕烷-20-酮（3α-OH-DHP）敏感性的影响。mPSC的衰减期显示出唑吡坦（0.03-100微摩尔）的浓度依赖性增强，乙醇暴露后这种增强作用明显减弱。由于在未处理的神经元中唑吡坦增强作用呈现出明显的年龄依赖性增加，这一发现支持了乙醇阻碍突触发育的观点。在未处理的神经元中，GABAA受体α1亚基蛋白也随年龄增加，与对唑吡坦的敏感性增强平行。令人惊讶的是，尽管mPSC对唑吡坦相对不敏感，但暴饮暴食乙醇后α1水平并未降低。锌（3-30微摩尔）以浓度和年龄相关的方式降低mPSC参数，未处理的老龄细胞显示出较少的抑制作用。然而，如果发生了突触成熟的普遍阻碍，则暴饮暴食乙醇后mPSC对锌的敏感性应会增加，但实际并未增加。3α-OH-DHP（3-1000纳摩尔）诱导mPSC衰减的浓度依赖性增强。尽管这种增强与年龄无关，但暴饮暴食乙醇处理会夸大对这种神经甾体的敏感性。最后，旨在模拟乙醇预处理对GABAA受体抑制作用的慢性印防己毒素预处理（100微摩尔）并未显著改变唑吡坦、锌或3α-OH-DHP对mPSC的调节作用。这些结果表明暴饮暴食乙醇处理选择性地阻碍了对突触后GABAA受体成熟重要的一部分过程。然而，乙醇不太可能通过直接抑制GABAA受体信号传导而导致突触后发育的广泛阻碍。
