Binge ethanol exposure delays development of GABAergic miniature postsynaptic currents in septal neurons
Binge ethanol exposure delays development of GABAergic miniature postsynaptic currents in septal neurons
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DOI：
10.1016/j.devbrainres.2004.06.017
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发表时间：
2004-09-17
期刊：
影响因子：
--
通讯作者：
Frye, GD
中科院分区：
文献类型：
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作者：
DuBois, DW;Parrish, AR;Frye, GD
从大鼠幼仔分离的隔神经元的全细胞GABA（A）R电流在生命的最初几周内迅速增加，此时抑制性突触正在形成。出生后第4 - 9天的早期酒精插管延迟了几天后分离的隔神经元中的这种成熟上调，表明抑制性突触形成可能被破坏[S. H.萧敬龙阿切韦多DuBois，K.R.史密斯，JR。华盛顿特区韦斯特Frye，Early postnatal ethanol interventions blunts GABA（A）receptor upregulation and modifies 3alpha-hydroxy-5alpha-dopan-20-one sensitivity in rat MS/DB neurons，Brain Res. Dev. 130（2001）25 - 40]。令人惊讶的是，当隔神经元在体外生长相同的时间段时，全细胞GABA（A）R功能不会迅速增加，并且不会因培养物的可比乙醇暴露而钝化[S. H.萧德威R.C.杜波依斯米兰达，G.D. Frye，临界时间乙醇暴露降低了体内而非体外发育的隔神经元上的GABA（A）R功能，Brain Res Dev. 1008（2004）69 - 80]。由于GABA能微型突触后电流（mPSC）显示出无论皮质神经元在体内还是体外生长的平行成熟模式[D. D.邓宁胡佛岛Soltesz，文学硕士史密斯，D.K. ODowd，GABAA receptor-mediated miniature postsynaptic currents and alpha-subunit expression in developing cortex neurons，J. Neurophysiol. 82（1999）3286 - 3297]，我们检测了过量乙醇暴露对隔培养物中由这些电流激活的突触受体的影响。在体外（DIV）6 - 11天内对胚胎隔神经元进行过量乙醇处理略微降低了GABA（A）R介导的mPSC振幅和频率，但当在DIV 13 - 18晚些时候记录mPSC时，也大大减缓了衰减动力学。乙醇后降低的频率和减慢的mPSC衰减动力学与未成熟神经元中测量的参数一致。未经处理的隔神经元表现出降低的mPSC振幅和频率与急性30 - 100 mM乙醇，而不改变衰减动力学表明直接抑制突触后受体。用100 μ M印防己毒素对DIV 6 - 11的GABA（A）Rs的持续抑制降低了mPSC振幅和频率，并减慢了衰减动力学，类似于酒精暴露。这些结果表明，酗酒暴露延迟mPSC的成熟，通过干扰营养突触后GABA（A）R信号在隔神经元的早期发育。(C)2004 Elsevier B.V.保留所有权利。
Whole cell GABA(A)R currents of septal neurons isolated from rat pups increase rapidly during the first weeks of life when inhibitory synapses are forming. Early postnatal binge ethanol intubation on days 4-9 delays this maturational up-regulation in septal neurons isolated several days later suggesting inhibitory synapse formation could be disrupted [S.-H. Hsiao, J.L. Acevedo, D.W. DuBois, K.R. Smith, JR. West, G.D. Frye, Early postnatal ethanol intubation blunts GABA(A) receptor upregulation and modifies 3alpha-hydroxy-5alpha-pregnan-20-one sensitivity in rat MS/DB neurons, Brain Res. Dev. Brain Res. 130 (2001) 25-40]. Surprisingly, whole cell GABA(A)R function does not increase rapidly when septal neurons are grown for the same period in vitro and is not blunted by comparable ethanol exposure of the cultures [S.-H. Hsiao, D.W. DuBois, R.C. Miranda, G.D. Frye, Critically timed ethanol exposure reduces GABA(A)R function on septal neurons developing in vivo but not in vitro, Brain Res Dev. Brain Res. 1008 (2004) 69-80]. Because GABAergic miniature postsynaptic currents (mPSCs) show parallel patterns of maturation whether cortical neurons are growing in vivo or in vitro [D.D. Dunning, C.L. Hoover, I. Soltesz, M.A. Smith, D.K. ODowd, GABAA receptor-mediated miniature postsynaptic currents and alpha-subunit expression in developing cortical neurons, J. Neurophysiol. 82 (1999) 3286-3297], we examined the impact of binge ethanol exposure on synaptic receptors activated by these currents in septal cultures. Binge ethanol treatment of embryonic septal neurons over 6-11 days in vitro (DIV) slightly reduced GABA(A)R-mediated mPSC amplitude and frequency, but also substantially slowed decay kinetics when mPSCs were recorded later on DIV 13-18. Decreased frequency and slowed mPSC decay kinetics after ethanol were consistent with parameters measured in immature neurons. Untreated septal neurons exhibited decreased mPSC amplitude and frequency with acute 30-100 mM ethanol, without changing decay kinetics suggesting a direct inhibition of postsynaptic receptors. Sustained inhibition of GABA(A)Rs with 100 muM picrotoxin on DIV 6-11 decreased mPSC amplitude and frequency and slowed decay kinetics similar to binge ethanol exposure. These results suggest that binge ethanol exposure delays mPSC maturation by interfering with trophic postsynaptic GABA(A)R signaling during the early development of septal neurons. (C) 2004 Elsevier B.V. All rights reserved.