Long-lasting distortion of GABA signaling in MS/DB neurons after binge-like ethanol exposure during initial synaptogenesis

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• 作者：Haiying Wang ; Dustin W. DuBois ; Angelika N. Tobery ; William H. Griffith ; Paul Brandt ; Gerald D. Frye ; ^{gdfrye@medicine.tamhsc.edu}
• 关键词：Fetal alcohol spectrum disorder ; GABAA receptor ; Miniature postsynaptic current ; Medial septum/diagonal band ; Development ; Zolpidem ; Allopregnanolone
• 刊名：Brain Research
• 出版年：2013
• 出版时间：3 July, 2013
• 年：2013
• 卷：1520
• 期：Complete
• 页码：36-50
• 全文大小：3477 K

文摘

Using a well-established model of binge-like ethanol treatment of rat pups on postnatal days (PD) 4-9, we found that maturation of GABA_A receptor (GABA_AR) miniature postsynaptic currents (mPSCs) was substantially blunted for medial septum/diagonal band (MS/DB) neurons in brain slices on PD 11-16. Ethanol reduced mPSC amplitude, frequency, and decay kinetics, while attenuating or exaggerating allosteric actions of zolpidem and allopregnanolone, respectively. The impact of ethanol in vivo was long lasting as most changes in MS/DB GABA_AR mPSCs were still observed as late as PD 60-85. Maturing MS/DB neurons in na?ve brain slices PD 4-16 showed increasing mPSC frequency, decay kinetics, and zolpidem sensitivity that were nearly identical to our earlier findings in cultured septal neurons (). These rapidly developing mPSC parameters continued to mature through the first month of life then stabilized throughout the remainder of the lifespan. Finally, equivalent ethanol-induced alterations in GABA_AR mPSC signaling were present in MS/DB neurons from both male and female animals. Previously, we showed ethanol treatment of cultured embryonic day 20 septal neurons distorts the maturation of GABA_AR mPSCs predicting that early stages of GABAergic transmission in MS/DB neurons are vulnerable to intoxication injury (). Since the overall character, timing, and magnitude of GABAergic mPSC developmental- and ethanol-induced changes in the in vivo model so closely mirror chronologically equivalent adaptations in cultured septal neurons, this suggests that such parallel models of ethanol impairment of GABAergic synaptic development in vivo and in vitro should be useful for translational studies exploring the efficacy and mechanism of action of potential therapeutic interventions from the cellular to whole animal level.