Excitatory Synaptic Function and Plasticity is Persistently Altered in Ventral Tegmental Area Dopamine Neurons after Prenatal Ethanol Exposure
Excitatory Synaptic Function and Plasticity is Persistently Altered in Ventral Tegmental Area Dopamine Neurons after Prenatal Ethanol Exposure
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DOI：
10.1038/npp.2014.265
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发表时间：
2015-03-01
影响因子：
7.6
通讯作者：
Shen, Roh-Yu
中科院分区：
文献类型：
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作者：
Hausknecht, Kathryn;Haj-Dahmane, Samir;Shen, Roh-Yu
产前酒精暴露(PE)是导致成瘾倾向(风险)增加的发育因素之一。然而，这种效应背后的神经机制仍不清楚。我们研究了PE是否影响与药物成瘾有关的腹侧被盖区(VTA)多巴胺(DA)神经元兴奋性突触传递的增加。孕鼠从妊娠第8-20天开始经胃管给予乙醇(0或6g/kg/d)。对2-12周龄的雄性后代进行了苯丙胺自我给药、全细胞记录和电子显微镜检查。结果表明，苯丙胺在PE动物体内的自我给药增强。在PE动物中，我们观察到钙通透性AMPA受体(CP-AMPAR)的表达持续增强，表现为AMPAR介导的兴奋性突触后电流(AMPAR-EPSCs)的整流增加和衰减时间缩短，NASPM(选择性CP-AMPAR拮抗剂)对AMPAR-EPSCs的抑制作用增强，并通过DA神经元树突增加GluA3亚单位。在PE动物中，CP-AMPAR的表达增加导致兴奋性突触强度增强，并诱导CP-AMPAR依赖的长时程增强(LTP)，LTP是一种抗Hebbian形式的LTP。这些观察表明，在PE动物中，即使在没有脉冲流的情况下，VTA DA神经元兴奋性突触强度的增加可能也容易进一步增强。PE诱导的CP-AMPAR表达的持续增加，由此导致的兴奋性突触强度的增强，以及CP-AMPAR依赖的LIP类似于反复暴露于滥用药物后观察到的效果，这些情况已知会增加成瘾风险。因此，这些机制可能是PE诱导苯丙胺自我给药增强和胎儿酒精谱障碍患者成瘾风险增加的重要神经底物。
Prenatal ethanol exposure (PE) is one of the developmental factors leading to increased addiction propensity (risk). However, the neuronal mechanisms underlying this effect remain unknown. We examined whether increased excitatory synaptic transmission in ventral tegmental area (VTA) dopamine (DA) neurons, which is associated with drug addiction, was impacted by PE. Pregnant rats were exposed to ethanol (0 or 6 g/kg/day) via intragastric intubation from gestational day 8-20. Amphetamine self-administration, whole-cell recordings, and electron microscopy were performed in male offspring between 2 and 12-week-old. The results showed enhanced amphetamine self-administration in PE animals. In PE animals, we observed a persistent augmentation in calcium-permeable AMPA receptor (CP-AMPAR) expression, indicated by increased rectification and reduced decay time of AMPAR-mediated excitatory postsynaptic currents (AMPAR-EPSCs), enhanced depression of AMPAR-EPSCs by NASPM (a selective CP-AMPAR antagonist), and increased GluA3 subunits in VIA DA neuron dendrites. Increased CP-AMPAR expression in PE animals led to enhanced excitatory synaptic strength and the induction of CP-AMPAR-dependent long-term potentiation (LTP), an anti-Hebbian form of LTP. These observations suggest that, in PE animals, increased excitatory synaptic strength in VTA DA neurons might be susceptible to further strengthening even in the absence of impulse flow. The PE-induced persistent increase in CP-AMPAR expression, the resulting enhancement in excitatory synaptic strength, and CP-AMPAR-dependent LIP are similar to effects observed after repeated exposure to drugs of abuse, conditions known to increase addiction risk. Therefore, these mechanisms could be important neuronal substrates underlying PE-induced enhancement in amphetamine self-administration and increased addiction risk in individuals with fetal alcohol spectrum disorders.