Histone Deacetylase Inhibition Rescues Maternal Deprivation-Induced GABAergic Metaplasticity through Restoration of AKAP Signaling
Histone Deacetylase Inhibition Rescues Maternal Deprivation-Induced GABAergic Metaplasticity through Restoration of AKAP Signaling
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DOI：
10.1016/j.neuron.2015.05.024
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发表时间：
2015-06-03
期刊：
影响因子：
16.2
通讯作者：
Nugent, Fereshteh S.
中科院分区：
文献类型：
--
作者：
Authement, Michael E.;Kodangattil, Jayaraj N.;Nugent, Fereshteh S.
不良的早期生活经历，如儿童忽视和虐待，通过改变动机系统（包括中脑边缘多巴胺（DA）通路），增加了成瘾和压力相关疾病的风险。在这里，我们调查了严重的早期生活压力（即，母亲剥夺，MD）通过腹侧被盖区（VTA）DA神经元内突触可塑性的表观遗传损伤促进DA调节异常。使用一个单一的24小时情节MD和全细胞膜片钳记录在大鼠中脑切片，我们表明，MD选择性地诱导长期抑郁症（LTD）和位移尖峰时间依赖性可塑性（STDP）向LTD在GABA能突触到腹侧被盖区DA神经元通过突触后支架A-激酶锚定蛋白79/150（AKAP 79/150）信号转导的表观遗传修饰。组蛋白去乙酰化酶（HDAC）抑制挽救了MD动物中的GABA能元可塑性并使AKAP信号正常化。MD诱导的VTA内可逆HDAC介导的GABA能功能障碍可能是MD后精神健康障碍倾向增加的机制联系。
Adverse early-life experiences such as child neglect and abuse increase the risk of developing addiction and stress-related disorders through alterations in motivational systems including the mesolimbic dopamine (DA) pathway. Here we investigated whether a severe early-life stress (i.e., maternal deprivation, MD) promotes DA dysregulation through an epigenetic impairment of synaptic plasticity within ventral tegmental area (VTA) DA neurons. Using a single 24-hr episode of MD and whole-cell patch clamp recording in rat midbrain slices, we show that MD selectively induces long-term depression (LTD) and shifts spike timing-dependent plasticity (STDP) toward LTD at GABAergic synapses onto VTA DA neurons through epigenetic modifications of postsynaptic scaffolding A-kinase anchoring protein 79/150 (AKAP79/150) signaling. Histone deacetylase (HDAC) inhibition rescues GABAergic metaplasticity and normalizes AKAP signaling in MD animals. MD-induced reversible HDAC-mediated GABAergic dysfunction within the VTA may be a mechanistic link for increased propensity to mental health disorders following MD.