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Histone deacetylase inhibition reduces ventral tegmental area dopamine neuronal hyperexcitability involving AKAP150 signaling following maternal deprivation in juvenile male rats.
Journal of Neuroscience Research ( IF 2.9 ) Pub Date : 2020-03-11 , DOI: 10.1002/jnr.24613 Ryan D Shepard 1 , Ludovic D Langlois 1 , Michael E Authement 1 , Fereshteh S Nugent 1
Journal of Neuroscience Research ( IF 2.9 ) Pub Date : 2020-03-11 , DOI: 10.1002/jnr.24613 Ryan D Shepard 1 , Ludovic D Langlois 1 , Michael E Authement 1 , Fereshteh S Nugent 1
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Traumatic early life stress (ELS) is linked to dopamine (DA) dysregulation which increases the probability of developing psychiatric disorders in adolescence and adulthood. Our prior studies demonstrated that a severe early life stressor, a 24-hr maternal deprivation (MD) in juvenile male rats, could lead to altered DA signaling from the ventral tegmental area (VTA) due to impairment of GABAergic synaptic plasticity (promoting GABAergic long-term depression, LTD) with concomitant changes in the abundance of synaptic regulators including A-kinase anchoring protein (AKAP150). Importantly, these MD-induced synaptic changes in the VTA were accompanied by upregulation of histone deacetylase 2, histone hypoacetylation, and were reversible by HDAC inhibition. Using cell-attached and whole-cell patch clamp recordings, we found that MD stress also increased spontaneous VTA DA neuronal activity and excitability in juvenile male rats without affecting intrinsic excitability. Postsynaptic chemical disruption of AKAP150 and protein kinase A interaction increased VTA DA neuronal excitability in control non-MD rats mimicking the effects of MD on DA cell excitability with similar changes in membrane properties. Interestingly, this disruption decreased MD-induced VTA DA hyperexcitability. This MD-induced DA neuronal hyperexcitability could also be normalized at 24 hr after injection of the class 1 HDAC inhibitor, CI-994. Altogether, our data suggest that AKAP150 plays a critical role in the regulation of VTA DA neuronal excitability and that HDAC-mediated targeting of AKAP150 signaling could normalize VTA DA dysfunction following ELS thereby providing novel therapeutic targets for prevention of later life psychopathology.
中文翻译：
组蛋白去乙酰化酶抑制降低了幼年雄性大鼠母体剥夺后腹侧被盖区多巴胺神经元过度兴奋性，涉及 AKAP150 信号传导。
创伤性早期生活压力 (ELS) 与多巴胺 (DA) 失调有关，后者会增加在青春期和成年期患精神疾病的可能性。我们之前的研究表明，由于 GABA 能突触可塑性受损（促进 GABA 能长期抑郁症，LTD）伴随着包括 A 激酶锚定蛋白（AKAP150）在内的突触调节因子的丰度的变化。重要的是，这些 MD 诱导的 VTA 突触变化伴随着组蛋白去乙酰化酶 2 的上调、组蛋白低乙酰化，并且通过 HDAC 抑制是可逆的。使用细胞附着和全细胞膜片钳记录，我们发现 MD 应激还增加了幼年雄性大鼠的自发性 VTA DA 神经元活动和兴奋性，而不影响内在兴奋性。AKAP150 和蛋白激酶 A 相互作用的突触后化学破坏增加了对照非 MD 大鼠的 VTA DA 神经元兴奋性，模拟了 MD 对 DA 细胞兴奋性的影响，膜特性发生了类似的变化。有趣的是，这种中断降低了 MD 诱导的 VTA DA 过度兴奋。这种 MD 诱导的 DA 神经元过度兴奋也可以在注射 1 类 HDAC 抑制剂 CI-994 后 24 小时正常化。共，
更新日期：2020-03-11
中文翻译：
组蛋白去乙酰化酶抑制降低了幼年雄性大鼠母体剥夺后腹侧被盖区多巴胺神经元过度兴奋性，涉及 AKAP150 信号传导。
创伤性早期生活压力 (ELS) 与多巴胺 (DA) 失调有关，后者会增加在青春期和成年期患精神疾病的可能性。我们之前的研究表明，由于 GABA 能突触可塑性受损（促进 GABA 能长期抑郁症，LTD）伴随着包括 A 激酶锚定蛋白（AKAP150）在内的突触调节因子的丰度的变化。重要的是，这些 MD 诱导的 VTA 突触变化伴随着组蛋白去乙酰化酶 2 的上调、组蛋白低乙酰化，并且通过 HDAC 抑制是可逆的。使用细胞附着和全细胞膜片钳记录，我们发现 MD 应激还增加了幼年雄性大鼠的自发性 VTA DA 神经元活动和兴奋性，而不影响内在兴奋性。AKAP150 和蛋白激酶 A 相互作用的突触后化学破坏增加了对照非 MD 大鼠的 VTA DA 神经元兴奋性，模拟了 MD 对 DA 细胞兴奋性的影响，膜特性发生了类似的变化。有趣的是，这种中断降低了 MD 诱导的 VTA DA 过度兴奋。这种 MD 诱导的 DA 神经元过度兴奋也可以在注射 1 类 HDAC 抑制剂 CI-994 后 24 小时正常化。共，
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