CB1R-Mediated Activation of Caspase-3 Causes Epigenetic and Neurobehavioral Abnormalities in Postnatal Ethanol-Exposed Mice.
CB1R-Mediated Activation of Caspase-3 Causes Epigenetic and Neurobehavioral Abnormalities in Postnatal Ethanol-Exposed Mice.
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DOI：
10.3389/fnmol.2018.00045
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发表时间：
2018
影响因子：
4.8
通讯作者：
Basavarajappa BS
中科院分区：
文献类型：
--
作者：
Subbanna S;Nagre NN;Shivakumar M;Joshi V;Psychoyos D;Kutlar A;Umapathy NS;Basavarajappa BS
酒精暴露会影响大脑发育，导致长期的行为问题，包括认知障碍，这两者被定义为胎儿酒精谱系障碍（FASD）。然而，这种情况发生的基本机制在很大程度上是未知的。在这项研究中，我们报告说，出生后第7天（P7）小鼠暴露于乙醇激活caspase-3通过大麻素受体1型（CB 1 R）在新生小鼠，并导致甲基化DNA结合蛋白（MeCP 2）水平的降低。MeCP 2在小鼠发育中的表达与突触发生和神经元成熟密切相关。结果表明，P7小鼠的乙醇处理增强了Mecp 2 mRNA水平，但降低了蛋白质水平。CB 1 R的基因缺失防止，和CB 1 R拮抗剂的乙醇处理前的P7小鼠的管理抑制半胱天冬酶-3激活。此外，它逆转了MeCP 2蛋白、cAMP反应元件结合蛋白（CREB）活化和活性调节的细胞因子相关蛋白（Arc）表达的丧失。在乙醇给药前抑制caspase-3活性可防止成年小鼠中乙醇诱导的MeCP 2丢失、CREB激活、Arc表达的表观遗传调节、长时程增强（LTP）、空间记忆缺陷和包括MeCP 2在内的几种信号分子的活性依赖性损伤。总的来说，这些结果表明，乙醇诱导的CB 1 R介导的半胱天冬酶-3活化降解了P7小鼠脑中的MeCP 2蛋白，并导致成年小鼠的长期神经行为缺陷。这种CB 1 R介导的MeCP 2在活跃的突触成熟过程中的不稳定性可能会破坏突触回路的成熟，并导致神经行为异常，如在FASD动物模型中所观察到的。
Alcohol exposure can affect brain development, leading to long-lasting behavioral problems, including cognitive impairment, which together is defined as fetal alcohol spectrum disorder (FASD). However, the fundamental mechanisms through which this occurs are largely unknown. In this study, we report that the exposure of postnatal day 7 (P7) mice to ethanol activates caspase-3 via cannabinoid receptor type-1 (CB1R) in neonatal mice and causes a reduction in methylated DNA binding protein (MeCP2) levels. The developmental expression of MeCP2 in mice is closely correlated with synaptogenesis and neuronal maturation. It was shown that ethanol treatment of P7 mice enhanced Mecp2 mRNA levels but reduced protein levels. The genetic deletion of CB1R prevented, and administration of a CB1R antagonist before ethanol treatment of P7 mice inhibited caspase-3 activation. Additionally, it reversed the loss of MeCP2 protein, cAMP response element binding protein (CREB) activation, and activity-regulated cytoskeleton-associated protein (Arc) expression. The inhibition of caspase-3 activity prior to ethanol administration prevented ethanol-induced loss of MeCP2, CREB activation, epigenetic regulation of Arc expression, long-term potentiation (LTP), spatial memory deficits and activity-dependent impairment of several signaling molecules, including MeCP2, in adult mice. Collectively, these results reveal that the ethanol-induced CB1R-mediated activation of caspase-3 degrades the MeCP2 protein in the P7 mouse brain and causes long-lasting neurobehavioral deficits in adult mice. This CB1R-mediated instability of MeCP2 during active synaptic maturation may disrupt synaptic circuit maturation and lead to neurobehavioral abnormalities, as observed in this animal model of FASD.
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影响因子：
25
作者：
Ballas, Nurit;Lioy, Daniel T.;Grunseich, Christopher;Mandel, Gail
通讯作者：
Mandel, Gail
影响因子：
6.1
作者：
Asaka, Y;Jugloff, DGM;Fitzsimonds, RM
通讯作者：
Fitzsimonds, RM
影响因子：
--
作者：
Alati, Rosa;Al Mamun, Abdullah;Bor, William
通讯作者：
Bor, William
影响因子：
4.7
作者：
Basavarajappa BS;Shivakumar M;Joshi V;Subbanna S
通讯作者：
Subbanna S
DOI：
10.1111/acer.12082
发表时间：
2013-07
期刊：
Alcoholism, clinical and experimental research
影响因子：
--
作者：
Bekdash RA;Zhang C;Sarkar DK
通讯作者：
Sarkar DK