Altered CREB Binding to Activity-Dependent Genes in Serine Racemase Deficient Mice, a Mouse Model of Schizophrenia.,ACS Chemical Neuroscience

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Altered CREB Binding to Activity-Dependent Genes in Serine Racemase Deficient Mice, a Mouse Model of Schizophrenia.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2017-11-27 , DOI: 10.1021/acschemneuro.7b00404
Darrick T Balu _{1,

2} , Joseph T Coyle _{1,

3}

Affiliation

cAMP-response-element-binding protein (CREB) is a transcription factor ubiquitously expressed in the brain that regulates neuroplasticity by modulating gene expression. The influx of calcium through N-methyl-d-aspartate receptors (NMDARs) is a well-defined mechanism that leads to the increased expression of CREB-dependent genes, including brain derived neurotrophic factor (BDNF), microRNA-132, and activity-regulated cytoskeleton-associated protein (Arc). These molecules are implicated in the pathophysiology of schizophrenia. We previously demonstrated that serine racemase knockout (SR-/-) mice, which exhibit NMDAR hypofunction due to a lack of the forebrain NMDAR co-agonist d-serine, also have reduced expression of CREB-dependent genes in the hippocampus. Using chromatin immunoprecipitation, we show here that, in SR-/- mice, there is less CREB bound to the promoter regions of BDNF, microRNA-132, and Arc. These data suggest that NMDAR hypofunction in SR-/- mice leads to reduced CREB binding on known activity-dependent genes, in turn contributing to their reduced expression.

中文翻译：

CREB绑定到丝氨酸消旋酶缺陷小鼠，精神分裂症的小鼠活动依赖基因的绑定。

cAMP反应元件结合蛋白（CREB）是在大脑中普遍表达的转录因子，可通过调节基因表达来调节神经可塑性。钙通过N-甲基-d-天冬氨酸受体（NMDARs）的流入是一个明确的机制，可导致CREB依赖性基因（包括脑源性神经营养因子（BDNF），microRNA-132和活性-调节的细胞骨架相关蛋白（Arc）。这些分子与精神分裂症的病理生理有关。我们以前证明，由于缺少前脑NMDAR协同激动剂d-丝氨酸而显示NMDAR功能低下的丝氨酸消旋酶敲除（SR-/-）小鼠，海马中CREB依赖性基因的表达也降低了。使用染色质免疫沉淀，我们在这里表明，在SR-/-小鼠中，与BDNF，microRNA-132和Arc的启动子区域结合的CREB较少。这些数据表明，SR-/-小鼠中的NMDAR功能低下会导致CREB与已知活性依赖基因的结合减少，进而导致其表达降低。

更新日期：2017-11-27

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