cAMP Response Element-Binding Protein (CREB): A Possible Signaling Molecule Link in the Pathophysiology of Schizophrenia

作者：Haitao Wang, Jiangping Xu, Philip Lazarovici, Rémi Quirion, Wenhua Zheng · 发表于：Frontiers in Molecular Neuroscience · 年份：2018 · DOI：10.3389/fnmol.2018.00255 · 被引用次数：460 · 研究领域：Receptor Mechanisms and Signaling、Nuclear Receptors and Signaling、Neuropeptides and Animal Physiology

Dopamine is a brain neurotransmitter involved in the pathology of schizophrenia. The dopamine hypothesis states that, in schizophrenia, dopaminergic signal transduction is hyperactive. The cAMP-response element binding protein (CREB) is an intracellular protein that regulates the expression of genes that are important in dopaminergic neurons. Dopamine affects the phosphorylation of CREB via G protein-coupled receptors. Neurotrophins, such as brain derived growth factor (BDNF), are critical regulators during neurodevelopment and synaptic plasticity. The CREB is one of the major regulators of neurotrophin responses since phosphorylated CREB binds to a specific sequence in the promoter of BDNF and regulates its transcription. Moreover, susceptibility genes associated with schizophrenia also target and stimulate the activity of CREB. Abnormalities of CREB expression is observed in the brain of individuals suffering from schizophrenia, and two variants (-933T to C and -413G to A) were found only in schizophrenic patients. The CREB was also involved in the therapy of animal models of schizophrenia. Collectively, these findings suggest a link between CREB and the pathophysiology of schizophrenia. This review provides an overview of CREB structure, expression, and biological functions in the brain and its interaction with dopamine signaling, neurotrophins, and susceptibility genes for schizophrenia. Animal models in which CREB function is modulated, by either overexpression of the pr...