Abstract
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 protein or knocked down through gene deletion/mutation, implicating CREB in schizophrenia and antipsychotic drugs efficacy are also discussed. Targeting research and drug development on CREB could potentially accelerate the development of novel medications against schizophrenia.
Highlights
The cAMP-response element binding protein (CREB) is localized in the nucleus and acts as a transcription factor, which binds to the cAMP response element (CRE) of the promoters of its target genes, upon phosphorylation at Ser133 by different receptor-activated protein kinases, such as protein kinase A (PKA), calmodulin-dependent protein kinase (CaMK), mitogen-activated
Upregulation of brain-derived neurotrophic factor (BDNF) mRNA expression is parallel to increased phosphorylated CREB expression (Guo et al, 2017), and inhibition of PKA/CREB pathway attenuates the level of BDNF in neurons (Xue et al, 2016)
Current studies suggest that CREB is a key integrator of diverse physiological processes in the CNS, including neurotransmission, neurodevelopment, neuronal survival, synaptic plasticity, and memory
Summary
The cAMP-response element binding protein (CREB) is localized in the nucleus and acts as a transcription factor, which binds to the cAMP response element (CRE) of the promoters of its target genes, upon phosphorylation at Ser133 by different receptor-activated protein kinases, such as protein kinase A (PKA), calmodulin-dependent protein kinase (CaMK), mitogen-activated. Recent studies propose that CREB is involved in signaling pathways leading to pathogenesis and therapy of certain mental disorders, including schizophrenia, making CREB an important focus of investigation (Ren et al, 2014). The following evidences propose CREB as a convergent dopaminergic signaling protein in schizophrenia: (1) in vitro and animal studies show that dopamine receptor signaling increases the phosphorylation of CREB (Lukasiewicz et al, 2016). The protein and gene levels of CREB and the binding activity of CREB to CRE in schizophrenic brains were significantly decreased in the cingulate gyrus (Yuan et al, 2010; Ren et al, 2014), an integral brain limbic system structure, which is involved with emotion, learning, and memory and found to be smaller and with lower neural activity in people with schizophrenia. The role of the CREB signaling pathway in the pathophysiology of schizophrenia will be discussed
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