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

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...

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Published in	Frontiers in molecular neuroscience Vol. 11; p. 255
Main Authors	Wang, Haitao, Xu, Jiangping, Lazarovici, Philip, Quirion, Remi, Zheng, Wenhua
Format	Journal Article
Language	English
Published	Switzerland Frontiers Research Foundation 30.08.2018 Frontiers Media S.A
Subjects	Animal models Antipsychotics Brain Brain-derived neurotrophic factor CREB Cyclic AMP response element-binding protein Dopamine Dopamine receptors Drug development Emotional disorders G protein-coupled receptors Gene deletion Genes Kinases Memory Mental disorders Neurodevelopment Neurogenesis Neuroscience neurotransmitter Neurotrophic factors Patients Phosphorylation Proteins Psychiatry Psychotropic drugs RNA polymerase Schizophrenia Signal transduction Synaptic plasticity Transcription factors China CREB schizophrenia neurodevelopment neurotransmitter dopamine
Online Access	Get full text
ISSN	1662-5099 1662-5099
DOI	10.3389/fnmol.2018.00255

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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.
AbstractList	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. Dopamine is a brain neurotransmitter involved in the pathology of schizophrenia. The dopamine hypothesis states that in schizophrenia dopaminergic signal transduction is hyperactive. cAMP-response element binding protein (CREB) is a transcription factor that is activated by various extracellular stimuli and regulates the expression of genes 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. CREB is one of the major regulators of neurotrophin responses since activated CREB binds to the promoter region of BDNF and regulate its transcription. Moreover, susceptibility genes associated with schizophrenia also target and stimulate the activity of CREB. Abnormalities of CREB expression is observed in the postmortem brain of subjects with schizophrenia, and two variants (-933T to C and -413G to A) were found only in schizophrenic patients. CREB was also involved in the therapy of animal models of schizophrenia. Collectively, these findings suggest a link between CREB and pathophysiology of schizophrenia. This review provides an overview of CREB structure, expression and biological functions in the brain, 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 enable the development of antidepressant medications with fundamentally new mechanisms of action. 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.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.
Author	Xu, Jiangping Lazarovici, Philip Zheng, Wenhua Quirion, Remi Wang, Haitao
AuthorAffiliation	1 Department of Neuropharmacology and Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University , Guangzhou , China 4 Faculty of Health Sciences, University of Macau , Taipa , China 2 School of Pharmacy Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem , Jerusalem , Israel 3 Douglas Mental Health University Institute, McGill University , Montreal, QC , Canada
AuthorAffiliation_xml	– name: 1 Department of Neuropharmacology and Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University , Guangzhou , China – name: 3 Douglas Mental Health University Institute, McGill University , Montreal, QC , Canada – name: 2 School of Pharmacy Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem , Jerusalem , Israel – name: 4 Faculty of Health Sciences, University of Macau , Taipa , China
Author_xml	– sequence: 1 givenname: Haitao surname: Wang fullname: Wang, Haitao – sequence: 2 givenname: Jiangping surname: Xu fullname: Xu, Jiangping – sequence: 3 givenname: Philip surname: Lazarovici fullname: Lazarovici, Philip – sequence: 4 givenname: Remi surname: Quirion fullname: Quirion, Remi – sequence: 5 givenname: Wenhua surname: Zheng fullname: Zheng, Wenhua
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/30214393$$D View this record in MEDLINE/PubMed
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Snippet	Dopamine is a brain neurotransmitter involved in the pathology of schizophrenia. The dopamine hypothesis states that, in schizophrenia, dopaminergic signal... Dopamine is a brain neurotransmitter involved in the pathology of schizophrenia. The dopamine hypothesis states that in schizophrenia dopaminergic signal...
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SubjectTerms	Animal models Antipsychotics Brain Brain-derived neurotrophic factor CREB Cyclic AMP response element-binding protein Dopamine Dopamine receptors Drug development Emotional disorders G protein-coupled receptors Gene deletion Genes Kinases Memory Mental disorders Neurodevelopment Neurogenesis Neuroscience neurotransmitter Neurotrophic factors Patients Phosphorylation Proteins Psychiatry Psychotropic drugs RNA polymerase Schizophrenia Signal transduction Synaptic plasticity Transcription factors
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Title	cAMP Response Element-Binding Protein (CREB): A Possible Signaling Molecule Link in the Pathophysiology of Schizophrenia
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