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

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.

Initiated by CREB: Resolving Gene Regulatory Programs in Learning and Memory

“…Interestingly, CREB genes are spliced in different isoforms, which can function as transcription activators or repressors. Repressor and activator isoforms seem to compete for CRE sequences, so the ratio between them is a part of their gene regulation function . An important step to regulate CREB activity is by phosphorylation and dephosphorylation .…”

“…This signaling mechanism is well recognized for its role in learning and memory from invertebrates to mammals . Besides PKA, CREB1 is also phosphorylated by Ca 2+ ‐signaling through Ca 2+ ‐calmodulin‐dependent kinases (CamK) . Ca 2+ is important in neuronal processes, e.g., through voltage‐gated channels or glutamate receptors .…”

“…Ca 2+ is important in neuronal processes, e.g., through voltage‐gated channels or glutamate receptors . Another upstream effector of CREB activation is growth signaling through receptor‐tyrosine kinases (RTK) and their downstream kinases such as PKB/AKT, extracellular‐signal‐regulated kinase (ERK), or mitogen‐activated protein kinase (MAPK) (Figure ). All the mentioned kinases and other kinases can either phosphorylate CREB at Ser‐133 or other phosphorylation sites on the protein.…”

“…A further prominent CREB target is the brain‐derived neurotrophic factor (BDNF), which is involved in the development of the nervous system and is also a key regulator in synaptic plasticity . BDNF is secreted and may act in an autocrine and paracrine fashion (Figure ).…”

“…BDNF is secreted and may act in an autocrine and paracrine fashion (Figure ). Interestingly, BDNF is both upstream and downstream of CREB . Whereas BDNF expression is mediated by CREB, binding of BDNF to its receptor tropomyosin receptor kinase B (TrkB) triggers CREB activity.…”