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Abnormal expression and functional characteristics of cyclic adenosine monophosphate response element binding protein
Yogesh Dwivedi1, Jagadeesh Sridhara Rao, Hooriyah S Rizavi
1Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 60612, USA. ydwivedi@psych.uic.edu
Background:
Cyclic adenosine monophosphate response element binding protein (CREB) is a transcription factor that, on phosphorylation by protein kinases, is activated, and in response, regulates the transcription of many neuronally expressed genes. In view of the recent observations that catalytic properties and/or expression of many kinases that mediate their physiological responses through the activation of CREB are altered in the postmortem brain of subjects who commit suicide (hereafter referred to as suicide subjects), we examined the status of CREB in suicidal behavior.
Methods:
These studies were performed in Brodmann area (BA) 9 and hippocampus obtained from 26 suicide subjects and 20 nonpsychiatric healthy control subjects. Messenger RNA levels of CREB and neuron-specific enolase were determined in total RNA by means of quantitative reverse transcriptase-polymerase chain reaction. Protein levels and the functional characteristics of CREB were determined in nuclear fractions by means of Western blot and cyclic adenosine monophosphate response element (CRE)-DNA binding activity, respectively. In the same nuclear fraction, we determined the catalytic activity of cyclic adenosine monophosphate-stimulated protein kinase A by means of enzymatic assay.
Results:
We observed a significant reduction in messenger RNA and protein levels of CREB, CRE-DNA binding activity, and basal and cyclic adenosine monophosphate-stimulated protein kinase A activity in BA 9 and hippocampus of suicide subjects, without any change in messenger RNA levels of neuron-specific enolase in BA 9. Except for protein kinase A activity, changes in CREB expression and CRE-DNA binding activity were present in all suicide subjects, irrespective of diagnosis. These changes were unrelated to postmortem intervals, age, sex, or antidepressant treatment.
Conclusions:
Given the significance of CREB in mediating various physiological functions through gene transcription, our results of decreased expression and functional characteristics of CREB in postmortem brain of suicide subjects suggest that CREB may play an important role in suicidal behavior.
Insights
Cyclic adenosine monophosphate response element binding protein (CREB) levels and activity are reduced in the brains of suicide subjects. These findings suggest CREB plays a role in suicidal behavior.
Area of Science:
- Neuroscience
- Molecular Biology
- Psychiatry
Background:
- Cyclic adenosine monophosphate response element binding protein (CREB) is a transcription factor crucial for regulating gene expression in neurons.
- Altered kinase activity linked to CREB activation has been observed in the postmortem brains of suicide subjects.
- This study investigates the role of CREB in suicidal behavior.
Purpose of the Study:
- To examine the expression and functional status of CREB in the brain of individuals who died by suicide.
- To determine if changes in CREB are associated with suicidal behavior.
Main Methods:
- Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was used to measure messenger RNA (mRNA) levels of CREB and neuron-specific enolase.
- Western blot analysis determined CREB protein levels.
- Cyclic adenosine monophosphate response element (CRE)-DNA binding activity and protein kinase A (PKA) activity were assessed in nuclear fractions.
Main Results:
- A significant reduction in CREB mRNA and protein levels was observed in Brodmann area 9 (BA 9) and hippocampus of suicide subjects.
- CRE-DNA binding activity and both basal and stimulated PKA activity were also decreased in the brains of suicide subjects.
- These alterations in CREB were consistent across suicide subjects, regardless of diagnosis, and were not influenced by postmortem interval, age, sex, or antidepressant treatment.
Conclusions:
- Decreased expression and functional characteristics of CREB in the postmortem brain suggest its involvement in the pathophysiology of suicidal behavior.
- CREB's role in mediating physiological functions through gene transcription highlights its potential significance in suicidal behavior.
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