Abstract
Phosphoinositide 3 (PI 3)-kinase is one of the key signaling enzymes that participates in a myriad of physiological functions in brain and is utilized by neurotrophins to mediate neuronal plasticity, cell survival, and inhibition of apoptosis for several neuronal subtypes. Our recent demonstration that expression of neurotrophic factors and activation of the receptor tyrosine kinase B are significantly altered in postmortem brain of suicide subjects led us to examine whether suicide brain is associated with alterations in PI 3-kinase signaling. In prefrontal cortex (PFC), hippocampus, and cerebellum of suicide (n=28) and nonpsychiatric control (n=21) subjects we examined catalytic activation of PI 3-kinase, and mRNA and protein levels of regulatory (p85α, p85β) and catalytic (p110α, p110β) subunits of PI 3-kinase. It was observed that the catalytic activity of PI 3-kinase was significantly reduced in PFC and hippocampus of suicide subjects compared with nonpsychiatric control subjects. Competitive PCR analysis revealed significantly reduced mRNA expression of p85β and p110α and increased expression of p85α subunit isoforms in PFC and hippocampus of suicide subjects. Alterations in these catalytic and regulatory subunits were accompanied by changes in their respective protein levels. These changes were not present in cerebellum of suicide subjects. Also, these changes were present in all suicide subjects irrespective of psychiatric diagnosis. Our findings of reduced activation and altered expression of specific PI 3-kinase regulatory and catalytic subunit isoforms demonstrate abnormalities in this signaling pathway in postmortem brain of suicide subjects and suggest possible involvement of aberrant PI 3-kinase signaling in the pathogenic mechanisms of suicide.
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Acknowledgements
This research was supported by NIMH R0168777, NARSAD, and the American Foundation for Suicide Prevention to Dr Dwivedi, NIMH RO1MH48153 to Dr Pandey, and NIMH R01MH60744 to Dr Roberts. We thank Prof. Robert Gibbons for his help analyzing data. We also thank Ms Miljana Petkovic and Ms Barbara Brown for their help in organizing the brain tissue, and members of the Maryland Brain Collection for their efforts, particularly in family interviews and dissection. We are grateful for the cooperation of the Office of the Chief Medical Examiner in Baltimore, MD, USA.
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The authors declare that, except for income received from the primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional services and that there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.
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Dwivedi, Y., Rizavi, H., Teppen, T. et al. Lower Phosphoinositide 3-Kinase (PI 3-kinase) Activity and Differential Expression Levels of Selective Catalytic and Regulatory PI 3-Kinase Subunit Isoforms in Prefrontal Cortex and Hippocampus of Suicide Subjects. Neuropsychopharmacol 33, 2324–2340 (2008). https://doi.org/10.1038/sj.npp.1301641
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DOI: https://doi.org/10.1038/sj.npp.1301641
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