1. ¹Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA
2. ²Department of Psychiatry, University of Alabama at Birmingham, Birmingham, AL, USA
3. ³Maryland Psychiatric Research Center, Baltimore, MD, USA

Correspondence: Dr Y Dwivedi, Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 West Taylor Street, Chicago, IL 60612, USA. Tel: +312 413 4557; Fax: +312 355 3857; E-mail: ydwivedi@psych.uic.edu

Received 5 July 2007; Revised 22 October 2007; Accepted 25 October 2007; Published online 12 December 2007.

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 (p85, p85) and catalytic (p110, p110) 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 p85 and p110 and increased expression of p85 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.