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

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 ¼ 28) and nonpsychiatric control (n ¼ 21) subjects we examined catalytic activation of PI 3-kinase, and mRNA and protein levels of regulatory (p85a, p85b) and catalytic (p110a, p110b) 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 p85b and p110a and increased expression of p85a 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.

Antidepressant-like effect of zinc is dependent on signaling pathways implicated in BDNF modulation

“…Abnormalities in PI3K/Akt/GSK-3β pathway are implicated in depressive disorders. It has been demonstrated that the prefrontal cortex and hippocampus of suicide subjects with depression have a decreased activation of PI3K (Dwivedi et al, 2008). Furthermore, inhibition of GSK-3β has been reported to be associated with antidepressant effects (Beaulieu et al, 2008;Rosa et al, 2008) and GSK-3β inhibitors were reported to enhance the antidepressant-like effect of some antidepressant compounds (Budni et al, 2011;Moretti et al, 2014).…”

Altered expression of neuroplasticity-related genes in the brain of depressed suicides

“…Brain tissues from the same cohort have been used previously in various studies published by our group (Dwivedi et al, 2008; Dwivedi et al, 2009, 2010; Pandey et al, 2014). Dissected regions of interest included predominantly cortical gray matter.…”

MicroRNA as therapeutic targets for treatment of depression

“…Downstream second messenger signaling pathways involving mitogen-activated protein kinase/ERK (MEK)1, extracellular signal-regulated protein kinase (ERK)1/2, Raf-1, and B-Raf are altered in both animal models of depression and in the post-mortem brains of depressed suicide victims 27–32. In addition, phosphoinositide 3 (PI-3)-kinase, protein kinase A (PKA), and protein kinase C (PKC) signaling all show depression-associated down-regulation 33–36. Unsurprisingly, therefore, decreased activation of the downstream transcription factor cyclic adenosine monophosphate (cAMP) response element-binding (CREB) is a prominent feature in both post-mortem tissue and animal models of depression 37,38…”