title: Alterations in phosphatidylinositol 3-kinase activity and PTEN phosphatase in the prefrontal cortex of depressed suicide victims.
abstract: BACKGROUND
  Recent studies have reported alterations in protein kinase B (PKB)/Akt and in its downstream target, glycogen synthase kinase 3β, in depression and suicide. The aim of the present study was to investigate possible impairment of the upstream regulators, namely phosphatidylinositol 3-kinase (PI3K) and PTEN.
  
  
  METHODS
  The ventral prefrontal cortex (Brodmann's area 11) of 24 suicide victims and 24 drug-free nonsuicide subjects was used. The antemortem diagnoses of major depression disorder were obtained from the institutional records or psychological autopsy, and toxicological analyses were performed. Protein levels of PI3K and PTEN were assayed using the immunoblot method, and the kinase activity of PI3K and Akt was determined by phosphorylation of specific substrates.
  
  
  RESULTS
  A decrease was observed in the enzymatic activity of PI3K [ANOVA: F(3, 44) = 9.20; p < 0.001] and Akt1 [ANOVA: F(3, 44) = 13.59; p < 0.001], without any change in protein levels, in both depressed suicide victims and depressed nonsuicide subjects (p < 0.01 and p < 0.002, respectively). PTEN protein levels were increased in the same groups [ANOVA: F(3, 44) = 10.5; p < 0.001]. No change was observed in nondepressed suicide victims.
  
  
  CONCLUSIONS
  This study concludes that attenuation of kinase activity of PKB/Akt in depressed suicide victims may be due to the combined dysregulation of PTEN and PI3K resulting in insufficient phosphorylation of lipid second messengers. The effect is associated with major depression rather than with suicide per se. Given the cellular deficits reported in major depression, the study of enzymes involved in cell survival and neuroplasticity is particularly relevant to neurotrophic factor dysregulation in depression.
authors.affiliation: Department of Psychiatry, Geneva University Hospitals, Chêne-Bourg, Switzerland. felicien.karege@unige.ch
authors.forename: Félicien
authors.initials: F
authors.lastname: Karege
authors.forename: Nader
authors.initials: N
authors.lastname: Perroud
authors.forename: Sandra
authors.initials: S
authors.lastname: Burkhardt
authors.forename: Rafael
authors.initials: R
authors.lastname: Fernandez
authors.forename: Eladia
authors.initials: E
authors.lastname: Ballmann
authors.forename: Romano
authors.initials: R
authors.lastname: La Harpe
authors.forename: Alain
authors.initials: A
authors.lastname: Malafosse
mesh_terms: D000328:Adult; D003865:Major Depressive Disorder / Q000150:complications / Q000201:enzymology*; D005260:Female; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D010766:Phosphorylation; D017397:Prefrontal Cortex / Q000201:enzymology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013405:Suicide / Q000523:psychology*
chemical_list: D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human