The role of the phosphatidylinositide 3-kinase-protein kinase B pathway in schizophrenia.
Neuroanatomical studies of brains from schizophrenic patients report evidence for neuronal dystrophy, while in genetic studies in schizophrenia there is evidence for mutations in growth factors and the downstream enzymes phosphatidylinositide 3-kinase (PI3K) and protein kinase B (PKB). Since the PI3K-PKB pathway is involved in cellular growth and proliferation, reduced activity of this cascade in schizophrenia could at least partly explain the neuronal dystrophy. Risk factors for schizophrenia, such as corticosteroids and cannabis, suppress the activity of the PI3K-PKB pathway. Conversely, estrogen and vitamin D, 2 factors with a moderate protective activity in schizophrenia, electroconvulsive shock therapy, and chronic treatment with antipsychotic compounds stimulate the pathway. Reduced activity of the PI3K-PKB pathway makes the brain more susceptible to virus infections, anoxia, and obstetric complications (recognized risk factors for schizophrenia), whereas a diminution of growth factor levels towards the end of puberty could contribute to an increase in schizophrenia symptoms observed around that time. On the other hand, constitutive (over)activation of the PI3K-PKB pathway increases cancer risk. Consequently, the presumed hypoactivity of the PI3K-PKB cascade might provide a partial explanation for the remarkable epidemiological finding of a reduced cancer rate in schizophrenic patients. Recognition of the role of a dysfunctional PI3K-PKB pathway in schizophrenia might help in the discovery of hitherto undetected causative gene mutations and could also lead to novel therapeutic approaches. However, a major challenge that remains to be solved is how the PI3K-PKB pathway can be activated without increasing the risk of cancer.
Kalkman
Hans O
HO
Neuroscience Research, Novartis Institutes of Biomedical Research Basel, Building WSJ-360.4.05, Novartis Pharma AG, CH4002 Basel, Switzerland. hans.kalkman@novartis.com
D000818:Animals; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D012559:Schizophrenia / Q000201:enzymology*; D015398:Signal Transduction / Q000502:physiology
D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt