Connectivity analyses of bioenergetic changes in schizophrenia: Identification of novel treatments

Courtney R. Sullivan; Catharine A. Mielnik; Sinead M. O’Donovan; Adam J. Funk; Eduard Bentea; Erica A.K. DePasquale; Zhexing Wen; Vahram Haroutunian; Pavel Katsel; Amy J. Ramsey; Jarek Meller; Robert E. McCullumsmith

We also found a decrease in the mRNA expression of GPI in an enriched population of pyramidal neurons in schizophrenia. GPI is a dimeric cytoplasmic enzyme that catalyzes the reversible isomerization of glucose-6-phosphate to fructose-6-phosphate in the second step in the glycolytic pathway. When expressed extracellularly, the GPI protein functions as a neurotrophic factor that promotes neuronal survival (71) . One study found an increase in glucose-6-phosphate levels, as well as several other metabolites in the glycolytic pathway, in peripheral blood mononuclear cells of schizophrenia patients, suggesting improper functioning of glycolytic enzymes (72) . Other data suggest that GPI deficiency results in an accumulation of glucose-6-phosphate and over activation of the mammalian target of rapamycin (mTOR) pathway (73) . A decrease in GPI expression in pyramidal neurons could contribute to dysregulation of both glycolysis and mTOR signaling. A disruption in mTOR signaling could affect protein synthesis and lead to aberrant neuronal growth and synapse connectivity.