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

Pioglitazone is a member of the thiolazinedione (TZD) drug family (that appeared in our knockdown signature connectivity analysis) that is approved to treat type 2 diabetes and hyperglycemia (48) . Pioglitazone is a synthetic ligand for PPARγ, a nuclear receptor that is responsible for the regulation of several bioenergetic functions such as lipid homeostasis, adipocyte differentiation, and insulin sensitivity (48, 49) . Interestingly, PPARγ agonists have the ability to reduce oxidative stress (via mediating nitric oxide production) as well as modifying mitochondrial metabolism by interacting with proteins associated with mitochondrial function (mitoNEET proteins) (49) (50) (51) (52) (53) . Activation of PPARγ via pioglitazone can also alter the transcription and expression of GLUT1, leading to changes in glucose uptake through PPARγ and other mechanisms (48, 54) . Thus, we hypothesize that treatment with pioglitazone will help restore cognitive endophenotypes associated with schizophrenia in the GluN1 knockdown model via stimulation of metabolic pathways.