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

To test this hypothesis, we first examined metabolic pathways in the GluN1 knockdown model of schizophrenia. GluN1 knockdown animals display a wide variety of endophenotypes associated with schizophrenia, including deficits in cognition (40) . We found that top pathways associated with protein changes at the synapse in GluN1 knockdown mice compared to WT controls were metabolic in nature ( Figure 5B ). Additionally, expression of glucose transporters (GLUT1 and GLUT3) were significantly decreased in the frontal cortex of GluN1 knockdown mice ( Figure 5C ). These results suggest there are similar abnormalities in bioenergetic systems in this model to schizophrenia, and that modulating these systems are viable treatment strategies. Thus, we examined the effects of pioglitazone, a PPAR agonist that increases glucose uptake, on behavioral endpoints in the GluN1 knockdown model. Pharmacological The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It . https://doi.org/10.1101/338392 doi: bioRxiv preprint manipulation of glycolytic pathways via pioglitazone could stimulate glucose uptake and metabolism, possibly restoring some behavioral deficits. We are also able to control for medication treatments, which can be difficult to interpret in human studies. It is important to distinguish significant metabolic changes as underlying features of the illness and not epiphenomena related to treatment with antipsychotics.