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

In a cohort of mice separate from our pioglitazone studies, we used a mouse anti-PSD-95 antibody to capture PSD-95 protein complexes from samples (3 male WT, 3 male GluN1 knockdown). The affinity purified samples were enriched for PSD95 when compared to the supernatant and total homogenate ( Figure 5A ). Following mass spectrometry on affinity purified samples, we analyzed the top 20 increased proteins in GluN1 knockdown mice relative to WT mice with Ingenuity Pathway Analysis (IPA). The top 5 implicated pathways in the GluN1 knockdown mice were gluconeogenesis, glucose metabolism, pyruvate and citric acid metabolism, metabolism of carbohydrates, and glycogen storage disease ( Figure 5B ). Finally, we examined mRNA expression of metabolic transporters (MCT1, MCT2, MCT4, GLUT1, GLUT3) using real time quantitative polymerase chain reaction (RT-qPCR) in a cohort of GluN1 knockdown and wildtype (WT) mice (n=5 per group). We found significant decreases in GLUT1 (47%, p=0.018) and GLUT3 (34%, p=0.013) in GluN1 knockdown mice compared to WT controls ( Figure 5C ), confirming that a strategy to increase glucose uptake capacity might be a successful intervention for schizophrenia.