Connectivity Analyses of Bioenergetic Changes in Schizophrenia: Identification of Novel Treatments

Abstract

We utilized a cell-level approach to examine glycolytic pathways in the DLPFC of subjects with schizophrenia (n=16) and control (n=16) subjects and found decreased mRNA expression of glycolytic enzymes in pyramidal neurons, but not astrocytes. To replicate these novel bioenergetic findings, we probed independent datasets for bioenergetic targets and found similar abnormalities. Next, we used a novel strategy to build a schizophrenia bioenergetic profile by a tailored application of the Library of Integrated Network-Based Cellular Signatures data portal (iLINCS) and investigated connected cellular pathways, kinases, and transcription factors using Enrichr. Finally, with the goal of identifying drugs capable of "reversing" the bioenergetic schizophrenia signature, we performed a connectivity analysis with iLINCS and identified peroxisome proliferator-activated receptor (PPAR) agonists as promising therapeutic targets. We administered a PPAR agonist to the GluN1 knockdown model of schizophrenia and found it improved long-term memory. Taken together, our findings suggest that tailored bioinformatics approaches, coupled with the LINCS library of transcriptional signatures of chemical and genetic perturbagens may be employed to identify novel treatment strategies for schizophrenia and related diseases.

Is There a Future for PPARs in the Treatment of Neuropsychiatric Disorders?

“…Pioglitazone provided benefits in reversing this metabolic condition. Also, administration of pioglitazone to the GluN1 knockdown model of schizophrenia improved long-term memory and helped to restore cognitive endophenotypes [50]. Unlike most anti-psychotics, pioglitazone had a restorative effect on cognitive function (measured by the puzzle box assay), thus suggesting a potential impact of pioglitazone as an augmentation therapy in schizophrenia [50,110].…”

Integrative Omics for Informed Drug Repurposing: Targeting CNS Disorders

“…It also increases expression of glucose transporters. As a confirmation study, decreased levels of the glucose transporters GLUT1 and GLUT3 were found in schizophrenia as well as in the Grin1KD mouse, an animal model of developmental disorders [105]. Treatment of Grin1KD mice with pioglitazone for 1 week improved executive function.…”

“…Combining the changes in expression of a small number of genes in a disease state along with LINCS gene knockdown and/or overexpression signatures permits interrogation of the LINCS perturbagen database for compounds that reverse or simulate consensus "seed gene" signatures. This approach is built on the assumption that seed genespecific signatures would reflect disease-associated changes at the network level [105].…”

“…Treatment of Grin1KD mice with pioglitazone for 1 week improved executive function. Start-to-finish this work illustrates the potential for repurposing FDA approved drugs, starting with candidate or seed genes, followed by bioinformatics-driven identification of drug candidates, and finally testing in animal models [105]. 1 V. Caveats.…”

Quantitative proteomic analysis shows alterations in patient Rett syndrome iPSC cultures at early neuronal progenitor stages

“…A previous study demonstrated that during early brain formation disturbances in the metabolism produces changes in the morphological and biochemical development of the brains [50]. Another study further observed that models with synaptic defects during development fail to couple to metabolic pathways [51].…”