Dataset Information

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) 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.

SUBMITTER: Sullivan CR

PROVIDER: S-EPMC7584383 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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

Sullivan Courtney R CR Mielnik Catharine A CA O'Donovan Sinead M SM Funk Adam J AJ Bentea Eduard E DePasquale Erica A EA Alganem Khaled K Wen Zhexing Z Haroutunian Vahram V Katsel Pavel P Ramsey Amy J AJ Meller Jarek J McCullumsmith Robert E RE

Molecular neurobiology 20181018 6

We utilized a cell-level approach to examine glycolytic pathways in the DLPFC of subjects with schizophrenia (n = 16) and control (n = 16) 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 Int ...[more]

PMID: 30338483

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Project description:Schizophrenia is a psychiatric disorder that causes great suffering and debilitation worldwide. We have a multitude of medications that are effective for psychosis. However, these have not been successful in treating the negative and cognitive symptom domains of schizophrenia. These symptoms are responsible for the larger part of functional impairments that result from schizophrenia. In addition, there are many patients for whom no significant improvement is achieved even in the positive symptom domain. Hence, other treatment modalities have been explored to help these patients. Electroconvulsive therapy and transcranial magnetic stimulation are two of the most promising adjunct treatment methods for medication resistant schizophrenia. Electroconvulsive therapy is the gold standard treatment for catatonias whether associated with schizophrenia, mood disorders or other non-psychiatric disorders. Although not effective for negative symptoms, electroconvulsive therapy provides substantial augmentation to antipsychotic medications in improving positive symptoms and overall severity. Electroconvulsive therapy should be considered more often in patients with inadequate response to antipsychotic medications even when they do not have prominent affective symptoms. Transcranial magnetic stimulation has emerged as a promising useful therapeutic tool in targeting medication resistant auditory hallucinations and negative symptoms. Transcranial magnetic stimulation has proven to be very safe and well-tolerated by the patients in spite of its labor intensiveness. The incorporation of transcranial magnetic stimulation to routine clinical use awaits further studies to substantiate its efficacy and to optimize and customize treatment parameters to individual patients and their symptom patterns. Moreover, combining transcranial magnetic stimulation with electroconvulsive therapy to synergize their likely different mechanisms of action is another exciting possibility.

Dataset Information

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

Publications

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

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