Carbamoylated erythropoietin modulates cognitive outcomes of social defeat and differentially regulates gene expression in the dorsal and ventral hippocampus

Monica Sathyanesan, Michael J. Watt, Jacob M. Haiar, Jamie L Scholl, Shaydel R. Davies, Riley T. Paulsen, Jayme Wiederin, Pawel S Ciborowski, Samuel Sathyanesan

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Cognitive deficits are widespread in psychiatric disorders and frequently as debilitating as the affective component. Widely prescribed antidepressants for treating depressive disorders have limited efficacy in normalizing cognitive function. Erythropoietin (Epo) has been shown to improve cognitive function in schizophrenia and treatment resistant depressed patients. However, the potent elevation of red blood cell counts by Epo can cause hematological complications in non-anemic patients. We investigated a chemically engineered, posttranslational modification of Epo, carbamoylation, which renders it non-erythropoietic. We conducted mass-spectrometry-based peptide mapping of carbamoylated Epo (Cepo) and tested its ability to improve cognitive function after social defeat stress. Gene expression analysis in discrete brain regions was performed to obtain mechanistic insight of Cepo action. Cepo reversed stress-induced spatial working memory deficits while affecting long-term (24 h) novel object recognition in these rats. Contextual fear conditioning following defeat was enhanced by Cepo, but attenuated in controls. However, Cepo improved fear extinction in all rats compared to vehicle treatment. Cepo induced differential gene expression of BDNF, VGF, Arc, TH. and neuritin in the mPFC and discrete hippocampal subfields, with strongest induction in the dorsal hippocampus. Analysis of gene-brain region-behavior interactions showed that Cepo-induced neurotrophic mechanisms influence cognitive function. Carbamoylated erythropoietin can be developed as a therapeutic neurotrophic agent to treat cognitive dysfunction in neuropsychiatric diseases. Due to its distinct mechanism of action, it is unlikely to cross react with the activity of currently prescribed small molecule drugs and can be used as an add-on biologic drug.

Original languageEnglish (US)
Article number113
JournalTranslational Psychiatry
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018

Fingerprint

Erythropoietin
Hippocampus
Cognition
Gene Expression
Fear
Erythrocyte Count
Aptitude
Peptide Mapping
Brain-Derived Neurotrophic Factor
Memory Disorders
Brain
Post Translational Protein Processing
Depressive Disorder
Short-Term Memory
Pharmaceutical Preparations
Antidepressive Agents
Psychiatry
Mass Spectrometry
Schizophrenia
Therapeutics

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Biological Psychiatry

Cite this

Carbamoylated erythropoietin modulates cognitive outcomes of social defeat and differentially regulates gene expression in the dorsal and ventral hippocampus. / Sathyanesan, Monica; Watt, Michael J.; Haiar, Jacob M.; Scholl, Jamie L; Davies, Shaydel R.; Paulsen, Riley T.; Wiederin, Jayme; Ciborowski, Pawel S; Sathyanesan, Samuel.

In: Translational Psychiatry, Vol. 8, No. 1, 113, 01.12.2018.

Research output: Contribution to journalArticle

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