Erythropoietin induction by electroconvulsive seizure, gene regulation, and antidepressant-like behavioral effects.
BACKGROUND
The neuroprotective and trophic actions of erythropoietin (EPO) have been tested in several animal models of insult, injury, and neurodegeneration. Recent studies in human volunteers demonstrated that EPO improves cognition and also elicits antidepressant effects. It is believed that the behavioral effects are mediated by EPO's trophic effect on neuronal systems. We therefore tested whether EPO is able to alter behavior and brain gene expression in rats.


METHODS
The expression of EPO and EPO receptor (EPOR) in multiple brain regions was examined by quantitative polymerase chain reaction, in situ hybridization, and immunohistochemistry. The regulation of EPO and the transcription factor hypoxia-induced factor-alpha (HIF1alpha) after electroconvulsive seizure (ECS) was investigated. Behavioral effects of EPO were tested in the rodent forced swimming and novelty-induced hypophagia (NIH) models. EPO gene profiles were obtained by microarray analysis of the hippocampus after intracerebroventricular infusion.


RESULTS
EPO and EPOR were widely expressed in the brain albeit at low levels. Highest level of EPO and EPOR were in the choroid plexus and striatum, respectively. Peripheral administration of EPO was sufficient to produce a robust antidepressant-like effect in the forced swim and NIH tests. Gene expression profiles revealed that EPO induces the expression of neurotrophic genes such as brain-derived neurotrophic factor, VGF (nonacronymic), and neuritin.


CONCLUSIONS
EPO is induced by ECS and independently exhibits antidepressant-like efficacy in the forced swim and NIH tests. EPO regulates the expression of genes implicated in antidepressant action and appears to be a candidate molecule for further testing in neuropsychiatry.
Girgenti
Matthew J
MJ
Division of Molecular Psychiatry, Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, Yale University School of Medicine, New Haven, Connecticut, USA.
Hunsberger
Joshua
J
Duman
Catharine H
CH
Sathyanesan
Monica
M
Terwilliger
Rose
R
Newton
Samuel S
SS
D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D003863:Depression / Q000188:drug therapy*; D004195:Disease Models, Animal; D004597:Electroshock / Q000009:adverse effects; D004921:Erythropoietin / Q000378:metabolism* / Q000627:therapeutic use*; D005106:Exploratory Behavior / Q000187:drug effects; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D017467:Receptors, Erythropoietin / Q000378:metabolism; D012640:Seizures / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D013550:Swimming
D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017467:Receptors, Erythropoietin; D004921:Erythropoietin