The EPO/EPOR system in the brain: Search for mechanisms of action

The EPO/EPOR system in the brain: Search for mechanisms of action

by Liane Dahm
Doctoral thesis
Date of Examination:2013-05-08
Date of issue:2014-04-17
Advisor:Prof. Dr. Dr. Hannelore Ehrenreich
Referee:Prof. Dr. Dr. Hannelore Ehrenreich
Referee:Prof. Dr. Klaus-Armin Nave
Persistent Address: http://dx.doi.org/10.53846/goediss-4465

 

 

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Abstract

English

Erythropoietin (EPO) and its receptor (EPOR) are known to be essential for erythropoiesis. However, the EPO/EPOR system turned out to have additional important functions in non-hematopoietic tissue. The brain is one of the target areas and both, EPO and EPOR, are expressed in the brain. EPO has been shown to be neuroprotective and to improve the cognitive performance of patients suffering from schizophrenia and multiple sclerosis. Interestingly, the mechanism of cognitive enhancement is also present in healthy individuals and genetic common variants of EPO/EPOR can actually influence cognitive performance. The cellular and molecular basis of this phenomenon is not totally understood and by systemically administered EPO, it is difficult to separate the direct effect on neural cells from hematopoietic effects through enhanced tissue oxygenation. In this study, a transgenic mouse line was generated expressing a constitutively active EPOR (cEPOR) in GABAergic and glycinergic interneurons in order to enable us to specifically examine the impact of EPO/EPOR on cognition, when expressed in inhibitory neurons. For this purpose, the cEPOR construct was inserted into the Viaat bacterial artificial chromosome (BAC) RP23-392P11 and microinjected into fertilized eggs of C57BL/6N females. Nine independent mouse strains were generated by breeding the founders with wildtype mice. The strains showed varying levels of construct expression and one strain actually had an insertion of different copy numbers in two different chromosomes. This relatively rare event in strain D14-0023 was further analyzed. Indeed, the offspring of D14-0023 segregated into low and high expressers, which was confirmed on the mRNA and protein levels. The phenotype of low and high expressers was then investigated in behavior and electrophysiological tests. Here, the basic behavior of the transgenic mice appeared to be comparable to wildtypes with respect to anxiety, olfaction, hearing, motor performance and pain perception. In the hole board working memory task, the transgenic mice showed a worse performance in rule learning in the acquisition phase, but no significant differences between the low and high expressers. Electrophysiological tests were conducted with the high expressers, measuring gamma oscillation and long term potentiation in the hippocampus. Whereas a significant influence of cEPOR could not be found in the gamma oscillation, short and long-term potentiation was increased. Hence, the study provides new information about the influence of the EPO/EPOR system on synaptic plasticity and cognitive performance. Importantly, the effects are pure neuronal effects, excluding hematopoietic side effects as confounding factors.
Keywords: Erythropoietin; Cognition; EPOR
 
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