Common variants of the genes encoding erythropoietin and its receptor modulate cognitive performance in schizophrenia

Erythropoietin (EPO) improves cognitive performance in clinical studies and rodent experiments. We hypothesized that an intrinsic role of EPO for cognition exists, with particular relevance in situations of cognitive decline, which is reflected by associations of EPO and EPO receptor (EPOR) genotypes with cognitive functions. To prove this hypothesis, schizophrenic patients (N > 1000) were genotyped for 5′ upstream-located gene variants, EPO SNP rs1617640 (T/G) and EPOR STR(GA)n. Associations of these variants were obtained for cognitive processing speed, fine motor skills and short-term memory readouts, with one particular combination of genotypes superior to all others (p 800), these associations were confirmed. A matching preclinical study with mice demonstrated cognitive processing speed and memory enhanced upon transgenic expression of constitutively active EPOR in pyramidal neurons of cortex and hippocampus. We thus predicted that the human genotypes associated with better cognition would reflect gain-of-function effects. Indeed, reporter gene assays and quantitative transcriptional analysis of peripheral blood mononuclear cells showed genotype-dependent EPO/EPOR expression differences. Together, these findings reveal a role of endogenous EPO/EPOR for cognition, at least in schizophrenic patients

Shift in expression of HLA-G mRNA spliceforms in pregnancies complicated by preeclampsia.

Contains fulltext : 57781.pdf (publisher's version ) (Closed access)OBJECTIVE: Despite emerging data on the in vitro modulatory effects of trophoblast-associated human leukocyte antigen G (HLA-G), its in vivo function needs to be determined. Immunohistochemical studies show a decrease in protein expression of trophoblast HLA-G in preeclampsia. Such a decrease in protein might be the consequence of a shift in HLA-G mRNA spliceform patterns. In an exploratory pilot study we determined trophoblast HLA-G mRNA spliceform distribution in preeclampsia. METHODS: Placental samples were collected immediately after cesarean delivery from pregnancies complicated by preeclampsia or the syndrome hemolysis, elevated liver enzymes, and low platelet count (HELLP) and uncomplicated normotensive pregnancies as controls. HLA-G mRNA spliceform distribution was analyzed using a semiquantitative reverse transcriptase polymerase chain reaction procedure. RESULTS: Analysis of HLA-G spliceform distribution showed a significant increase in frequency of the G5 form encoding for a soluble HLA-G molecule in preeclampsia. This increase in G5 form was not found in pregnancies complicated by HELLP. CONCLUSION: The increased frequency in the expression of the HLA-G G5 spliceform may play a role in the pathophysiology of preeclampsia, in particular through a recently suggested effect of this soluble HLA-G molecule on remodeling of the spiral arteries

Revisiting adult neurogenesis and the role of erythropoietin for neuronal and oligodendroglial differentiation in the hippocampus

Recombinant human erythropoietin (EPO) improves cognitive performance in neuropsychiatric diseases ranging from schizophrenia and multiple sclerosis to major depression and bipolar disease. This consistent EPO effect on cognition is independent of its role in hematopoiesis. The cellular mechanisms of action in brain, however, have remained unclear. Here we studied healthy young mice and observed that 3-week EPO administration was associated with an increased number of pyramidal neurons and oligodendrocytes in the hippocampus of similar to 20%. Under constant cognitive challenge, neuron numbers remained elevated until >6 months of age. Surprisingly, this increase occurred in absence of altered cell proliferation or apoptosis. After feeding a $^{15}$N-leucine diet, we used nanoscopic secondary ion mass spectrometry, and found that in EPO-treated mice, an equivalent number of neurons was defined by elevated $^{15}$N-leucine incorporation. In EPO-treated NG2-Cre-ERT2 mice, we confirmed enhanced differentiation of preexisting oligodendrocyte precursors in the absence of elevated DNA synthesis. A corresponding analysis of the neuronal lineage awaits the identification of suitable neuronal markers. In cultured neurospheres, EPO reduced Sox9 and stimulated miR124, associated with advanced neuronal differentiation. We are discussing a resulting working model in which EPO drives the differentiation of non-dividing precursors in both (NG2+) oligodendroglial and neuronal lineages. As endogenous EPO expression is induced by brain injury, such a mechanism of adult neurogenesis may be relevant for central nervous system regeneration