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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 ∼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. Fil: Hassouna, I.. Minufiya University; . Max Planck Institut Fur Experimentelle Medizin; Fil: Ott, C.. Max Planck Institut Fur Experimentelle Medizin; Fil: Wüstefeld, L.. Max Planck Institut Fur Experimentelle Medizin; Fil: Offen, N.. Universität Würzburg; Alemania Fil: Neher, R.A.. Max Planck Institute For Developmental Biology; Fil: Mitkovski, M.. Max Planck Institut Fur Experimentelle Medizin; Fil: Winkler, D.. Max Planck Institut Fur Experimentelle Medizin; Fil: Sperling, S.. Max Planck Institut Fur Experimentelle Medizin; Fil: Fries, L.. Universität Würzburg; Alemania Fil: Goebbels, S.. Max Planck Institut Fur Experimentelle Medizin; Fil: Vreja, I.C.. International Max Planck Research School Molecular Biology; . Universitatsmedizin Gottingen; Fil: Hagemeyer, N.. Max Planck Institut Fur Experimentelle Medizin; Fil: Dittrich, M.. Universität Würzburg; Alemania Fil: Rossetti, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Salud y Ambiente del Litoral. Universidad Nacional del Litoral. Instituto de Salud y Ambiente del Litoral; Argentina Fil: Kröhnert, K.. Universitatsmedizin Gottingen; Fil: Hannke, K.. Max Planck Institut Fur Experimentelle Medizin; Fil: Boretius, S.. Christian-albrechts-universitat Zu Kiel; Fil: Zeug, A.. Medizinische Hochschule Hannover (mhh); Fil: Höschen, C.. Universitat Technical Zu Munich; Alemania Fil: Dandekar, T.. Universität Würzburg; Alemania Fil: Dere, E.. Max Planck Institut Fur Experimentelle Medizin; Fil: Neher, E.. Max Planck Institute For Biophysical Chemistry (karl Friedrich Bonhoeffer Institute); . Deutsche Forschungsgemeinschaft (dfg); Fil: Rizzoli, S.O.. Universitatsmedizin Gottingen; . Deutsche Forschungsgemeinschaft (dfg); Fil: Nave, K.-A.. Deutsche Forschungsgemeinschaft (dfg); . Max Planck Institut Fur Experimentelle Medizin; Fil: Sirén, A.-L.. Universität Würzburg; Alemania Fil: Ehrenreich, H.. Max Planck Institut Fur Experimentelle Medizin; . Deutsche Forschungsgemeinschaft (dfg)

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 < 0.0001). In an independent healthy control sample (N > 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.

Context Schizophrenia is the collective term for a heterogeneous group of mental disorders with a still obscure biological basis. In particular, the specific contribution of risk or candidate gene variants to the complex schizophrenic phenotype is largely unknown. Objective To prepare the ground for a novel “phenomics” approach, a unique schizophrenia patient database was established by GRAS (Gottingen Research Association for Schizophrenia), designed to allow association of genetic information with quantifiable phenotypes. Because synaptic dysfunction plays a key role in schizophrenia, the complexin 2 gene ( CPLX2 ) was examined in the first phenotype-based genetic association study (PGAS) of GRAS. Design Subsequent to a classic case-control approach, we analyzed the contribution of CPLX2 polymorphisms to discrete cognitive domains within the schizophrenic population. To gain mechanistic insight into how certain CPLX2 variants influence gene expression and function, peripheral blood mononuclear cells of patients, Cplx -null mutant mice, and transfected cells were investigated. Setting Coordinating research center (Max Planck Institute of Experimental Medicine) and 23 collaborating psychiatric centers all over Germany. Participants One thousand seventy-one patients with schizophrenia ( DSM-IV ) examined by an invariant investigator team, resulting in the GRAS database with more than 3000 phenotypic data points per patient, and 1079 healthy control subjects of comparable ethnicity. Main Outcome Measure Cognitive performance including executive functioning, reasoning, and verbal learning/memory. Results Six single-nucleotide polymorphisms, distributed over the whole CPLX2 gene, were found to be highly associated with current cognition of schizophrenic subjects but only marginally with premorbid intelligence. Correspondingly, in Cplx2 -null mutant mice, prominent cognitive loss of function was obtained only in combination with a minor brain lesion applied during puberty, modeling a clinically relevant environmental risk (“second hit”) for schizophrenia. In the human CPLX2 gene, 1 of the identified 6 cognition-relevant single-nucleotide polymorphisms, rs3822674 in the 3′ untranslated region, was detected to influence microRNA-498 binding and gene expression. The same marker was associated with differential expression of CPLX2 in peripheral blood mononuclear cells. Conclusions The PGAS allows identification of marker-associated clinical/biological traits. Current cognitive performance in schizophrenic patients is modified by CPLX2 variants modulating posttranscriptional gene expression.

Background Erythropoietin (EPO) improves cognition of human subjects in the clinical setting by as yet unknown mechanisms. We developed a mouse model of robust cognitive improvement by EPO to obtain the first clues of how EPO influences cognition, and how it may act on hippocampal neurons to modulate plasticity. Results We show here that a 3-week treatment of young mice with EPO enhances long-term potentiation (LTP), a cellular correlate of learning processes in the CA1 region of the hippocampus. This treatment concomitantly alters short-term synaptic plasticity and synaptic transmission, shifting the balance of excitatory and inhibitory activity. These effects are accompanied by an improvement of hippocampus dependent memory, persisting for 3 weeks after termination of EPO injections, and are independent of changes in hematocrit. Networks of EPO-treated primary hippocampal neurons develop lower overall spiking activity but enhanced bursting in discrete neuronal assemblies. At the level of developing single neurons, EPO treatment reduces the typical increase in excitatory synaptic transmission without changing the number of synaptic boutons, consistent with prolonged functional silencing of synapses. Conclusion We conclude that EPO improves hippocampus dependent memory by modulating plasticity, synaptic connectivity and activity of memory-related neuronal networks. These mechanisms of action of EPO have to be further exploited for treating neuropsychiatric diseases.