NOVEL APPROACHES TO MODELING AND TREATMENT OF COGNITIVE DEFICITS IN NEUROPSYCHIATRIC DISEASES

Kognitive Defizite und Beeinträchtigungen höherer Hirnfunktionen sind die meist belastenden Aspekte neuropsychiatrischer Erkrankungen (z.B. Elvevag & Goldberg, 2000). Bis jetzt existieren keine zufriedenstellenden Therapien zur Behandlung kognitiver Störungen bei neuropsychiatrischen Erkrankungen (Stroup et al., 2006). In Anbetracht einer stetig alternden Gesellschaft in den Industrieländern und der damit verbundenen kognitiven und wirtschaftlichen Beeinträchtigung, ist die Entwicklung neuroprotektiver und regenerativer Therapieansätze dringend notwendig. Die vorliegende kumulative Promotionsarbeit wurde im Rahmen des Göttingen Research Association for Schizophrenia (GRAS) angefertigt. Sie beinhaltet zwei verwandte Themen: Erstens, einen neuen tierexperimentellen Ansatz zur Modellierung kognitiver Defizite der Schizophrenie, unter Berücksichtigung genetischer und umweltbezogener Faktoren. Zweitens, der Effekt von Erythropoietin (EPO) auf die Verbesserung höherer kognitiver Funktionen (Lernen und Gedächtnis, Aufmerksamkeit und exekutiver Funktionen) bei Mäusen. Die Arbeit enthält ein Buchkapitel und drei Original-Erstautorpublikationen. Das Kapitel (El-Kordi et al., 2009) gibt einen aktuellen Überblick über vergangene, gegenwärtige und zukünftige Nagermodelle der Schizophrenie. Es unterstreicht die dringende Notwendigkeit valider und reliabler Tiermodelle dieser belastenden Erkrankung. Des Weiteren definiert es zum ersten Mal DSM Kriterien für Schizophrenie im Nagermodell. Auf dieser Basis entstand die erste Veröffentlichung (Radyushkin, El-Kordi et al., 2010), welche eine Complexin2 Null-Mutation (als genetischer Faktor) mit einer parietalen experimentellen Kryoläsion im Jugendalter (als Umweltfaktor) bei Mäusen kombiniert. Dieses Tiermodell brachte verschiedene Schizophrenie-relevante Phänotypen hervor. Die zweite Veröffentlichung (El-Kordi et al., 2009) demonstriert Effekte der EPO-Behandlung auf verschiedene kognitive Leistungen gesunder Mäuse. Es beleuchtet methodologische Ansätze zur Untersuchung dieser Funktionen bei Nagern. Basierend auf den daraus resultierenden Erkenntnissen wurde versucht, Einsicht über die Mechanismen der EPO-mediierten kognitiven Verbesserung zu gewinnen. Zu diesem Zweck wurde die kognitive Leistung transgener Mäuse (konstitutiv aktiver EPO-Rezeptor unter ?-CaMKII-Promotor) charakterisiert. Diese dritte Arbeit zeigt den kognitiven Effekt des selektiv überexprimierten EPO-Rezeptors in Hippokampus- und Kortex-Neuronen, welche für höhere Hirnleistungen hoch relevant sind (Sargin, El-Kordi et al., submitted).Cognitive deficits and impairments of higher brain functions are the most burdening features in various neuropsychiatric disorders (e.g. Elvevag and Goldberg, 2000). Up to now, there are no satisfying proven treatments targeting the main cognitive domains affected in neuropsychiatric diseases (e.g. Stroup et al., 2006). In light of an increasingly aging society in industrialized countries and the herewith associated cognitive decline, novel neuroprotective / neuroregenerative approaches are desperately needed. The present cumulative thesis was conducted in the framework of the Göttingen Research Association for Schizophrenia (GRAS) and addresses two related topics: first, a novel experimental approach in mice combining genetic and environmental factors for modelling cognitive deficits relevant to schizophrenia, and second, the effect of erythropoietin (EPO) on improving higher cognitive functions (i.e. learning and memory, attention, executive functions) in mice. The thesis includes one book chapter and three original first-author publications. The chapter (El-Kordi, Radyushkin, Adamcio et al., 2009) gives a state-of-the-art overview of previous, present and future rodent models of schizophrenia. It highlights the urging need for valid and reliable animal models of this burdening disease. Moreover, it defines for the first time DSM criteria for rodent schizophrenia . On these grounds, the first paper evolves (Radyushkin, El-Kordi et al., 2010) which combines a complexin2 null mutation in mice as a genetic factor and a mild parietal neurotrauma applied during puberty, as an environmental factor. This genetic-environmental model yielded several phenotypes relevant to schizophrenia. The second publication (El-Kordi, Radyushkin and Ehrenreich, 2009) demonstrates the effect of EPO treatment on several types of learning, attention and executive control in mice. It sheds light on methodological approaches to study these functions in rodents and uncovers the role of EPO in improving these domains in healthy mice. From there, I wanted to obtain more mechanistic insight into EPO mediated cognitive improvement. For that purpose, I characterized the cognitive performance of constitutively active EPOR overexpressing mice (cEPOR under the ?-calcium/calmodulin-dependent protein kinase II (?-CaMKII) promoter). This third paper shows the effects of EPOR on cognition when overexpressed in selected hippocampal and cortical neurons, which are highly relevant to higher brain functions (Sargin, El-Kordi et al., 2010, submitted)

LA PREVENTION PRECOCE DES ENTREPRISES EN SITUATION DE DETRESSE FINANCIERE

Today, businesses face financial difficulties due to economic difficulties, declining performance and mismanagement. In other words, the process of financial distress begins with an incubation period characterized by a combination of poor economic conditions and mismanagement.In most cases, financial distress can push businesses to go bankrupt or reduce their reputation. As a result, early prevention of financial distress is one of the most important decision-making issues facing auditors, consultants and business leaders.Due to the seriousness of the issue for businesses, we will try, in the first part of this article, to highlight the symptoms or warning signals that can help business leaders to predict and prevent financial distress in advance. Then, in the second part, we will deal with the preventive measures to manage  the situation of financial distress

Expression of constitutively active erythropoietin receptor in pyramidal neurons of cortex and hippocampus boosts higher cognitive functions in mice

<p>Abstract</p> <p>Background</p> <p>Erythropoietin (EPO) and its receptor (EPOR) are expressed in the developing brain and their transcription is upregulated in adult neurons and glia upon injury or neurodegeneration. We have shown neuroprotective effects and improved cognition in patients with neuropsychiatric diseases treated with EPO. However, the critical EPO targets in brain are unknown, and separation of direct and indirect effects has remained difficult, given the role of EPO in hematopoiesis and brain oxygen supply.</p> <p>Results</p> <p>Here we demonstrate that mice with transgenic expression of a constitutively active EPOR isoform (cEPOR) in pyramidal neurons of cortex and hippocampus exhibit enhancement of spatial learning, cognitive flexibility, social memory, and attentional capacities, accompanied by increased impulsivity. Superior cognitive performance is associated with augmented long-term potentiation of cEPOR expressing neurons in hippocampal slices.</p> <p>Conclusions</p> <p>Active EPOR stimulates neuronal plasticity independent of any hematopoietic effects and in addition to its neuroprotective actions. This property of EPOR signaling should be exploited for defining novel strategies to therapeutically enhance cognitive performance in disease conditions.</p

A single gene defect causing claustrophobia

Claustrophobia, the well-known fear of being trapped in narrow/closed spaces, is often considered a conditioned response to traumatic experience. Surprisingly, we found that mutations affecting a single gene, encoding a stress-regulated neuronal protein, can cause claustrophobia. Gpm6a-deficient mice develop normally and lack obvious behavioral abnormalities. However, when mildly stressed by single-housing, these mice develop a striking claustrophobia-like phenotype, which is not inducible in wild-type controls, even by severe stress. The human GPM6A gene is located on chromosome 4q32-q34, a region linked to panic disorder. Sequence analysis of 115 claustrophobic and non-claustrophobic subjects identified nine variants in the noncoding region of the gene that are more frequent in affected individuals (P=0.028). One variant in the 3′untranslated region was linked to claustrophobia in two small pedigrees. This mutant mRNA is functional but cannot be silenced by neuronal miR124 derived itself from a stress-regulated transcript. We suggest that loosing dynamic regulation of neuronal GPM6A expression poses a genetic risk for claustrophobia

Erythropoietin enhances hippocampal long-term potentiation and memory

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>Conclusion</p> <p>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.</p

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

Role of DNA methylation in head and neck cancer

Head and neck cancer (HNC) is a heterogenous and complex entity including diverse anatomical sites and a variety of tumor types displaying unique characteristics and different etilogies. Both environmental and genetic factors play a role in the development of the disease, but the underlying mechanism is still far from clear. Previous studies suggest that alterations in the genes acting in cellular signal pathways may contribute to head and neck carcinogenesis. In cancer, DNA methylation patterns display specific aberrations even in the early and precancerous stages and may confer susceptibility to further genetic or epigenetic changes. Silencing of the genes by hypermethylation or induction of oncogenes by promoter hypomethylation are frequent mechanisms in different types of cancer and achieve increasing diagnostic and therapeutic importance since the changes are reversible. Therefore, methylation analysis may provide promising clinical applications, including the development of new biomarkers and prediction of the therapeutic response or prognosis. In this review, we aimed to analyze the available information indicating a role for the epigenetic changes in HNC