Novel treatment approaches based on identification of molecular determinants in neuropsychiatric diseases
Başlık çevirisi mevcut değil.
- Tez No: 400833
- Danışmanlar: DR. HANNELORE EHRENREICH
- Tez Türü: Doktora
- Konular: Nöroloji, Nöroşirürji, Neurology, Neurosurgery
- Anahtar Kelimeler: Belirtilmemiş.
- Yıl: 2008
- Dil: İngilizce
- Üniversite: Georg-August-Universität Göttingen
- Enstitü: Yurtdışı Enstitü
- Ana Bilim Dalı: Nörobilim Ana Bilim Dalı
- Bilim Dalı: Belirtilmemiş.
- Sayfa Sayısı: 128
Özet
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Özet (Çeviri)
In the first original publication, we investigated effects of EPO on cognition and mechanisms of how EPO improves cognitive functions and affects synaptic plasticity. We have shown that upon systemic EPO treatment for 3 weeks every other day, young healthy mice performed better in hippocampus-dependent memory tasks compared to the placebo treated group. This effect was observable 1 week after cessation of the treatment and interestingly, it was still maintained for another 3 weeks of EPO treatment-free period. 3 weeks after cessation of EPO treatment, the hematocrit levels were comparable between the 2 mouse groups. This has once more shown that EPO?s effect on cognition is independent of its hematopoietic effect. We performed a detailed analysis to reveal the mechanisms of EPO-induced cognitive improvement by focusing on synaptic function. Slices obtained from mice treated with EPO for 3 weeks and killed 1 week after cessation of the treatment, were subjected to electrophysiological analysis. The most intriguing finding was EPO?s effect on increasing LTP. In parallel, magnitudes of STP and STD were significantly greater in EPO-treated mice. Moreover, whole-cell patchclamp recordings on CA1 pyramidal neurons showed that EPO increased the frequency of sIPSCs and decreased the frequency of sEPSCs. Thus, EPO modulated inhibitory and excitatory transmission inversely. Interestingly, number of synapses in hippocampal subregions did not differ between EPO- and placebo-treated animals. MEA recordings performed on primary hippocampal neurons in culture confirmed the direct EPO effect on neural cells. Primary hippocampal neurons isolated from mice at E17 were grown on MEA dishes and were treated with EPO every other day starting from day 5 in culture until day 25. Chronic application of EPO similar to our in vivo approach resulted in prevention of a decrease in the number of silent channels upon maturation of the culture. Moreover, EPO treatment led to an increase in the number of bursting-channels. These results were in line with the in vivo data which also showed EPO?s favourable action on inhibitory transmission. To reveal EPO?s action on single cell level, we used autaptic hippocampal neurons treated with EPO at day 7 and subjected to electrophysiological and immunocytochemical analyses on days 9-14. Single EPO addition led to a decrease in EPSC amplitude and readily-releasable pool size without affecting the total number of synapses. Based on these findings, we conclude that, in addition to its effect on improving cognition under pathological conditions, EPO leads to an increase in hippocampus-dependent memory in the healthy brain. EPO?s mechanism of action on synaptic plasticity seems to be in favor of inhibitory transmission without affecting the total number of synapses. We hypothesize that EPO modulates synaptic plasticity by increasing the activity of selected networks while keeping the others silent. In the second original publication, we focused on a rare form of bipolar disorder, rapid cycling syndrome, and analyzed gene expression changes in different disease episodes in a rapid cycling patient. Depending on the gene expression results, we performed a clinical experiment offering a new treatment approach for our patient. RNA isolated from PBMC collected at different manic and depressed episodes from the patient was subjected to a detailed microarray analysis. Genes selected based on microarray analysis, after excluding the ones that showed daily and monthly variations, were confirmed by qRT-PCR. With this approach, we identified a group of genes that showed alterations in different episodes of the disease. These included genes that were involved in prostaglandin metabolism, neurodevelopment, immune and hematopoietic systems. Based on our hypothesis that cyclic alterations in rapid cycling syndrome might reflect an ancient evolutionary program similar to hibernation cycle of mammals which is characterized by periodic eating, drinking, sleep and altered metabolism and that this program might be reactivated under certain pathological conditions, we focused on genes involved in prostaglandin synthesis which has been shown to have important roles in hibernation cycle of mammals (O'Hara et al., 1999). We performed a clinical experiment by offering the patient a treatment approach using a cyclooxygenase inhibitor celecoxib. Treatment with celecoxib over 5 months led to stabilization of manic and depressed episodes by reducing manic and depressed rating scores. Keeping in mind that celecoxib has been the only effective drug for our patient who has a 16 year disease history, we believe that more patients should be tested for the efficacy of this treatment in rapid cycling syndrome and to reveal the role of prostaglandin metabolism in this disorder. In the third study, we investigated the mechanisms of atrophy and EPO-induced recovery upon a discrete cryo-lesion performed on the right parietal cortex of juvenile mice. Mice lesioned at an early age (28 days old) developed a progressive neurodegenerative process characterized by gray matter loss, ventricular enlargement and cognitive decline which was highly significant 9 months after injury. EPO treatment right after the lesion for 2 weeks every other day prevented lesion-induced brain atrophy and cognitive decline (Siren et al., 2006). In order to investigate the mechanisms of lesion-induced atrophy, we performed a detailed histological analysis based on stereology on 1 year old mice. At this age, brain atrophy and cognitive decline induced by lesion were already evident. Histological analysis was performed on anterior cingulate cortex and subregions of hippocampus. Interestingly, despite progressive global brain atrophy, lesioned mice had comparable number of neurons and astrocytes to the sham-operated and EPO-treated mice. This indicated a degenerative process going on without neuronal loss and gliosis similar to the characterization of brain atrophy in schizophrenic patients. We next focused on differences in neuronal and glial subpopulations between different groups of mice. 24 hours after a discrete unilateral lesion, a bilateral increase in the number of microglia was observed in all brain areas investigated. Interestingly, 11 months after lesion, increase in the microglial number was still observable in hippocampus. This showed a chronic persistent inflammatory response going on in the brains of lesioned mice. Early EPO treatment prevented the increase in microglial number at both time points. Lesioned mice at the age of 1 year had a slight reduction in the number of oligodendrocytes accompanied by reduced expression in myelin proteins. EPO treatment increased the number of oligodendrocytes and prevented the reduction in myelin protein expression. Moreover, EPO prevented lesion-induced increase in the ratio of Parvalbumin positive interneurons and GAD67 protein expression. Decrease in the expression of synapsin 1 protein upon lesion was also prevented by early EPO treatment. Morphological and pathological consequences of an early brain injury are similar to those observed in schizophrenic brain. Thus, our parietal injury model serves a good basis to study the mechanisms of progressive atrophy and EPO treatment in cognitive disorders such as schizophrenia. Based on our findings, we conclude that EPO treatment in cognitive disorders might be beneficial in preventing the pathological changes leading to the outcome of these diseases.
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