EURON and THEME joint PhD meeting

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54 EURON and THEME joint meeting 2011 Repair mechanisms at the neuromuscular junction. The role of Dok7 Alejandro Gomez, Jo Stevens, Peter Molenaar, Mario Losen, Marc H. De Baets, and Pilar Martinez-Martinez. Department of Neuroscience. Maastricht University. Myasthenia gravis (MG) is an autoimmune disease that is caused by antibodies against the acetylcholine receptor (AChR) at the neuromuscular junction (NMJ). The disease is caused by a continuous attack of the auto-antibodies in the postsynaptic membrane of the NMJ, where the AChR is located at high density. Antibody binding leads to damage of the synapse, to AChR loss and to loss of AChR-associated proteins. Expression of less active forms of AChR subunits or of the AChR-associated proteins rapsyn, MuSK and Dok7 are the cause of congenital myasthenic syndromes (CMS). Therefore the loss of these proteins in autoimmune MG could aggravate the disease. The muscle responds to an autoimmune attack by upregulating the proteins that can compensate for the loss of function (e.g. AChR subunits, Dok7). However, in MG these repair mechanisms might be insufficient and some patients have severe disease despite of low antibody levels. MuSK and its activator Dok7 are very important factors for the dense clustering of AChR at the postsynaptic membrane. To study the relevance of this clustering machinery in the context of MG, we will investigate both the silencing and overexpression of Dok7 in the animal model of MG (experimental autoimmune myasthenia gravis, EAMG). To this end, we designed siRNA’s that targets Dok7 and tested them in vitro for their silencing efficiency. Afterwards, we will transfect the validated siRNAs into the tibialis anterior muscle of rats by electroporation. We hypothesize that silencing Dok7 expression in the adult muscle leads to an increased susceptibility to passive-transfer EAMG and a delayed recovery from the EAMG. Besides, we will study if Dok7 over-expression in the muscle increases the resistance to EAMG. We will evaluate the animal’s neuromuscular transmission by electromyography, quantify AChR content at the NMJ by radioimmunoassay, and study the morphology of the endplate by electron microscopy.
55 EURON and THEME joint meeting 2011 Epigenetic marks in brains of susceptible and resilient mice after social defeat stress Caroline Hammels 1,2 , Jos Prickaerts 2,3 , Tim Vanmierlo 2,3 , Gunter Kenis 1,2 , Harry W. M. Steinbusch 2,3 , Jim van Os 1,2,4 , Daniel van den Hove 2,3 , Bart Rutten 1,2 1 Dept. of Psychiatry and Psychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands; 2 European Graduate School of Neuroscience (EURON), Maastricht University, Maastricht, The Netherlands; 3 Dept. of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands; 4 King’s College London, Institute of Psychiatry, London, United Kingdom. When subjected to aversive life events, most individuals do not develop depressive-like psychopathology. The molecular mechanisms underlying this resilience remain to be elucidated. Yet, recent studies using social defeat as a mouse model for depression suggest that epigenetic mechanisms might be involved. We used the chronic social defeat paradigm in which eight-week-old experimental C57Bl6 are exposed for 10 consecutive days to an aggressor CD1 mouse for ten minutes daily, followed by a 24 hours sensory (but not physical) contact. Social avoidance was measured by the social interaction test. We found that 50% of the mice showed a susceptible phenotype, characterized by social avoidance, while the other 50% showed a resilient phenotype in this test, which is in line with previous studies. Defeated mice did not display anhedonia, as measured by the sucrose intake test or increased anxiety-like behavior in the elevated zero maze. On the other hand they do display increased despair in the forced swim test. These data support previous findings displaying a prodepressant effect of the social defeat paradigm. However, effects of social defeat are generally reported on anhedonia instead of despair. Furthermore, repeated social avoidance testing revealed that ‘resilience’ can change over time, i.e. some resilient mice can become susceptible and vice versa. This interesting observation needs further research, in particular on the question which selection criterium is most valid. In order to start determining whether certain epigenetic mechanisms are associated with (and possibly mediate) these behavioral differences after social defeat, immunohistochemical stainings for epigenetic marks are currently performed.
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EURON and THEME joint PhD meeting U
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The local organizing committee: Pro
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Page 9 and 10: EURON a short introduction 7 EURON
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Page 29 and 30: THEME Lecture Eckhard Mandelkow POS
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Page 105 and 106: List of Participants 103 EURON and
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Nuersailike Abuduwali University of
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Marianne Eisenhardt University of B
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Sabine Klein University of Bonn PhD
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Viktoriya Peeva University of Bonn
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Sylvie van der Kruijs Maastricht Un
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EURON and THEME joint PhD meeting

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