Reinhard, Judith. The function of Copine 6 in the brain. 2012, PhD Thesis, University of Basel, Faculty of Science.
Official URL: http://edoc.unibas.ch/diss/DissB_10216
This project started with an initial characterization of Copine 6 in vitro. A shRNA-mediated knockdown of Copine 6 in primary hippocampal culture increases the number of dendritic spines and influences their maintenance upon changes in neuronal activity. The cytosolic Copine 6 is recruited into postsynaptic sites upon NMDA receptor activation. This translocation of Copine 6 upon increase in the intracellular calcium concentration influences the localization of its binding partner, the actin cytoskeleton modulator Rac1. We demonstrate that presence of Copine 6 affects not only the localization but also the activation state of Rac1. These data indicate that in vitro Copine 6 translates activity-induced calcium signals into morphological changes of the postsynapse through translocation and promotion of Rac1 activity in activated spines.
By the generation of mice deficient for Copine 6 we aimed to identify the role of Copine 6 in vivo. We found that Copine 6 expression is strongest in the hippocampus and starts postnatally when synapses are formed. In the hippocampus, Copine 6 expression is restricted to excitatory neurons. In line with its expression pattern, Copine 6 is dispensable for development. Copine 6 knockout mice thrive indistinguishable from their littermate controls and do not show an overt phenotype. In the hippocampus of adult Copine 6 knockout mice the spine density and morphology, and overall synaptic function is not changed, consistent with an unaffected Rac1 signaling. In contrast, loss of Copine 6 in vivo strongly affects synaptic plasticity. Copine 6 knockout mice are deficient in hippocampal long-term potentiation, suggesting that Copine 6 is dispensable for spine formation but essential for synaptic plasticity.
In a yeast-two hybrid screen we identified SIMPL as a novel Copine 6 interacting partner. We provide evidence that presence of Copine 6 anchors the NF-kappaB co-activator SIMPL in the cytoplasm and prevents its translocation into the nucleus. In consequence, absence of Copine 6 increases the transcriptional activity of NF-kappaB. These data indicate that Copine 6 may regulate long-term adaptations in neuronal functions that involve transcriptional regulations.
Taken together, this thesis identifies Copine 6 as an important player in the regulation of synaptic plasticity in vitro and in vivo.
|Advisors:||Rüegg, Markus A.|
|Committee Members:||Bettler, Bernhard|
|Faculties and Departments:||05 Faculty of Science > Departement Biozentrum > Neurobiology > Pharmacology/Neurobiology (Rüegg)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||103 Bl.|
|Last Modified:||30 Jun 2016 10:51|
|Deposited On:||14 Jan 2013 14:22|
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