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The function of Copine 6 in the brain

Reinhard, Judith. The function of Copine 6 in the brain. 2012, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_10216

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Abstract

The formation of new or the remodeling of pre-existing synapses is thought to provide the cellular correlate of learning and memory processes. In the mammalian forebrain, the postsynaptic site of most excitatory synapses is located on dendritic spines. Even after their formation, dendritic spines remain plastic and undergo experience-dependent remodeling that correlates with adaptations in the synaptic strength. Hereby, changes in neuronal activity have to be translated into long- and short-term modifications of dendritic spines. Here, we identify Copine 6 as a novel activity sensor critically involved in these processes.
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)
Item Type:Thesis
Thesis no:10216
Bibsysno:Link to catalogue
Number of Pages:103 Bl.
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:51
Deposited On:14 Jan 2013 14:22

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