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dc.contributor.advisor Dean, Camin Dr.
dc.contributor.author Wolfes, Anne
dc.date.accessioned 2015-12-01T10:51:11Z
dc.date.available 2015-12-01T10:51:11Z
dc.date.issued 2015-12-01
dc.identifier.uri http://hdl.handle.net/11858/00-1735-0000-0028-8651-6
dc.language.iso eng de
dc.relation.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.ddc 570 de
dc.title Molecular Mechanisms of Astrocyte Vesicle Fusion at Synaptic Interfaces de
dc.type doctoralThesis de
dc.contributor.referee Dean, Camin Ph.D.
dc.date.examination 2015-09-28
dc.description.abstracteng Astrocytes are key to neuronal trophic support, development, and synaptic signalling and plasticity. Astrocytes can detect synaptic events at tripartite synapses –a major site of bidirectional communication between neurones and astrocytes– and alter synaptic function by gliotransmitter release. This is reflected in basic research studies as well as neurodevelopmental disease models, where astrocyte-derived factors shape synapse structure and function. Despite the many roles of astrocytes in brain (patho-) physiology, the mechanisms that underlie release of gliotransmitters to affect astro-neuronal communication are poorly understood. To investigate astrocytic signalling at synaptic interfaces and which molecules mediate astrocytic vesicle fusion, I developed a simple and economical protocol for growing more “in vivo-like” astrocyte monocultures. In comparison to other astrocyte monocultures, spontaneous Ca2+ signalling in astrocytes of my protocol was more similar to that of astrocytes co-cultured with neurones. Moreover, I observed distinct subcellular domains in which different Ca2+ event types occurred that were similar to those of astrocytes in slices and in vivo. Using this culture protocol, I confirmed that astrocytes express several vesicle-associated proteins, two of which localised to two distinct vesicle populations that underwent recycling: Vamp2 and Syt7. Vamp2 was previously found in astrocytes, and cleaving Vamp2 by clostridial toxins blocks Ca2+-dependent glutamate release from astrocytes. Syt7, which is implicated in lysosomal secretion in different cell types (but also regulates synaptic vesicle replenishment), is a Ca2+ sensor with high Ca2+ affinity that has not yet been reported in astrocytes. The Ca2+ signalling patterns I observed in cultured astrocytes provide a context for Syt7-mediated vesicle fusion, which I further investigated using Syt7-/- mouse cultures: When co-cultured with Syt7-/- astrocytes, wild-type neurones had fewer synapses. Further, I showed that Syt7 and the synaptogenic factor Hevin are developmentally regulated and partially co-localise in cultured astrocytes. These data suggest that Syt7 may regulate vesicular Hevin release from astrocytes, which in turn shapes how neuronal circuits develop. Astrocytic exocytosis contributes to neurodevelopmental diseases, where aberrant astrocytic Hevin release has been implicated in epileptogenesis. Together, these data support that astrocytic Syt7 (and perhaps other Syts) may mediate the release of astrocytic factors that are important for brain development. de
dc.contributor.coReferee Jahn, Reinhard Prof. Dr.
dc.subject.eng Astrocytes de
dc.subject.eng Vesicle de
dc.subject.eng Synaptogenesis de
dc.identifier.urn urn:nbn:de:gbv:7-11858/00-1735-0000-0028-8651-6-5
dc.affiliation.institute Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB) de
dc.subject.gokfull Biologie (PPN619462639) de
dc.identifier.ppn 841254761

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