| dc.contributor.advisor | Schlüter, Oliver Dr. Dr. | |
| dc.contributor.author | Samaddar, Tanmoy | |
| dc.date.accessioned | 2014-10-16T13:09:07Z | |
| dc.date.issued | 2014-10-16 | |
| dc.identifier.uri | http://hdl.handle.net/11858/00-1735-0000-0023-9908-C | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-4742 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/ | |
| dc.subject.ddc | 570 | de |
| dc.title | Role of DLG-MAGUKs in surface NMDAR localization and its patho-physiological functions | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Jahn, Reinhard Prof. Dr. | |
| dc.date.examination | 2014-05-12 | |
| dc.description.abstracteng | The post-synaptic side of an excitatory synapse is characterized by an electron-dense, highly dynamic architecture of proteins, called the post-synaptic density or PSD. PSDs comprises of a diverse group of proteins, from glutamate receptors, scaffolding proteins, signaling molecules and cyto-skeletal elements. Amongst this protein en-semble, the MAGUK family of scaffolding proteins is well known for their roles in synaptic maturation, glutamatergic receptor organization and for serving as platform for post-translational modifications of other proteins in the PSD. PSD-93, one of the lesser-known members of this family of proteins had been reported to have contradic-tory functions in maintaining AMPA and NMDA receptor levels in different brain regions. In this study, using diverse biochemical approaches in a mouse model, I stud-ied the role of PSD-93 in maintaining surface level of glutamatergic receptors and its patho-physiological significance in glutamate induced neuronal toxicity.
By using surface protein cross-linking approach, I could demonstrate that in the layer 2/3 visual cortex of a PSD-93 knockout mice, there is a reduction in the surface level of both NMDA receptor subunits GluN2A and GluN2B. Additionally, I could also demonstrate that this reduction in surface level of GluN2B is caused independent of the change in phosphorylation of the GluN2B-Y1472 site, possibly through other phosphorylation mechanism.
Since, NMDA receptors are classically linked with glutamate-induced neurotoxicity during ischemic brain damage, I looked at the level of neurotoxicity in PSD-93KO cortical cultures. I established a NMDA challenge protocol that enabled neuronal apoptosis and I could show an almost 80% reduction in cortical cell death, when PSD-93 is absent. This form of NMDA neurotoxicity was largely mediated via the GluN2B subunit of NMDA receptors and the neuro-protection effect in PSD-93KO was medi-ated by perturbation of the P38 MAPK pathway of apoptosis induction.
PSD-95 had been classically reported to link NMDA receptor activation with down-stream apoptotic signaling cascade. I could show that deletion of both PSD-93 and
VI
PSD-95 showed equal degrees of neuro-protection at lower doses of NMDA chal-lenge whereas at higher doses, only PSD-93 retained its neuro-protective effects.
Overall, my data helps to understand the role of PSD-93 in maintaining surface NMDA receptors levels in cortical neurons and linking them to their patho-physiological functions. | de |
| dc.contributor.coReferee | Urlaub, Henning Prof. Dr. | |
| dc.subject.eng | PSD93, PSD-95, MAGUK, neurotoxicity, ischemia | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-11858/00-1735-0000-0023-9908-C-1 | |
| dc.affiliation.institute | Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB) | de |
| dc.subject.gokfull | Biologie (PPN619462639) | de |
| dc.description.embargoed | 2014-12-03 | |
| dc.identifier.ppn | 798640863 | |