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A post-synaptic forgetting mechanism controlled by synaptotagmin 3

dc.contributor.advisorDean, Camin Dr.
dc.contributor.authorAwasthi, Ankit
dc.titleA post-synaptic forgetting mechanism controlled by synaptotagmin 3de
dc.contributor.refereeDean, Camin Dr.
dc.description.abstractengActivity-induced regulation of surface post-synaptic receptor number is a well-known mechanism underlying synaptic plasticity, but the molecular machinery mediating this process is poorly understood. In a screen of synaptotagmin (syt) isoforms, we found that pHluorin-syt3 undergoes Ca2+-dependent endocytosis in hippocampal neurons upon stimulation. Syt3 was present at synapses, and enriched on post-synaptic membranes. Recombinant syt3 pulled down the endocytic protein AP-2 and GluA2, but not GluA1, GluN1, GluN2 or GABAAR1, and also pulled down BRAG2, a protein important for activity-dependent internalization of AMPA receptors. Overexpression or knockdown of syt3 post-synaptically did not change mEPSCs, and basal transmission in hippocampal syt3 knockout slices was unchanged. However, syt3-overexpressing neurons internalized more GluA1 and GluA2 than control neurons upon stimulation with AMPA or NMDA. This internalization was blocked in syt3 KO, syt3 knockdown, and syt3 calciumbinding mutant expressing neurons, and was mimicked by application of the GluA2-3Y peptide, a tyrosine rich sequence important for activity-mediated GluA2-AMPAR internalization. Strong LTP was normal in syt3 KO hippocampal slices, but weak LTP failed to decay and persisted for hours, consistent with syt3 internalizing receptors, which is necessary for decay of weak LTP. The reinforcement of weak LTP in syt3 KO slices was mimicked and occluded by the GluA2-3Y peptide. ZIP (a peptide that blocks atypical PKCs leading to GluA2-AMPAR internalization and decay of potentiation) failed to cause decay of synaptic potentiation in both strong and weak LTP in syt3 KO hippocampal slices consistent with a defect in receptor internalization. LFS-LTD was also abolished in syt3 KO slices. Syt3 KO mice learned as well as wild-type littermates in the reference memory version of the water maze, but persevered to the original platform position more than WT mice even 4 days after platform reversal. In addition, syt3 KO mice performed worse than WT mice in the delayed matching to place task, and persevered to previous platform positions more than WT, indicating a higher consolidation of working memory and/or an impairment in forgetting. In summary, we found that syt3 is involved in a post-synaptic ‘forgetting’ mechanism by which receptors are internalized following stimulation to promote decay of synaptic
dc.contributor.coRefereeNeher, Erwin Prof. Dr.
dc.contributor.thirdRefereeSacktor, Todd Prof. Dr.
dc.subject.engMolecular neurobiologyde
dc.subject.engPost-synaptic mechanismde
dc.subject.engactivity dependentde
dc.subject.engAMPA receptor traffickingde
dc.subject.engAMPA receptor traffickingde
dc.affiliation.instituteGöttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB)de
dc.subject.gokfullBiologie (PPN619462639)de

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