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Mechanisms of synaptic plasticity mediated by Clathrin Adaptor-protein complexes 1 and 2 in mice

dc.contributor.advisorSchu, Peter Prof. Dr.
dc.contributor.authorMishra, Ratnakar
dc.titleMechanisms of synaptic plasticity mediated by Clathrin Adaptor-protein complexes 1 and 2 in micede
dc.contributor.refereeSchu, Peter Prof. Dr.
dc.description.abstractengClathrin adaptor protein complexes 1 and 2 (AP1 and AP2) have essential functions in synaptic vesicle (SV) recycling. In all cell types and tissues, AP1 mediates TGN/endosome protein sorting via clathrin-coated-vesicles (CCV), whereas AP2 transports proteins by clathrin-mediated endocytosis (CME). Both AP complexes are heterotetrameric, made of four adaptins. Neurons express the ubiquitous AP1/σ1A complex and in addition, the tissue-specific AP1/σ1B complex. In our lab, we have generated σ1B-/- mice. The deficiency of σ1B adaptin leads to severe learning, memory and motor coordination deficits in the knockout mice. σ1B knockout mice are also a model for a severe X-linked mental retardation disease in humans, where the σ1B gene has a premature STOP codon. Synapses lacking the AP1/σ1B complex, display two major phenotypes. Firstly, synaptic vesicle (SV) recycling is impaired, and early endosomes accumulate. The ubiquitous AP1/σ1A complex binds to these endosomes and stimulates their maturation into late, multi-vesicular-body endosomes, up regulating endolysosomal protein transport. Secondly, the endocytic AP2 CCV accumulate, a surprise given the reduction in the major vesicular transport route, SV recycling. This indicated that CME is a major mechanism of synaptic plasticity. AP2 CCV accumulation could be caused by up-regulation of CME or by the stabilization of AP2 CCV extending their half-life. In this project, I have biochemically characterized these AP2 CCV and demonstrated that two populations of AP2 CCV exist in synapses. One formed by canonical clathrin-mediated-endocytosis (CME) and the other one formed by a specialized pathway, which is characterized by a stabilized CCV coat. Both CME routes are upregulated two-fold in AP1/σ1B deficient synapses. In addition, the longer-lived AP2 CCV of the AP1/σ1B-/- synapses are stabilized by three distinct molecular mechanisms compared to the respective AP2 CCV from wt synapses. The stabilized AP2 CCV of AP1/σ1B-/- synapses are enriched in the active zone proteins, Stonin2 and Git1. The AP1/σ1B deficient synapses contain more Git1 than wild-type synapses, indicating alterations in the dynamics of the active zone in these synapses. Thus, two CME routes characterized by specific lifetimes and specific cargo proteins contribute to synaptic
dc.contributor.coRefereeSchmitt, Hans Dieter Dr.
dc.contributor.thirdRefereeBayer, Thomas A. Prof. Dr.
dc.contributor.thirdRefereeRizzoli, Silvio O. Prof. Dr.
dc.contributor.thirdRefereeOppermann, Martin Prof. Dr.
dc.contributor.thirdRefereeDosch, Roland Dr.
dc.subject.engAP1S2,AP-1,AP-2, Clathrin-coated vesicles (CCV), Synaptic plasticity, Mice, Stabilized AP-2 CCV, Clathrin mediated endocytosisde
dc.affiliation.instituteGöttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB)de
dc.subject.gokfullBiologie (PPN619462639)de

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