<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Implications of the Val66Met polymorphism of the BDNF gene\r\non neuronal morphology and function\r\nusing human iPSC-derived neuronal cultures"^^ . "Psychiatric disorders such as schizophrenia or major depression are often associated with\r\nspecific congenital genetic variants. One of these variants, which has been associated with\r\nthat kind of disorder, is the human-specific single nucleotide polymorphism (SNP, rs6265) in\r\nthe brain-derived neurotrophic factor (BDNF) gene. About 30 to 60% of the worldwide\r\npopulation is either homo- or heterozygous for this SNP which is located at codon 66 in the\r\npro-domain of the protein (Val66Met). It results in a substitution of valine (Val) to methionine\r\n(Met) that impairs the intracellular trafficking as well as the activity-dependent release of the\r\nprotein. BDNF, a member of the neurotrophin family, is known to be important in brain\r\ndevelopment being involved in neuronal survival, neurite outgrowth and synaptic plasticity.\r\nThe aim of this thesis was to investigate the effects of the Val66Met polymorphism on BDNF\r\ntrafficking, neuronal morphology and function on an endogenous expression level in humaninduced\r\npluripotent stem cell (iPSC)-derived neuronal cultures generated from healthy donors\r\nhomozygous for either the BDNFVal or BDNFMet variant. To account for the given genetic\r\nheterogeneity of humans, I additionally generated isogenic cell lines using CRISPR/Cas9 gene\r\nediting. Analysis of BDNF localization revealed a decreased number of BDNF+ vesicles on\r\nneurites of BDNFMet/Met neurons compared to BDNFVal/Val neurons. Interestingly, the BDNF\r\nsignal was accumulated at the soma of BDNFMet/Met neurons, indicating impaired trafficking of\r\nBDNFMet. Furthermore, a significant reduction in neurite length and complexity in neurons\r\nderived from BDNFMet/Met carriers at early developmental stages was observed. This was\r\npersistent up to later stages of development and could be rescued by external application of\r\nrecombinant BDNF. The morphological alterations were accompanied by a reduced synaptic\r\ndensity in BDNFMet/Met neurons analyzed by immunocytochemistry. These results were\r\nconfirmed by functional characterization including calcium imaging and electrophysiological\r\nmeasurements that showed an altered synaptic function in neurons carrying BDNFMet/Met.\r\nTaken together, my data provide first experimental evidence identifying morphological and\r\nneurophysiological differences in human neurons carrying the BDNF Val66Met polymorphism.\r\nMy work demonstrates that human iPSC-derived cortical neurons can be used as a cellular\r\nmodel to recapitulate previous results gained with animal studies, but also to highlight humanspecific\r\naspects, which might help to strengthen our understanding of BDNF signaling."^^ . "2024" . . . . . . . "Elena"^^ . "Munoz Perez-Vico"^^ . "Elena Munoz Perez-Vico"^^ . . . . . . "Implications of the Val66Met polymorphism of the BDNF gene\r\non neuronal morphology and function\r\nusing human iPSC-derived neuronal cultures (PDF)"^^ . . . "Implications of the Val66Met polymorphism of the BDNF gene\r\non neuronal morphology and function\r\nusing human iPSC-derived neuronal cultures (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "Implications of the Val66Met polymorphism of the BDNF gene\r\non neuronal morphology and function\r\nusing human iPSC-derived neuronal cultures (Other)"^^ . . . . . . "preview.jpg"^^ . . . "Implications of the Val66Met polymorphism of the BDNF gene\r\non neuronal morphology and function\r\nusing human iPSC-derived neuronal cultures (Other)"^^ . . . . . . "medium.jpg"^^ . . . "Implications of the Val66Met polymorphism of the BDNF gene\r\non neuronal morphology and function\r\nusing human iPSC-derived neuronal cultures (Other)"^^ . . . . . . "small.jpg"^^ . . . "Implications of the Val66Met polymorphism of the BDNF gene\r\non neuronal morphology and function\r\nusing human iPSC-derived neuronal cultures (Other)"^^ . . . . . . "indexcodes.txt"^^ . . "HTML Summary of #33451 \n\nImplications of the Val66Met polymorphism of the BDNF gene \non neuronal morphology and function \nusing human iPSC-derived neuronal cultures\n\n" . "text/html" . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . .