Olivieri, Stefano. Biosynthesis and release of brain-derived neurotrophic factor : a study using neurons derived from embryonic stem cells. 2014, PhD Thesis, University of Basel, Faculty of Science.
Official URL: http://edoc.unibas.ch/diss/DissB_10790
My results indicate that BDNF overexpression is incompatible with complete processing and leads to a progressive accumulation and constitutive secretion of pro-BDNF. By contrast, in wild-type neuronal cultures pro-BDNF is fully converted to mature BDNF that is released in an activity dependent fashion.
Regarding the important question of the release of endogenous BDNF from neurons, I observed that basal BDNF release is fully dependent on extracellular calcium influx through specific voltage gate calcium channels. By contrast, calcium efflux from sarcoplasmic reticulum, which triggers BDNF release during specific stimulation patterns, does not affect the basal BDNF secretion.
In order to identify the mechanisms underlying BDNF release during elevated neuronal activity, I derived a new ES cell line from Bassoon mutant mice (Bsn m/m), which develop epileptic seizures and exhibit higher BDNF protein levels in various brain areas. Neurons derived from the Bsn m/m ES cell lines show significantly higher levels of BDNF secretion. In addition, the release of BDNF observed in Bassoon mutant ES cell-derived neurons activates TrKB in these cells and down-regulates the expression of KCC2, a gene encoding for the major neuronal Cl-/K+ co-transporter.
My results thus shed new light on physiological mechanisms of endogenous BDNF biosynthesis and release and invite a critical re-consideration of data obtained using overexpression paradigms.
|Advisors:||Rüegg, Markus A.|
|Committee Members:||Barde, Yves-Alain|
|Faculties and Departments:||05 Faculty of Science > Departement Biozentrum > Neurobiology > Pharmacology/Neurobiology (Rüegg)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||87 S.|
|Last Modified:||30 Jun 2016 10:55|
|Deposited On:||16 Jun 2014 08:12|
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