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Brain-derived neurotrophic factor : generation and characterization of adult mice lacking BDNF in the adult brain

Rauskolb, Stefanie. Brain-derived neurotrophic factor : generation and characterization of adult mice lacking BDNF in the adult brain. 2008, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_8363

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Abstract

BDNF (brain-derived neurotrophic factor) plays an important role in neuronal survival, growth and maintenance of several neuronal systems, serves as neurotransmitter modulator and participates in plasticity important for learning and memory. BDNF is widely expressed in the CNS, beginning early in development and extending throughout life. In the mammalian brain, it is most abundant in the cerebral cortex and hippocampus. BDNF is of special interest because of the regulation of its expression and release as a function of the state of neuronal activity. In humans the most direct link between BDNF and pathological conditions is the recent discovery that the loss of one BDNF allele causes a strong obesity phenotype. In addition, there is accumulating evidence that in conditions such as Huntington (HD) decreased levels of BDNF may contribute to the disease. Finally, it is also associated with depression and anxiety. One key difficulty in understanding the role of BDNF in the adult brain has been the generation of suitable animal models as the germline deletion of BDNF leads to early postnatal death. To circumvent this difficulty, we generated conditional mutant mice in which BDNF is eliminated from the CNS through the use of the Cre-loxP recombination system. This was achieved by crossingexisting mouse lines, one carrying two floxed BDNF alleles and the other expressing Cre from the tau locus. Our results indicated that such conditional BDNF knockout mice (cbdnf ko) can survive for several months after birth with almost no detectable BDNF in their brain. This creates a novel opportunity to ask the general question of the role of BDNF in the adult CNS. Histological analysis indicated that the brain of these mutant mice is generally smaller, but in an unexpected region-specific manner affecting mostly the striatum and surprisingly not the hippocampus. The marked reduction in the volume of the striatum could not be explained by cell loss, defects of axonal diameter or hypomyelination, but most likely by a marked reduction in the volume of striatal neurons and their processes, which is currently quantified. The lack of hippocampal volume reduction could not be explained due to compensatory changes in the expression levels of NT4 and/or NT3. It thus seems that the postnatal increase of BDNF may be essential for the growth of striatal neurons, and perhaps other GABAergic neurons, but not for hippocampal pyramidal neurons. At the behavioural level cbdnf ko animals exhibit a variety of defects, including a clasping phenotype similar to that observed in mouse models of Huntington’s disease.
The cbdnf ko mice also provided a key control for parallel studies examining the biosynthesis,
processing and storage of endogenous BDNF in the CNS. We showed that in hippocampal neurons
pro-BDNF is a transient intermediate that is converted intracellularly to the mature form of BDNF,
which is stored and released by excitatory input (Matsumoto et al., 2008).
The new bdnf mutant animals generated during the course of this PhD thesis thus represent a new
opportunity to study the role of BDNF in the adult mouse nervous system.
Advisors:Barde, Yves-Alain
Committee Members:Rüegg, Markus A.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Former Organization Units Biozentrum > Pharmacology/Neurobiology (Barde)
Item Type:Thesis
Thesis no:8363
Bibsysno:Link to catalogue
Number of Pages:93
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:41
Deposited On:13 Feb 2009 16:34

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