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Drp1 ablation in the adult mouse forebrain

Oettinghaus, Bjorn. Drp1 ablation in the adult mouse forebrain. 2014, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_10897

Abstract

Due to their high energy demand, their highly polarized nature and the sheer length of their processes, neurons - more than any other cell type - depend on a well-balanced dynamic mitochondrial network. Drp1, the only known mammalian mediator of mitochondrial fission, is essential for neuronal development. Apart from studies in Purkinje cells, not much is known about the role of Drp1 in the postnatal brain. Tamoxifen-inducible Drp1 ablation in the forebrain leads to a swollen, perinuclearly aggregated mitochondrial phenotype and mitochondrial depletion from synapses resulting in impaired synaptic transmission. In contrast to Drp1-ablated neuronal cultures however, dendritic morphology and synapse numbers are not affected; however, Drp1-ablated neurons show an increased sensitivity to ischemia. Forebrain-specific Drp1-ablated mice also develop a complex metabolic phenotype characterized by weight loss, increased lipolysis and elevated corticosterone levels. Investigating this catabolic shift we found evidence for the activation of the unfolded protein response pathway (UPR) and altered ER morphology in Drp1-ablated brain regions, culminating in the induction of the multifaceted metabolic cytokine Fgf21. Fgf21 is normally produced in liver, fat and skeletal muscle in response to metabolic stress as fasting or exercise. It increases insulin sensitivity, regulates lipolysis in adipocytes and stimulates corticosterone production via receptors in the hypothalamus, thus explaining essential aspects of the observed catabolic phenotype. In summary, our results show that brain tissue can signal metabolic stress via Fgf21 induction, which induces a systemic metabolic shift.
Advisors:Frank, Stephan
Committee Members:Handschin, Christoph
Faculties and Departments:03 Faculty of Medicine > Bereich Querschnittsfächer (Klinik) > Pathologie USB > Neuropathologie (Frank)
Item Type:Thesis
Thesis no:10897
Bibsysno:Link to catalogue
Number of Pages:95 S.
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:56
Deposited On:04 Sep 2014 09:38

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