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Analysis of ablation of mitochondrial fission in adult forebrain neurons

ABSTRACT: Well-balanced mitochondrial fission and fusion processes are essential for nervous system development. Loss of function of the main mitochondrial fission mediator, dynamin-related protein 1 (Drp1), is lethal early during embryonic development or around birth, but the role of mitochondrial fission in adult neurons remains unclear. Here we show that inducible Drp1 ablation in neurons of the adult mouse forebrain results in progressive, neuronal subtype-specific alterations of mitochondrial morphology in the hippocampus that are marginally responsive to antioxidant treatment. Furthermore, DRP1 loss affects synaptic transmission and memory function. Although these changes culminate in hippocampal atrophy, they are not sufficient to cause neuronal cell death within 10 weeks of genetic Drp1 ablation. Collectively, our in vivo observations clarify the role of mitochondrial fission in neurons, demonstrating that Drp1 ablation in adult forebrain neurons compromises critical neuronal functions without causing overt neurodegeneration.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Alexander Schmidt

LAB HEAD: Alexander Schmidt

PROVIDER: PXD004890 | Pride | 2016-08-25

REPOSITORIES: pride

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Synaptic dysfunction, memory deficits and hippocampal atrophy due to ablation of mitochondrial fission in adult forebrain neurons.

Oettinghaus B B Schulz J M JM Restelli L M LM Licci M M Savoia C C Schmidt A A Schmitt K K Grimm A A Morè L L Hench J J Tolnay M M Eckert A A D'Adamo P P Franken P P Ishihara N N Mihara K K Bischofberger J J Scorrano L L Frank S S

Cell death and differentiation 20150424 1

Well-balanced mitochondrial fission and fusion processes are essential for nervous system development. Loss of function of the main mitochondrial fission mediator, dynamin-related protein 1 (Drp1), is lethal early during embryonic development or around birth, but the role of mitochondrial fission in adult neurons remains unclear. Here we show that inducible Drp1 ablation in neurons of the adult mouse forebrain results in progressive, neuronal subtype-specific alterations of mitochondrial morphol ...[more]

PMID: 25909888

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Project description:Purpose:to verify Drp1-mediated biological pathways under physiological and ischemia conditions.Methods:C57BL/6 mice and Drp1 knockdown mice were used for ischemia treatment. Right femoral arteries were catheterized with polyethylene catheters for bleeding 50% of total blood volume (≈7% of weight). The ischemia time started to calculate after the model was established. A laparotomy was then carried out to obtain superior mesenteric artery tissues (SMAs) for transcriptome analysis. Series-Cluster analysis was performed to identify the global trends of mitochondrial DEGs after Drp1 knockdown. Gene ontology (GO) analysis was performed to facilitate elucidating the biological process (BP), molecular function (MF) and cellular component (CC) of unique genes in the significant or representative profiles. Results:In addition to its traditional roles in GTPase regulation and mitochondrial fission, Drp1 may also regulate actin cytoskeleton and the movement of microtubules. Besides, Drp1 may participate in the regulation of morphology and functions of other organelles, including endoplasmic reticulum, peroxisome, phagolysosome, etc. As for general organ functions, Drp1 may regulate vascular constriction and dilation. These consequences indicated the important role of Drp1 in ischemia-induced cellular regulation. Conclusions: Drp1 deficiency proves the important role of Drp1 in ischemia-induced biomedical processes through multiple potential fission-independent manners. Methods:C57BL/6 mice and Drp1 knockdown mice were used for ischemia treatment. Right femoral arteries were catheterized with polyethylene catheters for bleeding 50% of total blood volume (≈7% of weight). The ischemia time started to calculate after the model was established. A laparotomy was then carried out to obtain superior mesenteric artery tissues (SMAs) for transcriptome analysis. Series-Cluster analysis was performed to identify the global trends of mitochondrial DEGs after Drp1 knockdown. Gene ontology (GO) analysis was performed to facilitate elucidating the biological process (BP), molecular function (MF) and cellular component (CC) of unique genes in the significant or representative profiles. Results:In addition to its traditional roles in GTPase regulation and mitochondrial fission, Drp1 may also regulate actin cytoskeleton and the movement of microtubules. Besides, Drp1 may participate in the regulation of morphology and functions of other organelles, including endoplasmic reticulum, peroxisome, phagolysosome, etc. As for general organ functions, Drp1 may regulate vascular constriction and dilation. These consequences indicated the important role of Drp1 in ischemia-induced cellular regulation. Conclusions: Drp1 deficiency proves the important role of Drp1 in ischemia-induced biomedical processes through multiple potential fission-independent manners.

Project description:The lack of axonal growth after injury in the adult central nervous system (CNS) is partly due to the presence of growth-inhibitory molecules associated with myelin and the intrinsic growth-state of the injured neurons. To date, three inhibitors have been identified in myelin: Myelin- Associated Glycoprotein (MAG), Nogo A, and Oligodendrocyte-Myelin glycoprotein (OMgp). These three proteins all appear to be located in the periaxonal surface of the myelin membrane placing them in an optimal location to mediate axon-glial interaction. In addition, the three proteins have been shown to bind the same neuronal receptor, known as the Nogo-66 receptor (NgR). It has been hypothesized that inhibition of NgR may be a strategy to increase regeneration, plasticity and functional recovery of the lesioned central nervous system. Strong NgR mRNA expression is observed in the hippocampal pyramidal cell layers (CA1-3) and the granular layer of the dentate gyrus. It has been shown that animals exposed to entorhinal lesions show a biphasic regulation of NgR in the hippocampus, suggesting a tightly regulated mechanism mediated by this receptor. We have access to a transgenic model to over-express NgR in forebrain hippocampal neurons. Preliminary results have shown a phenotypic response in behavior and some molecular markers, as result of NgR overexpression. Knowledge of what genes are reacting in this novel transgenic model may provide insights into what pathways are affected by NgR to control synaptic plasticity in normal animals and during injury. We have access to a bitrasgenic conditional mouse model to everexpress the NgR receptor in forebrain neurons, through the CamKII promoter. This conditional model uses the tetracycline transactivator (tTA), which is expressed through the CamKII promoter. Upon removal of doxycycline, the TetOp target gene becomes active and over-expression of NgR in cells with an active CaMKII promoter is achieved. We will determine gene expression patterns in the dentate gyrus of transgenic animals engineered to over-express NgR through the CamKII promoter (present in several forebrain areas), and upon removal of doxyxycline. We hypothesize that over-expression of NgR in the hippocampus inhibits synaptic plasticity, thereby suppressing the formation of new synapses necessary for the formation of memory. EXPERIMENT 1; - Effects of NgR overexpression in the mature forebrain -; 1) Experimental group: Bitrasgenic + water: Overexpresses NgR in forebrain neurons. In this group, doxyxycline was removed from the drinking water in adult animals. All the control groups were aged matched. 2) Control group: Bitransgenic + doxy: Should control for leakage by the TetOp target gene, or for any effects mediated by doxycycline, as compared to other control groups. 3) Control group: Monotransgenic + water: Should control for any leakage mediated by the TetOp target gene, as compared to other control groups. 4) Control group: Monotrangenic + water: Should control for leakage by the TetOp target gene, or for any effects mediated by doxycycline, as compared to other control groups. EXPERIMENT 2; - Effects of NgR overexpression in the developing forebrain -; We will also analyze the effects of NgR overexpression in bitransgenic animals raised on water. In these animals, the NgR transgene is expressed in the forebrain upon activation of the CamKII promoter. Since neuronal differentiation and neuronal pathways are being formed during development, we anticipate that NgR overexpression (de)effects in these animals will be markedly different to those observed in adult animals. 1) Bitransgenic + water (through entire lifespan): The animals in this group were never treated with doxycycline, and therefore expressed the NgR transgene upon activity of the CamKII promoter. 2) Monotransgenic + water: This control group will control for leakage by the Tet Op gene, or for effects of the tTA expression.

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