Mitochondrial metabolism in astrocytes - impact on hippocampal neurogenesis and gliogenesis
Final Report Abstract
Astrocytes are highly abundant in the brain and central to physiology of the nervous system by e.g., regulating metabolite, ion and water homeostasis, synapse formation and modulation, tissue repair, energy storage and defense against oxidative stress. Converging evidence from an ever-increasing number of studies is revealing a strong contribution of astrocytes to neurodegenerative, neurodevelopmental and neuropsychiatric diseases as well as injury of the brain. The aim of project 1 was to understand on a functional level how mitochondrial metabolism in astrocytes contribute to CNS function in development and disease. We determined that mitochondrial dysfunction in cortical astrocytes does not impair astrocyte survival under physiological conditions, but leads to impaired proliferation of reactive astrocytes and increased neuronal cell death in a model of ischemic stroke. In a neurodevelopmental disorder, Bosch-Boonstra-Schaaf optic atrophy syndrome (BSSOAS), dysfunctional mitochondrial metabolism in the adult hippocampal neurogenic lineage contributes to disease progression. Our research identified astrocytic mitochondrial metabolisms as a potentially new therapeutic target to increase neuronal survival after brain injury, emphasizing the need to shed light on ill-defined astrocytic properties in order to use their potential for brain repair. The dentate gyrus (DG) of the hippocampus is unique in its plasticity due to the persists of adult neural stem cells (NSCs). NSCs generate new neurons life-long, which integrate into existing neural circuitries and contribute to hippocampus-dependent memory processes. The aim of my group is to understand how astrocyte participate in hippocampal plasticity using adult neurogenesis as a readout. In order to do so, it was indispensable to find better tools to target and manipulate astrocytes in the DG. Due to highly overlapping transcriptional profiles, it was hithero impossible to discriminate DG astrocytes from NSCs using existing Cre mouse lines based on promoter activity of GFAP or GLAST. In aim 2, we were able to identify a novel mouse line expressing Cre recombinase under the Tamoxifen-inducible Aldh1L1 promoter, which specifically labels astrocytes but not NSCs within the hippocampal neurogenic niche. The Aldh1L1::CreERT2 mouse line therefore represents a crucial tool to specifically manipulate astrocytes without affecting NSCs, and to eventually address the role of DG astrocytes to hippocampal plasticity. Furthermore, these mice can be also used to target cells of the melanocytic lineage.
Publications
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Mitochondrial Dysfunction in Astrocytes Impairs the Generation of Reactive Astrocytes and Enhances Neuronal Cell Death in the Cortex Upon Photothrombotic Lesion. Frontiers in Molecular Neuroscience, 12.
Fiebig, Christian; Keiner, Silke; Ebert, Birgit; Schäffner, Iris; Jagasia, Ravi; Lie, D. Chichung & Beckervordersandforth, Ruth
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Distribution of Aldh1L1-CreERT2 Recombination in Astrocytes Versus Neural Stem Cells in the Neurogenic Niches of the Adult Mouse Brain. Frontiers in Neuroscience, 15.
Beyer, Felix; Lüdje, Wichard; Karpf, Julian; Saher, Gesine & Beckervordersandforth, Ruth
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Two novel CreERT2 transgenic mouse lines to study melanocytic cells in vivo. Pigment Cell & Melanoma Research, 35(6), 613-621.
Stüfchen, Isabel; Beckervordersandforth, Ruth; Fischer, Stefan; Kappelmann‐Fenzl, Melanie; Bosserhoff, Anja Katrin & Beyer, Felix
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NR2F1 shapes mitochondria in the mouse brain, providing new insights into Bosch-Boonstra-Schaaf optic atrophy syndrome. Disease Models & Mechanisms, 16(6).
Bonzano, Sara; Dallorto, Eleonora; Molineris, Ivan; Michelon, Filippo; Crisci, Isabella; Gambarotta, Giovanna; Neri, Francesco; Oliviero, Salvatore; Beckervordersandforth, Ruth; Lie, Dieter Chichung; Peretto, Paolo; Bovetti, Serena; Studer, Michèle & Marchis, Silvia De
