Mitochondrial metabolism in astrocytes - impact on hippocampal neurogenesis and gliogenesis

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The continuous generation and integration of new neurons into existing circuitries is a key contribution to an adult's brain plasticity and is restricted to specific neurogenic niches in the forebrain - one of them is the hippocampus. Here, the production of neurons is achieved through a stereotypic developmental sequence that requires precise regulatory mechanisms to prevent exhaustion or uncontrolled growth of resident neural stem cells (NSCs). Recently, I discovered a critical role of mitochondrial electron transport and oxidative phosphorylation in regulating progression of the hippocampal neurogenic lineage specifically at the intermediate progenitor cell state. Disrupting these pathways in NSCs and astrocytes induces premature ageing phenotypes while enhancing mitochondrial function significantly improves neurogenesis during ageing. My data identify mitochondrial function as a potential target to ameliorate neurogenesis defects in the aged hippocampus and support the emerging notion that stage-specific metabolic programs are functionally linked to distinct steps within the NSC lineage. Like in other stem cell systems, interaction of stem cells and stem cell progeny with their microenvironment is critical for regulation of hippocampal neurogenesis. Astrocytes are key components of the neurogenic niches and provide the necessary local microenvironment for the generation of new neurons. An intriguing question emerging from the obtained results is if the defects in hippocampal neurogenesis are caused by mitochondria dysfunction in NSCs or due to metabolic changes in niche astrocytes. In project 1 I will induce conditional Tfam deletion in two different mouse models - a NSC-specific Cre-driver and a Cre-driver specific for niche astrocytes - and investigate the impact on neurogenic lineage progression. These studies will give important insights into whether and how mitochondrial metabolism in niche astrocytes affects hippocampal neurogenesis. Furthermore, I will investigate the novel aspect of a potential regulatory function of mitochondrial metabolism in gliogenesis and glial lineage progression. Project 2 will assess if generation, survival and maturation of new astrocytes from adult hippocampal NSCs and local astrocyte progenitors require intact mitochondrial complex machinery or if this is a specific hallmark of the neuronal lineage. Together, these studies will provide important insights into a regulatory function of mitochondrial metabolism in astrocytes on neurogenesis and gliogenesis in the adult hippocampus.