Mitochondrial biogenesis in developing astrocytes regulates astrocyte maturation and synapse formation

The mechanisms controlling the post-natal maturation of astrocytes play a crucial role in ensuring correct synaptogenesis. We show that mitochondrial biogenesis in developing astrocytes is necessary for coordinating post-natal astrocyte maturation and synaptogenesis. The astrocytic mitochondrial biogenesis depends on the transient upregulation of metabolic regulator peroxisome proliferator-activated receptor gamma (PPARγ) co-activator 1α (PGC-1α), which is controlled by metabotropic glutamate receptor 5 (mGluR5). At tissue level, the loss or downregulation of astrocytic PGC-1α sustains astrocyte proliferation, dampens astrocyte morphogenesis, and impairs the formation and function of neighboring synapses, whereas its genetic re-expression is sufficient to restore the mitochondria compartment and correct astroglial and synaptic defects. Our findings show that the developmental enhancement of mitochondrial biogenesis in astrocytes is a critical mechanism controlling astrocyte maturation and supporting synaptogenesis, thus suggesting that astrocytic mitochondria may be a therapeutic target in the case of neurodevelopmental and psychiatric disorders characterized by impaired synaptogenesis. [Display omitted] •Developing astrocytes contain a highly interconnected functional network of mitochondria•Mitochondrial biogenesis in developing astrocytes is controlled by PGC-1α•mGluR5 signaling modulates PGC-1α levels in developing astrocytes•Deletion of PGC1-1α and mGluR5 impairs astrocyte maturation and synaptogenesis Zehnder et al. demonstrate that proper levels of PGC-1α are necessary to induce a correct mitochondrial biogenesis in developing astrocytes and, consequently, to coordinate post-natal astrocyte morphogenesis and synaptogenesis.