Mitochondrial biogenesis in developing astrocytes regulates astrocyte maturation and synapse formation
Tamara Zehnder,
Francesco Petrelli,
Jennifer Romanos,
Eva C. De Oliveira Figueiredo,
Tommy L. Lewis, Jr.,
Nicole Déglon,
Franck Polleux,
Mirko Santello,
Paola Bezzi
Affiliations
Tamara Zehnder
Department of Fundamental Neurosciences, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 9, 1005 Lausanne, Switzerland
Francesco Petrelli
Department of Fundamental Neurosciences, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 9, 1005 Lausanne, Switzerland
Jennifer Romanos
Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland
Eva C. De Oliveira Figueiredo
Department of Fundamental Neurosciences, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 9, 1005 Lausanne, Switzerland
Tommy L. Lewis, Jr.
Department of Neuroscience, Columbia University, New York, NY 10032, USA; Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10032, USA
Nicole Déglon
Department of Clinical Neurosciences, Laboratory of Neurotherapies and Neuromodulation (LNTM), Lausanne University Hospital (CHUV) and University of Lausanne, 1011 Lausanne, Switzerland; Neurosciences Research Center (CRN), Laboratory of Neurotherapies and Neuromodulation (LNTM), Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland
Franck Polleux
Department of Neuroscience, Columbia University, New York, NY 10032, USA; Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10032, USA
Mirko Santello
Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland; Corresponding author
Paola Bezzi
Department of Fundamental Neurosciences, Faculty of Biology and Medicine, University of Lausanne, Rue du Bugnon 9, 1005 Lausanne, Switzerland; Department of Physiology and Pharmacology, Sapienza University of Rome, 00185 Rome, Italy; Corresponding author
Summary: 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.
