16p11.2 haploinsufficiency reduces mitochondrial biogenesis in brain endothelial cells and alters brain metabolism in adult mice
Alexandria Béland-Millar,
Alexia Kirby,
Yen Truong,
Julie Ouellette,
Sozerko Yandiev,
Khalil Bouyakdan,
Chantal Pileggi,
Shama Naz,
Melissa Yin,
Micaël Carrier,
Pavel Kotchetkov,
Marie-Kim St-Pierre,
Marie-Ève Tremblay,
Julien Courchet,
Mary-Ellen Harper,
Thierry Alquier,
Claude Messier,
Adam J. Shuhendler,
Baptiste Lacoste
Affiliations
Alexandria Béland-Millar
Neuroscience Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada; School of Psychology, University of Ottawa, Ottawa, ON, Canada
Alexia Kirby
Faculty of Science, Department of Biology, University of Ottawa, Ottawa, ON, Canada
Yen Truong
Faculty of Science, Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON, Canada
Julie Ouellette
Neuroscience Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada; Faculty of Medicine, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
Sozerko Yandiev
University Lyon 1, CNRS, INSERM, Physiopathologie et Génétique du Neurone et du Muscle, UMR5261, U1315, Institut NeuroMyoGène, 69008 Lyon, France
Khalil Bouyakdan
Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Department of Medicine Université de Montréal, Montreal, QC, Canada
Chantal Pileggi
Faculty of Medicine, Department of Biochemistry Microbiology and Immunology, Ottawa, ON, Canada
Shama Naz
University of Ottawa Metabolomics Core Facility, Faculty of Medicine, Ottawa, ON, Canada
Melissa Yin
FUJIFILM VisualSonics, Inc, Toronto, ON, Canada
Micaël Carrier
Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
Pavel Kotchetkov
Neuroscience Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada; Faculty of Medicine, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
Marie-Kim St-Pierre
Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
Marie-Ève Tremblay
Division of Medical Sciences, University of Victoria, Victoria, BC, Canada; Neurology and Neurosurgery Department, McGill University, Montreal, QC, Canada; Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, BC, Canada
Julien Courchet
University Lyon 1, CNRS, INSERM, Physiopathologie et Génétique du Neurone et du Muscle, UMR5261, U1315, Institut NeuroMyoGène, 69008 Lyon, France
Mary-Ellen Harper
Faculty of Medicine, Department of Biochemistry Microbiology and Immunology, Ottawa, ON, Canada
Thierry Alquier
Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Department of Medicine Université de Montréal, Montreal, QC, Canada
Claude Messier
School of Psychology, University of Ottawa, Ottawa, ON, Canada
Adam J. Shuhendler
Faculty of Science, Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON, Canada; University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada
Baptiste Lacoste
Neuroscience Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada; Faculty of Medicine, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada; University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada; Corresponding author
Summary: Neurovascular abnormalities in mouse models of 16p11.2 deletion autism syndrome are reminiscent of alterations reported in murine models of glucose transporter deficiency, including reduced brain angiogenesis and behavioral alterations. Yet, whether cerebrovascular alterations in 16p11.2df/+ mice affect brain metabolism is unknown. Here, we report that anesthetized 16p11.2df/+ mice display elevated brain glucose uptake, a phenomenon recapitulated in mice with endothelial-specific 16p11.2 haplodeficiency. Awake 16p11.2df/+ mice display attenuated relative fluctuations of extracellular brain glucose following systemic glucose administration. Targeted metabolomics on cerebral cortex extracts reveals enhanced metabolic responses to systemic glucose in 16p11.2df/+ mice that also display reduced mitochondria number in brain endothelial cells. This is not associated with changes in mitochondria fusion or fission proteins, but 16p11.2df/+ brain endothelial cells lack the splice variant NT-PGC-1α, suggesting defective mitochondrial biogenesis. We propose that altered brain metabolism in 16p11.2df/+ mice is compensatory to endothelial dysfunction, shedding light on previously unknown adaptative responses.
