16p11.2 haploinsufficiency reduces mitochondrial biogenesis in brain endothelial cells and alters brain metabolism in adult mice
Date
2023
Authors
Béland-Millar, Alexandria
Kirby, Alexia
Truong, Yen
Ouellette, Julie
Yandiev, Sozerko
Bouyakdan, Khalil
Pileggi, Chantal
Naz, Shama
Yin, Melissa
Carrier, Micaël
Journal Title
Journal ISSN
Volume Title
Publisher
Cell Reports
Abstract
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.
Description
We thank Carlie Boisvert (Lacoste lab) for technical assistance and Andrew Heinmiller (Fujifilm VisualSonics) for guidance on photoacoustic imaging. We thank the CRCHUM rodent metabolic phenotyping core facility for their help with tolerance tests.
Keywords
autism, endothelium, 16p11.2 deletion, metabolism, brain, glucose, lactate, mouse, mitochondrion
Citation
Béland-Millar, A., Kirby, A., Truong, Y., Ouellette, J., Yandiev, S., Bouyakdan, K., ... Lacoste, B. (2023). 16p11.2 haploinsufficiency reduces mitochondrial biogenesis in brain endothelial cells and alters brain metabolism in adult mice. Cell Reports, 42(5), 112485. https://doi.org/10.1016/j.celrep.2023.112485