المؤلفون: St-Pierre, Marie-Kim^1,2,3 (AUTHOR), González Ibáñez, Fernando^1,2,3 (AUTHOR), Kroner, Antje^4,5,6 (AUTHOR) akroner@mcw.edu, Tremblay, Marie-Ève^1,2,3,7,8,9 (AUTHOR) evetremblay@uvic.ca

المصدر: Journal of Neuroinflammation. 11/21/2023, Vol. 20 Issue 1, p1-15. 15p.

مصطلحات موضوعية: *SPINAL cord injuries, *MICROGLIA, *MACROPHAGES, *SPINAL cord, *DENDRITIC spines, *SCANNING electron microscopy

مستخلص: Traumatic spinal cord injury can cause immediate physical damage to the spinal cord and result in severe neurological deficits. The primary, mechanical tissue damage triggers a variety of secondary damage mechanisms at the injury site which significantly contribute to a larger lesion size and increased functional damage. Inflammatory mechanisms which directly involve both microglia (MG) and monocyte-derived macrophages (MDM) play important roles in the post-injury processes, including inflammation and debris clearing. In the current study, we investigated changes in the structure and function of MG/MDM in the injured spinal cord of adult female mice, 7 days after a thoracic contusion SCI. With the use of chip mapping scanning electron microscopy, which allows to image large samples at the nanoscale, we performed an ultrastructural comparison of MG/MDM located near the lesion vs adjacent regions to provide novel insights into the mechanisms at play post-injury. We found that MG/MDM located near the lesion had more mitochondria overall, including mitochondria with and without morphological alterations, and had a higher proportion of altered mitochondria. MG/MDM near the lesion also showed an increased number of phagosomes, including phagosomes containing myelin and partiallydigested materials. MG/MDM near the injury interacted differently with the spinal cord parenchyma, as shown by their reduced number of direct contacts with synaptic elements, axon terminals and dendritic spines. In this study, we characterized the ultrastructural changes of MG/MDM in response to spinal cord tissue damage in mice, uncovering changes in phagocytic activity, mitochondrial ultrastructure, and inter-cellular interactions within the spinal cord parenchyma. [ABSTRACT FROM AUTHOR]

المؤلفون: Béland-Millar, Alexandria, Kirby, Alexia, Truong, Yen, Ouellette, Julie, Yandiev, Sozerko, Bouyakdan, Khalil, Pileggi, Chantal, Naz, Shama, Yin, Melissa, Carrier, Micaël, Kotchetkov, Pavel, St-Pierre, Marie-Kim, Tremblay, Marie-Ève, Courchet, Julien, Harper, Mary-Ellen, Alquier, Thierry, Messier, Claude, Shuhendler, Adam J., Lacoste, Baptiste

مصطلحات موضوعية: autism, endothelium, 16p11.2 deletion, metabolism, brain, glucose, lactate, mouse, mitochondrion

الوصف: 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. ; 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. ; Metabolites were analyzed at the University of Ottawa Metabolomics Core Facility; this facility is supported by the Terry Fox Foundation and Ottawa University. B.L. was supported by start-up funds from the Ottawa Hospital Research Institute, a Canadian Institutes of Health Research (grant #388805), an award from The Scottish Rite Charitable Foundation of Canada (grant #17112), and a J.P. Bickell Foundation medical research grant. Part of this work is also funded by an Autism Research Program Idea Development Award from the US Department of Defense office of the ...

وصف الملف: application/pdf

العلاقة: 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.2023.112485Test; https://doi.org/10.1016/j.celrep.2023.112485Test; http://hdl.handle.net/1828/15598Test

الإتاحة: https://doi.org/10.1016/j.celrep.2023.112485Test
http://hdl.handle.net/1828/15598Test