Evidence of Energy Metabolism Alterations in Cultured Neonatal Astrocytes Derived from the Ts65Dn Mouse Model of Down Syndrome

Abstract

For many decades, neurons have been the central focus of studies on the mechanisms underlying the neurodevelopmental and neurodegenerative aspects of Down syndrome (DS). Astrocytes, which were once thought to have only a passive role, are now recognized as active participants of a variety of essential physiological processes in the brain. Alterations in their physiological function have, thus, been increasingly acknowledged as likely initiators of or contributors to the pathogenesis of many nervous system disorders and diseases. In this study, we carried out a series of real-time measurements of oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in hippocampal astrocytes derived from neonatal Ts65Dn and euploid control mice using a Seahorse XFp Flux Analyzer. Our results revealed a significant basal OCR increase in neonatal Ts65Dn astrocytes compared with those from control mice, indicating increased oxidative phosphorylation. ECAR did not differ between the groups. Given the importance of astrocytes in brain metabolic function and the linkage between astrocytic and neuronal energy metabolism, these data provide evidence against a pure “neurocentric” vision of DS pathophysiology and support further investigations on the potential contribution of disturbances in astrocytic energy metabolism to cognitive deficits and neurodegeneration associated with DS.

Brain Mitochondrial Bioenergetics in Genetic Neurodevelopmental Disorders: Focus on Down, Rett and Fragile X Syndromes

“…Indeed, glycolysis and the levels of brain lactate remain high in DS to compensate for the mitochondrial OXPHOS deficit [134,138], and it might be that the glycolytic environment can change the fate of neural progenitor differentiation negatively, affecting neurogenesis and favoring astrocyte formation [18]. Recently, this hypothesis has been confirmed in neonatal astrocytes from a Ts65Dn mouse model of DS [139] and in the trisomic neural progenitor cells (NPCs) obtained from Hsa21 trisomic-induced pluripontent stem cells (iPSCs). NPCs display early mitochondrial dysfunction and an abnormal mitochondrial network during differentiation with respect to euploid cells and show greater potential in producing glial-like cells, which leads to a failing energy metabolism transition [125,140].…”

The implication of a diversity of non-neuronal cells in disorders affecting brain networks

“…To ensure proper sending and receiving of neuronal information, the CNS comprises a complex support system primary composed of glial cells such as microglia, astrocytes, and oligodendrocytes achieving various roles (Figure 1; Oberheim et al, 2012;Butt and Verkhratsky, 2018;Foerster et al, 2019;Stratoulias et al, 2019). Microglia, astrocytes and oligodendrocytes were shown to display a wide diversity across the CNS, by which they play main roles as immune sentinels, metabolic regulators and myelin producers, respectively (Davalos et al, 2005;Nimmerjahn et al, 2005;Foerster et al, 2019;Zampieri and Costa, 2022). Even though myelination is mainly performed by oligodendrocytes, microglia are able to help by removing myelin through phagocytosis, while releasing sulfatide, a myelin-specific galactolipid, able to promote myelin basic protein (MBP) production (Gitik et al, 2011;Traiffort et al, 2020).…”