Ultrastructural view of astrocyte arborization, astrocyte-astrocyte and astrocyte-synapse contacts, intracellular vesicle-like structures, and mitochondrial network

Aten, Sydney; Kiyoshi, Conrad M.; Arzola, Emily P.; Patterson, Jeremy A.; Taylor, Anne; Du, Yixing; Guiher, Ally M.; Philip, Merna; Camacho, Elizabeth Gerviacio; Mediratta, Devin; Collins, Kelsey A.; Boni, Kirsten; Garcia, Silvana A; Kumar, Rahul; Drake, Aiden N; Hegazi, Ahlam; Trank, Lindsey; Benson, Emily; Kidd, Grahame J.; Terman, David; Zhou, Min

doi:10.1016/j.pneurobio.2022.102264

Cited by 70 publications

(60 citation statements)

References 115 publications

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“…S1C). These findings are consistent with a recent three-dimensional (3D) ultrastructural study that shows similar mitochondria densities in astrocytes and neuronal processes ( 17 ). Overrepresentation analysis (ORA) of the 67 mitochondrial proteins chiefly found in astrocytes implied active mitochondrial remodeling and transport especially in these glial cells ( Fig.…”

Section: Resultssupporting

confidence: 92%

“…Our functional assays demonstrate ATP generation not only by glycolysis but also by OXPHOS in astrocytes, which is reflected in the astroglial sensitivity to changes in the partial pressure of oxygen (39,40). Accordingly, astrocyte cell bodies contain a higher density and volume fraction of mitochondria compared to neurons, as reported in a 3D ultrastructural study (17).…”

Section: Discussionsupporting

confidence: 75%

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Ketogenic diet uncovers differential metabolic plasticity of brain cells

Düking¹,

Spieth²,

Berghoff³

et al. 2022

Sci. Adv.

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To maintain homeostasis, the body, including the brain, reprograms its metabolism in response to altered nutrition or disease. However, the consequences of these challenges for the energy metabolism of the different brain cell types remain unknown. Here, we generated a proteome atlas of the major central nervous system (CNS) cell types from young and adult mice, after feeding the therapeutically relevant low-carbohydrate, high-fat ketogenic diet (KD) and during neuroinflammation. Under steady-state conditions, CNS cell types prefer distinct modes of energy metabolism. Unexpectedly, the comparison with KD revealed distinct cell type–specific strategies to manage the altered availability of energy metabolites. Astrocytes and neurons but not oligodendrocytes demonstrated metabolic plasticity. Moreover, inflammatory demyelinating disease changed the neuronal metabolic signature in a similar direction as KD. Together, these findings highlight the importance of the metabolic cross-talk between CNS cells and between the periphery and the brain to manage altered nutrition and neurological disease.

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Section: Resultssupporting

confidence: 92%

Section: Discussionsupporting

confidence: 75%

Ketogenic diet uncovers differential metabolic plasticity of brain cells

Düking¹,

Spieth²,

Berghoff³

et al. 2022

Sci. Adv.

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show abstract

“…We then examined the interastrocytic distance that is critical for the formation of gap junctional coupling at the interfaces of astrocytic domains (Aten, Kiyoshi, et al, 2022; Bushong et al, 2004). There was no significant change from P1 (18.2 ± 0.5 μm, n = 45) to P3 (17.9 ± 0.6 μm, n = 45, p = 1.000), but that was followed by a significant increase at P9 (32.4 ± 0.6 μm, n = 45, p = 7.29E−08), and P15 (40.3 ± 1.1 μm, n = 45, p = 8.08E−08, Figure 2c).…”

Section: Resultsmentioning

confidence: 99%

Genesis of a functional astrocyte syncytium in the developing mouse hippocampus

Zhong

Kiyoshi

et al. 2023

Glia

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Astrocytes are increasingly shown to operate as an isopotential syncytium in brain function. Protoplasmic astrocytes acquire this ability to functionally go beyond the single‐cell level by evolving into a spongiform morphology, cytoplasmically connecting into a syncytium, and expressing a high density of K+ conductance. However, none of these cellular/functional features exist in neonatal newborn astrocytes, which imposes a basic question of when a functional syncytium evolves in the developing brain. Our results show that the spongiform morphology of individual astrocytes and their spatial organization all reach stationary levels by postnatal day (P) 15 in the hippocampal CA1 region. Functionally, astrocytes begin to uniformly express a mature level of passive K+ conductance by P11. We next used syncytial isopotentiality measurement to monitor the maturation of the astrocyte syncytium. In uncoupled P1 astrocytes, the substitution of endogenous K+ by a Na+‐electrode solution ([Na+]p) resulted in the total elimination of the physiological membrane potential (VM), and outward K+ conductance as predicted by the Goldman‐Hodgkin‐Katz (GHK) equation. As more astrocytes are coupled to each other through gap junctions during development, the [Na+]p‐induced loss of physiological VM and the outward K+ conductance is progressively compensated by the neighboring astrocytes. By P15, a stably established syncytial isopotentiality (−73 mV), and a fully compensated outward K+ conductance appeared in all [Na+]p‐recorded astrocytes. Thus, in view of the developmental timeframe wherein a singular syncytium is anatomically and functionally established for intra‐syncytium K+ equilibration, an astrocyte syncytium becomes fully operational at P15 in the mouse hippocampus.

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“…A biphasic response of astrocytic [ATP] consisting of a short increase followed by a prolonged decrease below basal levels was reported in hippocampal organotypic cultures during treatment with 0 Mg 2+ /bicuculline (Lerchundi et al, 2020). Within the GM of the brain, astrocytes extend uncountable fine processes contacting numerous synapses and forming local microdomains (Aten et al, 2022; Grosche et al, 1999; Reichenbach et al, 2010). Subcellular regulation of astrocytic metabolism on the spatial scale of these microdomains has been proposed (Oheim et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Gray and white matter astrocytes differ in basal metabolism but respond similarly to neuronal activity

Köhler

Winkler

Junge

et al. 2022

Glia

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Astrocytes are a heterogeneous population of glial cells in the brain, which adapt their properties to the requirements of the local environment. Two major groups of astrocytes are protoplasmic astrocytes residing in gray matter as well as fibrous astrocytes of white matter. Here, we compared the energy metabolism of astrocytes in the cortex and corpus callosum as representative gray matter and white matter regions, in acute brain slices taking advantage of genetically encoded fluorescent nanosensors for the NADH/NAD + redox ratio and for ATP.Astrocytes of the corpus callosum presented a more reduced basal NADH/NAD + redox ratio, and a lower cytosolic concentration of ATP compared to cortical astrocytes. In cortical astrocytes, the neurotransmitter glutamate and increased extracellular concentrations of K + , typical correlates of neuronal activity, induced a more reduced NADH/NAD + redox ratio. While application of glutamate decreased [ATP], K + as well as the combination of glutamate and K + resulted in an increase of ATP levels. Strikingly, a very similar regulation of metabolism by K + and glutamate was observed in astrocytes in the corpus callosum. Finally, strong intrinsic neuronal activity provoked by application of bicuculline and withdrawal of Mg 2+ caused a shift of the NADH/NAD + redox ratio to a more reduced state as well as a slight reduction of [ATP] in gray and white matter astrocytes. In summary, the metabolism of astrocytes in cortex and corpus callosum shows distinct basal properties, but qualitatively similar responses to neuronal activity, probably reflecting the different environment and requirements of these brain regions.

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Ultrastructural view of astrocyte arborization, astrocyte-astrocyte and astrocyte-synapse contacts, intracellular vesicle-like structures, and mitochondrial network

Cited by 70 publications

References 115 publications

Ketogenic diet uncovers differential metabolic plasticity of brain cells

Ketogenic diet uncovers differential metabolic plasticity of brain cells

Genesis of a functional astrocyte syncytium in the developing mouse hippocampus

Gray and white matter astrocytes differ in basal metabolism but respond similarly to neuronal activity

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