Astrocytes: new evidence, new models, new roles

Brazhe, Alexey; Verisokin, Andrey; Verveyko, Darya; Postnov, Dmitry

doi:10.1007/s12551-023-01145-7

Cited by 4 publications

(2 citation statements)

References 306 publications

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“…Hippocampal astrocytes are known to participate actively during memory consolidation and the location-specific encoding of the reward system (Brazhe et al, 2023;Curreli et al, 2022;Denizot et al, 2019;Doron et al, 2022;Polykretis and Michmizos, 2022). In addition, APDAs have been shown to reduce the number of synapses in adjacent neurons (Lee et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

“…Although a direct relevance to cognitive function was not shown, these autophagy dysregulated astrocytes had detrimental effects on the number of synapses in adjacent neurons (Lee et al, 2022). Furthermore, astrocytic dysfunction could directly affect the age-related decline of hippocampal function, considering that hippocampal astrocytes play an active role in memory consolidation and the location-specific encoding of the reward system (Brazhe et al, 2023;Curreli et al, 2022;Denizot et al, 2019;Doron et al, 2022;Polykretis and Michmizos, 2022).…”

Section: Introductionmentioning

confidence: 99%

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ThePgb1locus controls glycogen aggregation in astrocytes of the aged hippocampus without impacting cognitive function

Gómez-Pascual,

Glikman,

et al. 2023

Preprint

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Aging can be associated with the accumulation of hypobranched glycogen molecules (polyglucosan bodies, PGBs), particularly in astrocytes of the hippocampus. While PGBs have a detrimental effect on cognition in diseases such as adult polyglucosan body disease and Lafora disease, the underlying mechanism and clinical relevance of age-related PGB accumulation remains unknown. Here, we have investigated the genetic basis and functional impact of age-related PGB accumulation in 32 fully sequenced BXD-type strains of mice which exhibit a 400-fold variation in PGB burden in 16-18 month old females. We mapped a major locus controlling PGB density in the hippocampus to chromosome 1 at 72–75 Mb (linkage of 4.9 –logP), which we defined as thePgb1locus. To identify potentially causal gene variants withinPgb1, we generated extensive hippocampal transcriptome datasets and identified two strong candidate genes for which mRNA correlates with PGB density—Smarcal1andUsp37. In addition, bothSmarcal1andUsp37contain non-synonymous allele variations likely to impact protein function. A phenome-wide association analysis highlighted a trans-regulatory effect of thePgb1locus on expression ofHp1bp3, a gene known to play a role in age-related changes in learning and memory. To investigate the potential impact of PGBs on cognition, we performed conditioned fear memory testing on strains displaying varying degrees of PGB burden, and a phenome-wide association scan of ~12,000 traits. Importantly, we did not find any evidence suggesting a negative impact of PGB burden on cognitive capacity. Taken together, we have identified a major modifier locus controlling PGB burden in the hippocampus and shed light on the genetic architecture and clinical relevance of this strikingly heterogeneous hippocampal phenotype.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ThePgb1locus controls glycogen aggregation in astrocytes of the aged hippocampus without impacting cognitive function

Gómez-Pascual,

Glikman,

et al. 2023

Preprint

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ATP Restoration by ATP-Deprived Cultured Primary Astrocytes

Karger,

Willker,

Harders

et al. 2024

Neurochem Res

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A high cellular concentration of adenosine triphosphate (ATP) is essential to fuel many important functions of brain astrocytes. Although cellular ATP depletion has frequently been reported for astrocytes, little is known on the metabolic pathways that contribute to ATP restoration by ATP-depleted astrocytes. Incubation of cultured primary rat astrocytes in glucose-free buffer for 60 min with the mitochondrial uncoupler BAM15 lowered the cellular ATP content by around 70%, the total amount of adenosine phosphates by around 50% and the adenylate energy charge (AEC) from 0.9 to 0.6. Testing for ATP restoration after removal of the uncoupler revealed that the presence of glucose as exclusive substrate allowed the cells to restore within 6 h around 80% of the initial ATP content, while coapplication of adenosine plus glucose enabled the cells to fully restore their initial ATP content within 60 min. A rapid but incomplete and transient ATP restoration was found for astrocytes that had been exposed to adenosine alone. This restoration was completely prevented by application of the pyruvate uptake inhibitor UK5099, the respiratory chain inhibitor antimycin A or by the continuous presence of BAM15. However, the presence of these compounds strongly accelerated the release of lactate from the cells, suggesting that the ribose moiety of adenosine can serve as substrate to fuel some ATP restoration via mitochondrial metabolism. Finally, the adenosine-accelerated ATP restoration in glucose-fed astrocytes was inhibited by the presence of the adenosine kinase inhibitor ABT-702. These data demonstrate that astrocytes require for a rapid and complete ATP restoration the presence of both glucose as substrate and adenosine as AMP precursor.

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