@article{9b9b2f18592e4396a0a456c8aa68ae5a,
title = "Loss of maturity and homeostatic functions in Tuberous Sclerosis Complex-derived astrocytes",
abstract = "Introduction: Constitutive activation of the mTOR pathway, as observed in Tuberous Sclerosis Complex (TSC), leads to glial dysfunction and subsequent epileptogenesis. Although astrocytes are considered important mediators for synaptic clearance and phagocytosis, little is known on how astrocytes contribute to the epileptogenic network. Methods: We employed singlenuclei RNA sequencing and a hybrid fetal calf serum (FCS)/FCS-free cell culture model to explore the capacity of TSC-derived astrocytes to maintain glutamate homeostasis and clear debris in their environment. Results: We found that TSC astrocytes show reduced maturity on RNA and protein level as well as the inability to clear excess glutamate through the loss of both enzymes and transporters complementary to a reduction of phagocytic capabilities. Discussion: Our study provides evidence of mechanistic alterations in TSC astrocytes, underscoring the significant impairment of their supportive functions. These insights enhance our understanding of TSC pathophysiology and hold potential implications for future therapeutic interventions.",
keywords = "TSC, astrocytes, epilepsy, glutamate buffering, inflammation, phagocytosis",
author = "Luinenburg, {Mark J.} and Mirte Scheper and S{\o}rensen, {Frederik N. F.} and Anink, {Jasper J.} and {van Hecke}, Wim and Irina Korshunova and Jansen, {Floor E.} and Kate Riney and {van Eijsden}, Pieter and Peter Gosselaar and Mills, {James D.} and Kalf, {Rozemarijn S.} and Zimmer, {Till S.} and Broekaart, {Diede W. M.} and Konstantin Khodosevich and Eleonora Aronica and Angelika M{\"u}hlebner",
note = "Funding Information: The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research has received funding from the European Union{\textquoteright}s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 602391; the Dutch Epilepsy Foundation, project number 2020-02 (AM and ML); TSC foundation project number 2019-02 (AM and ML); the ZonMw, Programme Translational Research no. 95105004 (EA); the European Union{\textquoteright}s Horizon 2020 WIDESPREAD-05-2020–Twinning and EpiEpiNet; grant agreement no. 952455 (EA). The snRNA-seq work was supported by Novo Nordisk Hallas-M{\o}ller Investigator grant (NNF21OC0067146) to KK. Publisher Copyright: Copyright {\textcopyright} 2023 Luinenburg, Scheper, S{\o}rensen, Anink, Van Hecke, Korshunova, Jansen, Riney, van Eijsden, Gosselaar, Mills, Kalf, Zimmer, Broekaart, Khodosevich, Aronica and M{\"u}hlebner.",
year = "2023",
doi = "https://doi.org/10.3389/fncel.2023.1284394",
language = "English",
volume = "17",
journal = "Frontiers in cellular neuroscience",
issn = "1662-5102",
publisher = "Frontiers Media S.A.",
}