TY - JOUR

T1 - Loss of maturity and homeostatic functions in Tuberous Sclerosis Complex-derived astrocytes

AU - Luinenburg, Mark J.

AU - Scheper, Mirte

AU - Sørensen, Frederik N.F.

AU - Anink, Jasper J.

AU - Van Hecke, Wim

AU - Korshunova, Irina

AU - Jansen, Floor E.

AU - Riney, Kate

AU - van Eijsden, Pieter

AU - Gosselaar, Peter

AU - Mills, James D.

AU - Kalf, Rozemarijn S.

AU - Zimmer, Till S.

AU - Broekaart, Diede W.M.

AU - Khodosevich, Konstantin

AU - Aronica, Eleonora

AU - Mühlebner, Angelika

N1 - Publisher Copyright: Copyright © 2023 Luinenburg, Scheper, Sørensen, Anink, Van Hecke, Korshunova, Jansen, Riney, van Eijsden, Gosselaar, Mills, Kalf, Zimmer, Broekaart, Khodosevich, Aronica and Mühlebner.

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

KW - astrocytes

KW - epilepsy

KW - glutamate buffering

KW - inflammation

KW - phagocytosis

KW - TSC

U2 - 10.3389/fncel.2023.1284394

DO - 10.3389/fncel.2023.1284394

M3 - Journal article

C2 - 38089143

AN - SCOPUS:85179329577

VL - 17

JO - Frontiers in Cellular Neuroscience

JF - Frontiers in Cellular Neuroscience

SN - 1662-5102

M1 - 1284394

ER -