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Open Access 01-06-2024 | Tuberous Sclerosis | Original Paper

Impaired GABAergic regulation and developmental immaturity in interneurons derived from the medial ganglionic eminence in the tuberous sclerosis complex

Authors: Mirte Scheper, Frederik N. F. Sørensen, Gabriele Ruffolo, Alessandro Gaeta, Lilian J. Lissner, Jasper J. Anink, Irina Korshunova, Floor E. Jansen, Kate Riney, Wim van Hecke, Angelika Mühlebner, Konstantin Khodosevich, Dirk Schubert, Eleonora Palma, James D. Mills, Eleonora Aronica

Published in: Acta Neuropathologica | Issue 1/2024

Abstract

GABAergic interneurons play a critical role in maintaining neural circuit balance, excitation–inhibition regulation, and cognitive function modulation. In tuberous sclerosis complex (TSC), GABAergic neuron dysfunction contributes to disrupted network activity and associated neurological symptoms, assumingly in a cell type-specific manner. This GABAergic centric study focuses on identifying specific interneuron subpopulations within TSC, emphasizing the unique characteristics of medial ganglionic eminence (MGE)- and caudal ganglionic eminence (CGE)-derived interneurons. Using single-nuclei RNA sequencing in TSC patient material, we identify somatostatin-expressing (SST+) interneurons as a unique and immature subpopulation in TSC. The disrupted maturation of SST+ interneurons may undergo an incomplete switch from excitatory to inhibitory GABAergic signaling during development, resulting in reduced inhibitory properties. Notably, this study reveals markers of immaturity specifically in SST+ interneurons, including an abnormal NKCC1/KCC2 ratio, indicating an imbalance in chloride homeostasis crucial for the postsynaptic consequences of GABAergic signaling as well as the downregulation of GABA_A receptor subunits, GABRA1, and upregulation of GABRA2. Further exploration of SST+ interneurons revealed altered localization patterns of SST+ interneurons in TSC brain tissue, concentrated in deeper cortical layers, possibly linked to cortical dyslamination. In the epilepsy context, our research underscores the diverse cell type-specific roles of GABAergic interneurons in shaping seizures, advocating for precise therapeutic considerations. Moreover, this study illuminates the potential contribution of SST+ interneurons to TSC pathophysiology, offering insights for targeted therapeutic interventions.

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Title: Impaired GABAergic regulation and developmental immaturity in interneurons derived from the medial ganglionic eminence in the tuberous sclerosis complex
Authors: Mirte Scheper
Frederik N. F. Sørensen
Gabriele Ruffolo
Alessandro Gaeta
Lilian J. Lissner
Jasper J. Anink
Irina Korshunova
Floor E. Jansen
Kate Riney
Wim van Hecke
Angelika Mühlebner
Konstantin Khodosevich
Dirk Schubert
Eleonora Palma
James D. Mills
Eleonora Aronica
Publication date: 01-06-2024
Publisher: Springer Berlin Heidelberg
Keyword: Tuberous Sclerosis
Published in: Acta Neuropathologica / Issue 1/2024
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-024-02737-7

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Impaired GABAergic regulation and developmental immaturity in interneurons derived from the medial ganglionic eminence in the tuberous sclerosis complex

Abstract

Keynote webinar | Spotlight on medication adherence

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Abstract

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