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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

Dokumenter

  • Fulltext

    Forlagets udgivne version, 11,3 MB, PDF-dokument

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 GABAA 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.

OriginalsprogEngelsk
Artikelnummer80
TidsskriftActa Neuropathologica
Vol/bind147
Antal sider18
ISSN0001-6322
DOI
StatusUdgivet - 2024

Bibliografisk note

Funding Information:
We thank Single Cell Genomics Core Facility at BRIC, University of Copenhagen.

Funding Information:
This research has received funding from the ZonMw, Programme Translational Research no. 95105004 (EA, DS); the European Union\u2019s Horizon 2020 WIDESPREAD-05-2020\u2013Twinning and EpiEpiNet; grant agreement no. 952455 (EA, EP). The snRNA-seq work was supported by Novo Nordisk Hallas-M\u00F8ller Investigator grant (NNF21OC0067146) to KK. This work was also supported by the Fondi Ateneo grants, nos. RM11916B84D24429 (EP), RG12117A8697DCF1 (EP, GR) funded by Sapienza University, PRIN 2022 (EP, GR) and PRIN-PNRR 2022 (EP) from the Italian Ministry of University and Research. GR was also supported by the Italian Ministry of Health, \u201CRicerca corrente\u201D.

Publisher Copyright:
© The Author(s) 2024.

ID: 392922431