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Impaired GABAergic regulation and developmental immaturity in interneurons derived from the medial ganglionic eminence in the tuberous sclerosis complex.
Scheper, Mirte; Sørensen, Frederik N F; Ruffolo, Gabriele; Gaeta, Alessandro; Lissner, Lilian J; Anink, Jasper J; Korshunova, Irina; Jansen, Floor E; Riney, Kate; van Hecke, Wim; Mühlebner, Angelika; Khodosevich, Konstantin; Schubert, Dirk; Palma, Eleonora; Mills, James D; Aronica, Eleonora.
Afiliación
  • Scheper M; Department of (Neuro)Pathology, Amsterdam Neuroscience, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands. m.scheper@amsterdamumc.nl.
  • Sørensen FNF; Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark.
  • Ruffolo G; Department of Physiology and Pharmacology, University of Rome Sapienza, 00185, Rome, Italy.
  • Gaeta A; IRCCS San Raffaele Roma, 00163, Rome, Italy.
  • Lissner LJ; Department of Physiology and Pharmacology, University of Rome Sapienza, 00185, Rome, Italy.
  • Anink JJ; Department of Physiology and Pharmacology, University of Rome Sapienza, 00185, Rome, Italy.
  • Korshunova I; Department of (Neuro)Pathology, Amsterdam Neuroscience, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.
  • Jansen FE; Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark.
  • Riney K; Department of Child Neurology, Brain Center University Medical Center, Member of ERN EpiCare, 3584 BA, Utrecht, The Netherlands.
  • van Hecke W; Faculty of Medicine, The University of Queensland, St Lucia, QLD, 4067, Australia.
  • Mühlebner A; Neurosciences Unit, Queensland Children's Hospital, South Brisbane, QLD, 4101, Australia.
  • Khodosevich K; Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
  • Schubert D; Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
  • Palma E; Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark.
  • Mills JD; Department of Cognitive Neurosciences, Radboudumc, Donders Institute for Brain Cognition and Behaviour, 6525 HR, Nijmegen, The Netherlands.
  • Aronica E; Department of Physiology and Pharmacology, University of Rome Sapienza, 00185, Rome, Italy.
Acta Neuropathol ; 147(1): 80, 2024 05 07.
Article en En | MEDLINE | ID: mdl-38714540
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 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Esclerosis Tuberosa / Neuronas GABAérgicas / Interneuronas Límite: Animals / Humans Idioma: En Revista: Acta Neuropathol Año: 2024 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Alemania

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Esclerosis Tuberosa / Neuronas GABAérgicas / Interneuronas Límite: Animals / Humans Idioma: En Revista: Acta Neuropathol Año: 2024 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Alemania