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

Autor: 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.; IRCCS San Raffaele Roma, 00163, Rome, Italy., Gaeta A; Department of Physiology and Pharmacology, University of Rome Sapienza, 00185, Rome, Italy., Lissner LJ; Department of Physiology and Pharmacology, University of Rome Sapienza, 00185, Rome, Italy., Anink JJ; Department of (Neuro)Pathology, Amsterdam Neuroscience, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands., Korshunova I; Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark., Jansen FE; Department of Child Neurology, Brain Center University Medical Center, Member of ERN EpiCare, 3584 BA, Utrecht, The Netherlands., Riney K; Faculty of Medicine, The University of Queensland, St Lucia, QLD, 4067, Australia.; Neurosciences Unit, Queensland Children's Hospital, South Brisbane, QLD, 4101, Australia., van Hecke W; Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands., Mühlebner A; Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands., Khodosevich K; Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark., Schubert D; Department of Cognitive Neurosciences, Radboudumc, Donders Institute for Brain Cognition and Behaviour, 6525 HR, Nijmegen, The Netherlands., Palma E; Department of Physiology and Pharmacology, University of Rome Sapienza, 00185, Rome, Italy.; IRCCS San Raffaele Roma, 00163, Rome, Italy., Mills JD; Department of (Neuro)Pathology, Amsterdam Neuroscience, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.; UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK.; Chalfont Centre for Epilepsy, Bucks, SL9 0RJ, UK., Aronica E; Department of (Neuro)Pathology, Amsterdam Neuroscience, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.; Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, The Netherlands.
Jazyk: angličtina
Zdroj: Acta neuropathologica [Acta Neuropathol] 2024 May 07; Vol. 147 (1), pp. 80. Date of Electronic Publication: 2024 May 07.
DOI: 10.1007/s00401-024-02737-7
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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