Article, 2024
Impaired GABAergic regulation and developmental immaturity in interneurons derived from the medial ganglionic eminence in the tuberous sclerosis complex
Acta Neuropathologica,
ISSN
0001-6322,
1432-0533,
Volume 147,
1,
Page 80,
10.1007/s00401-024-02737-7
Contributors
Scheper, Mirte
(Corresponding author)
[1]
Sørensen, Frederik N F
0009-0000-7018-0690
[2]
Ruffolo, Gabriele
0000-0002-6554-5496
[3]
[4]
Gaeta, Alessandro
[4]
Lissner, Lílian Juliana
0000-0003-4471-2782
[4]
Anink, Jasper Joris
[1]
Korshunova, Irina V
0000-0003-1921-6170
[2]
Jansen, Floor E
[5]
Riney, Kate
[6]
[7]
Van Hecke, Wim
0000-0002-3058-0937
[8]
Mühlebner, Angelika
0000-0001-9102-7353
[8]
Khodosevich, Konstantin V
0000-0001-7232-5558
[2]
Schubert, Dirk
0000-0002-1202-4363
[9]
Palma, Eleonora
0000-0001-6026-927X
[3]
[4]
Mills, James Dominic
[1]
[10]
[11]
Aronica, Eleonora M A
0000-0002-3542-3770
[1]
[12]
Affiliations
- [1]
Amsterdam Neuroscience
[NORA names:
Netherlands; Europe, EU; OECD];
- [2]
University of Copenhagen
[NORA names:
KU University of Copenhagen; University; Denmark; Europe, EU; Nordic; OECD];
- [3]
IRCCS Ospedale San Raffaele
[NORA names:
Italy; Europe, EU; OECD];
- [4]
Sapienza University of Rome
[NORA names:
Italy; Europe, EU; OECD];
- [5]
Department of Child Neurology, Brain Center University Medical Center, Member of ERN EpiCare, 3584 BA, Utrecht, The Netherlands
[NORA names:
Netherlands; Europe, EU; OECD];
(... more)
- [6]
Queensland Children's Hospital
[NORA names:
Australia; Oceania; OECD];
- [7]
University of Queensland
[NORA names:
Australia; Oceania; OECD];
- [8]
University Medical Center Utrecht
[NORA names:
Netherlands; Europe, EU; OECD];
- [9]
Radboud University Nijmegen Medical Centre
[NORA names:
Netherlands; Europe, EU; OECD];
- [10]
Epilepsy Society
[NORA names:
United Kingdom; Europe, Non-EU; OECD];
- [11]
University College London
[NORA names:
United Kingdom; Europe, Non-EU; OECD];
- [12]
Stichting Epilepsie Instellingen Nederland
[NORA names:
Netherlands; Europe, EU; OECD]
(less)
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.
Keywords
GABAA receptor subunits,
GABAergic interneurons,
GABAergic neuron dysfunction,
GABAergic regulation,
GABAergic signaling,
GABRA1,
GABRA2,
NKCC1/KCC2 ratio,
RNA sequencing,
SST+,
SST+ interneurons,
activity,
balance,
brain tissue,
caudal ganglionic eminence,
cell type-specific manner,
cells,
chloride,
chloride homeostasis,
circuit balance,
complex,
considerations,
context,
cortical dyslamination,
cortical layers,
development,
developmental immaturity,
disrupt network activity,
disrupted maturation,
downregulation,
dysfunction,
dyslamination,
eminence,
epilepsy,
exploration,
functional modules,
ganglionic eminence,
homeostasis,
imbalance,
immature subpopulations,
immaturity,
incomplete switching,
inhibitory properties,
interneuron subpopulations,
interneurons,
intervention,
layer,
local patterns,
localization,
manner,
markers,
markers of immaturity,
materials,
medial ganglionic eminence,
modulation,
network activity,
neurological symptoms,
neuronal dysfunction,
pathophysiology,
patient material,
patterns,
postsynaptic consequences,
potential contribution,
properties,
ratio,
receptor subunits,
regulation,
research,
seizures,
sequence,
signal,
single-nuclei RNA sequencing,
somatostatin expression,
study,
subpopulations,
subunit,
switching,
symptoms,
targeted therapeutic interventions,
therapeutic considerations,
therapeutic interventions,
tissue,
tuberous sclerosis complex,
unique characteristics,
upregulation
Funders
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