TY  - JOUR
AU  - Balduin, Carina
AU  - Qi, Guanxiao
AU  - Schöneck, Michael
AU  - Trinkel, Verena
AU  - Schemmert, Sarah
AU  - Guzman, Gustavo A.
AU  - Bungert-Plümke, Stefanie
AU  - Klüssendorf, Malte
AU  - Neumaier, Bernd
AU  - Feldmeyer, Dirk
AU  - Shah, N. Jon
AU  - Stauber, Tobias
AU  - Langen, Karl-Josef
AU  - Guzman, Raul E.
AU  - Willuweit, Antje
TI  - Disruption of ClC-3-mediated 2Cl−/H+ exchange leads to behavioural deficits and thalamic atrophy
JO  - Scientific reports
VL  - 15
IS  - 1
SN  - 2045-2322
CY  - [London]
PB  - Springer Nature
M1  - FZJ-2025-04252
SP  - 33326
PY  - 2025
N1  - Open Access funding enabled and organized by Projekt DEAL.
AB  - CLCN3 encodes ClC-3, an endosomal 2Cl⁻/H⁺ exchanger, with pathogenic variants causing aneurodevelopmental condition marked by developmental delays, intellectual disability, seizures,hyperactivity, anxiety, and brain and retinal abnormalities. Clcn3−/− mice show hippocampal and retinaldegeneration, recapitulating key symptoms observed in humans. ClC-3 forms homodimers (ClC-3/ClC-3) and heterodimers with ClC-4 (ClC-3/ClC-4), with overlapping brain expression. This suggestsdistinct functional roles for homo- and heterodimeric assemblies and raises the question of which brainregions specifically depend on ClC-3/ClC-3 rather than ClC-3/ClC-4 complexes. Using ex vivo PET traceranalyses, Clcn3−/− and Clcn3td/td mice, we found neurodegeneration in the hippocampus and thalamusof Clcn3−/−, while Clcn3td/td mice showed thalamic degeneration and altered neuronal excitability,including changes in action potential threshold and after hyperpolarization. Clcn3td/td mice carryinga transport-deficient p.E281Q ClC-3 variant that still associates with ClC-4, thereby allowing ClC-4 tobe sorted to endosomes as ClC-4/ClC-3 heterodimers, unlike in the Clcn3−/− model. Clcn3td/td mice alsoexhibited reduced weight, hyperactivity, and motor deficits, reflecting clinical features. Lower ClC-4levels in thalamus predict a predominant thalamic expression of ClC-3/ClC-3 homodimers. Overall,our findings indicate a region-specific function of ClC-3/ClC-3 homodimeric complexes and highlightthe importance of ClC-3 transport activity in thalamic neuron survival, with electrophysiologicaldysfunction likely contributing to neurodegeneration.
LB  - PUB:(DE-HGF)16
DO  - DOI:10.1038/s41598-025-19757-2
UR  - https://juser.fz-juelich.de/record/1047356
ER  -