%0 Journal Article
%A Balduin, Carina
%A Qi, Guanxiao
%A Schöneck, Michael
%A Trinkel, Verena
%A Schemmert, Sarah
%A Guzman, Gustavo A.
%A Bungert-Plümke, Stefanie
%A Klüssendorf, Malte
%A Neumaier, Bernd
%A Feldmeyer, Dirk
%A Shah, N. Jon
%A Stauber, Tobias
%A Langen, Karl-Josef
%A Guzman, Raul E.
%A Willuweit, Antje
%T Disruption of ClC-3-mediated 2Cl−/H+ exchange leads to behavioural deficits and thalamic atrophy
%J Scientific reports
%V 15
%N 1
%@ 2045-2322
%C [London]
%I Springer Nature
%M FZJ-2025-04252
%P 33326
%D 2025
%Z Open Access funding enabled and organized by Projekt DEAL.
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%R 10.1038/s41598-025-19757-2
%U https://juser.fz-juelich.de/record/1047356