Journal Article

FZJ-2025-04252

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Disruption of ClC-3-mediated 2Cl−/H+ exchange leads to behavioural deficits and thalamic atrophy

Balduin, C.FZJ* ; Qi, G.FZJ* ; Schöneck, M.FZJ* ; Trinkel, V. ; Schemmert, S.FZJ* ; Guzman, G. A. ; Bungert-Plümke, S.FZJ* ; Klüssendorf, M. ; Neumaier, B.FZJ* ; Feldmeyer, D.FZJ* ; Shah, N. J.FZJ* ; Stauber, T. ; Langen, K.-J.FZJ* ; Guzman, R. E. (Corresponding author)FZJ* ; Willuweit, A. (Corresponding author)FZJ*

2025
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41598-025-19757-2  doi:10.34734/FZJ-2025-04252

Abstract: 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.

Note: Open Access funding enabled and organized by Projekt DEAL.

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Contributing Institute(s):

1. Molekular- und Zellphysiologie (IBI-1)
2. Projektträger Energie, Technologie, Nachhaltigkeit (ETN)
3. Jara-Institut Brain structure-function relationships (INM-10)
4. Physik der Medizinischen Bildgebung (INM-4)
5. Strukturbiochemie (IBI-7)
6. Nuklearchemie (INM-5)

Research Program(s):

1. 5241 - Molecular Information Processing in Cellular Systems (POF4-524) (POF4-524)
2. 5253 - Neuroimaging (POF4-525) (POF4-525)

Appears in the scientific report 2025

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