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@ARTICLE{Balduin:1047356,
      author       = {Balduin, Carina and Qi, Guanxiao and Schöneck, Michael and
                      Trinkel, Verena and Schemmert, Sarah and Guzman, Gustavo A.
                      and Bungert-Plümke, Stefanie and Klüssendorf, Malte and
                      Neumaier, Bernd and Feldmeyer, Dirk and Shah, N. Jon and
                      Stauber, Tobias and Langen, Karl-Josef and Guzman, Raul E.
                      and Willuweit, Antje},
      title        = {{D}isruption of {C}l{C}-3-mediated 2{C}l−/{H}+ exchange
                      leads to behavioural deficits and thalamic atrophy},
      journal      = {Scientific reports},
      volume       = {15},
      number       = {1},
      issn         = {2045-2322},
      address      = {[London]},
      publisher    = {Springer Nature},
      reportid     = {FZJ-2025-04252},
      pages        = {33326},
      year         = {2025},
      note         = {Open Access funding enabled and organized by Projekt DEAL.},
      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.},
      cin          = {IBI-1 / ETN / INM-10 / INM-4 / IBI-7 / INM-5},
      ddc          = {600},
      cid          = {I:(DE-Juel1)IBI-1-20200312 / I:(DE-Juel1)ETN-20090406 /
                      I:(DE-Juel1)INM-10-20170113 / I:(DE-Juel1)INM-4-20090406 /
                      I:(DE-Juel1)IBI-7-20200312 / I:(DE-Juel1)INM-5-20090406},
      pnm          = {5241 - Molecular Information Processing in Cellular Systems
                      (POF4-524) / 5253 - Neuroimaging (POF4-525)},
      pid          = {G:(DE-HGF)POF4-5241 / G:(DE-HGF)POF4-5253},
      typ          = {PUB:(DE-HGF)16},
      doi          = {10.1038/s41598-025-19757-2},
      url          = {https://juser.fz-juelich.de/record/1047356},
}