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<p><i>CLCN3</i> encodes ClC-3, an endosomal 2Cl⁻/H⁺ exchanger, with pathogenic variants causing a neurodevelopmental condition marked by developmental delays, intellectual disability, seizures, hyperactivity, anxiety, and brain and retinal abnormalities. <i>Clcn3</i><sup><i>−/−</i></sup> mice show hippocampal and retinal degeneration, 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 suggests distinct functional roles for homo- and heterodimeric assemblies and raises the question of which brain regions specifically depend on ClC-3/ClC-3 rather than ClC-3/ClC-4 complexes. Using <i>ex vivo</i>&#xa0;PET tracer analyses, <i>Clcn3</i><sup><i>−/−</i></sup> and <i>Clcn3</i><sup><i>td/td</i></sup> mice, we found neurodegeneration in the hippocampus and thalamus of <i>Clcn3</i><sup><i>−/−</i></sup>, while <i>Clcn3</i><sup><i>td/td</i></sup> mice showed thalamic degeneration and altered neuronal excitability, including changes in action potential threshold and after hyperpolarization. <i>Clcn3</i><sup><i>td/td</i></sup> mice carrying a transport-deficient p.E281Q ClC-3 variant that still associates with ClC-4, thereby allowing ClC-4 to be sorted to endosomes as ClC-4/ClC-3 heterodimers, unlike in the <i>Clcn3</i><sup><i>−/−</i></sup> model. <i>Clcn3</i><sup><i>td/td</i></sup> mice also exhibited reduced weight, hyperactivity, and motor deficits, reflecting clinical features. Lower ClC-4 levels 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 highlight the importance of ClC-3 transport activity in thalamic neuron survival, with electrophysiological dysfunction likely contributing to neurodegeneration.</p>

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Disruption of ClC-3-mediated 2Cl−/H+ exchange leads to behavioural deficits and thalamic atrophy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月29日

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  • Carina Balduin,
  • Guanxiao Qi,
  • Michael Schöneck,
  • Verena Trinkel,
  • Sarah Schemmert,
  • Gustavo A. Guzman,
  • Stefanie Bungert-Plümke,
  • Malte Klüssendorf,
  • Bernd Neumaier,
  • Dirk Feldmeyer,
  • N. Jon Shah,
  • Tobias Stauber,
  • Karl-Josef Langen,
  • Raul E. Guzman,
  • Antje Willuweit

摘要

CLCN3 encodes ClC-3, an endosomal 2Cl⁻/H⁺ exchanger, with pathogenic variants causing a neurodevelopmental condition marked by developmental delays, intellectual disability, seizures, hyperactivity, anxiety, and brain and retinal abnormalities. Clcn3−/− mice show hippocampal and retinal degeneration, 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 suggests distinct functional roles for homo- and heterodimeric assemblies and raises the question of which brain regions specifically depend on ClC-3/ClC-3 rather than ClC-3/ClC-4 complexes. Using ex vivo PET tracer analyses, Clcn3−/− and Clcn3td/td mice, we found neurodegeneration in the hippocampus and thalamus of Clcn3−/−, while Clcn3td/td mice showed thalamic degeneration and altered neuronal excitability, including changes in action potential threshold and after hyperpolarization. Clcn3td/td mice carrying a transport-deficient p.E281Q ClC-3 variant that still associates with ClC-4, thereby allowing ClC-4 to be sorted to endosomes as ClC-4/ClC-3 heterodimers, unlike in the Clcn3−/− model. Clcn3td/td mice also exhibited reduced weight, hyperactivity, and motor deficits, reflecting clinical features. Lower ClC-4 levels 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 highlight the importance of ClC-3 transport activity in thalamic neuron survival, with electrophysiological dysfunction likely contributing to neurodegeneration.