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| Home > Publications database > Endosomal 2Cl-/H+ exchangersregulate neuronal excitability Bytuning Kv7/KCNQ channel density |
| Home > Publications database > Endosomal 2Cl-/H+ exchangersregulate neuronal excitability Bytuning Kv7/KCNQ channel density |
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| Hybrid-OA | 4709.46 | 0.00 | EUR | 100.00 % | (Zahlung erfolgt) | 44500 |
| Sum | 4709.46 | 0.00 | EUR | |||
| Total | 4709.46 |
| Journal Article | FZJ-2025-02933 |
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2025
Oxford Univ. Press
Oxford
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Please use a persistent id in citations: doi:10.1093/brain/awaf243 doi:10.34734/FZJ-2025-02933
Abstract: CLCN3 and CLCN4 encode the endosomal 2Cl−/H+ exchangers ClC-3 and ClC-4, which are highly expressed within the CNS, including the hippocampal formation. Pathogenic variants recently found in these genes have given rise to the rare CLCN3- and CLCN4-related neurodevelopmental conditions, characterized by a range of neurological and neuropsychiatric complications, such as global developmental delay, intellectual disability as a core feature, seizures, behavioural issues and brain abnormalities. The mechanisms by which ClC-3 and ClC-4 regulate neuronal function and viability, in addition to the molecular pathways affected in CLCN3- and CLCN4-related neurodevelopmental conditions, remain unknown. In neurodegenerative diseases, neuronal dendrites undergo pathological changes often associated with aberrant electrical activity.To investigate how ClC-3 or ClC-4 deficit alters neuronal excitability and morphology, we combined patch-clamp recordings in acute hippocampal slice preparations with simultaneous intracellular biocytin filling. We analysed the functional and structural properties of Clcn3−/− and Clcn4−/− neurons. Two firing patterns are found in the cornu ammonis 2 (CA2) region of the hippocampus: regular and burst firing. At postnatal Day 13, 62% of the assessed CA2 wild-type neurons showed a rhythmic bursting behaviour; this was reduced to 19% in Clcn4−/− and completely absent in the Clcn3−/− condition. Changes in the firing patterns were accompanied by a depolarizing shift in the action potential threshold and an increase in the after-hyperpolarizing phase of the action potentials. Blockade of Kv7/KCNQ and, to a lesser extent, Kv1, but not BK, SK or Kv2 channels, recapitulates the wild-type firing pattern phenotype in the Clcn3−/− condition. Moreover, we detected abnormalities in the complexity of the dendritic arborization. Branching and lengths of apical and basal domains were significantly reduced in the Clcn3−/− neurons and moderately altered in the Clcn4−/− neurons. At postnatal Day 3, we found 25% of bursting neurons in Clcn3−/− with no significant morphological abnormalities in the dendritic arborization in comparison to the wild-type, suggesting that functional defects precede structural changes in Cl−/H+ exchanger-deficient neurons. Likewise, dentate granule cells exhibited defective action potential properties and reduced burst-firing activity, which was substantially but not fully rescued by Kv7/KCNQ blockage.We conclude that Cl−/H+ exchangers regulate the electrical excitability and firing patterns of neurons primarily by fine- tuning Kv7/KCNQ channel density, and that functional defects might contribute to alterations in dendritic morphology. Our findings provide new insights into the underlying molecular mechanisms of Cl−/H+ exchangers in neurons and pave the way for potential therapeutic interventions for CLCN3- and CLCN4-related patients associated with disruption of Cl−/H+ exchange function.
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