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@ARTICLE{Guzman:1043576,
      author       = {Guzman, Raul and Diaz Castillo, Alberto Rafael and
                      Aretzweiler von Schwartzenberg, Christoph and guanxiao, qi
                      and Steinmetz, Lilly and Bungert, Stefanie and Müller,
                      Frank and Feldmeyer, Dirk and Guzman, Raul},
      title        = {{E}ndosomal 2{C}l-/{H}+ exchangersregulate neuronal
                      excitability {B}ytuning {K}v7/{KCNQ} channel density},
      journal      = {Brain},
      volume       = {148},
      issn         = {0006-8950},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {FZJ-2025-02933},
      pages        = {4299–4314},
      year         = {2025},
      note         = {This work was funded by the German Research Foundation
                      (DFG) (GU 2042/2-1 to R.E.G.) and the European Union’s
                      Horizon 2020 Framework Programme for Research and Innovation
                      under the Human Brain Project Framework Partnership
                      Agreement (HBP FPA) (No. 650003 to D.F.).},
      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.},
      cin          = {IBI-1 / INM-10},
      ddc          = {610},
      cid          = {I:(DE-Juel1)IBI-1-20200312 / I:(DE-Juel1)INM-10-20170113},
      pnm          = {5244 - Information Processing in Neuronal Networks
                      (POF4-524) / 5241 - Molecular Information Processing in
                      Cellular Systems (POF4-524) / DFG project
                      G:(GEPRIS)430631456 - Funktionelle Rolle der
                      intrazellulären Chlorid/Proton Austauscher ClC-3, ClC-4 und
                      ClC-5 in der Neurosekretion (430631456)},
      pid          = {G:(DE-HGF)POF4-5244 / G:(DE-HGF)POF4-5241 /
                      G:(GEPRIS)430631456},
      typ          = {PUB:(DE-HGF)16},
      doi          = {10.1093/brain/awaf243},
      url          = {https://juser.fz-juelich.de/record/1043576},
}