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@ARTICLE{Masala:258241,
      author       = {Masala, Nicola and Pofahl, Martin and Haubrich, André N
                      and Sameen Islam, Khondker Ushna and Nikbakht, Negar and
                      Pasdarnavab, Maryam and Bohmbach, Kirsten and Araki,
                      Kunihiko and Kamali, Fateme and Henneberger, Christian and
                      Golcuk, Kurtulus and Ewell, Laura A and Blaess, Sandra and
                      Kelly, Tony and Beck, Heinz},
      title        = {{T}argeting aberrant dendritic integration to treat
                      cognitive comorbidities of epilepsy.},
      journal      = {Brain},
      volume       = {146},
      number       = {6},
      issn         = {0006-8950},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DZNE-2023-00587},
      pages        = {2399 - 2417},
      year         = {2023},
      abstract     = {Memory deficits are a debilitating symptom of epilepsy, but
                      little is known about mechanisms underlying cognitive
                      deficits. Here, we describe a Na+ channel-dependent
                      mechanism underlying altered hippocampal dendritic
                      integration, degraded place coding and deficits in spatial
                      memory. Two-photon glutamate uncaging experiments revealed a
                      marked increase in the fraction of hippocampal first-order
                      CA1 pyramidal cell dendrites capable of generating dendritic
                      spikes in the kainate model of chronic epilepsy. Moreover,
                      in epileptic mice dendritic spikes were generated with lower
                      input synchrony, and with a lower threshold. The Nav1.3/1.1
                      selective Na+ channel blocker ICA-121431 reversed dendritic
                      hyperexcitability in epileptic mice, while the Nav1.2/1.6
                      preferring anticonvulsant S-Lic did not. We used in vivo
                      two-photon imaging to determine if aberrant dendritic
                      excitability is associated with altered place-related firing
                      of CA1 neurons. We show that ICA-121431 improves degraded
                      hippocampal spatial representations in epileptic mice.
                      Finally, behavioural experiments show that reversing
                      aberrant dendritic excitability with ICA-121431 reverses
                      hippocampal memory deficits. Thus, a dendritic channelopathy
                      may underlie cognitive deficits in epilepsy and targeting it
                      pharmacologically may constitute a new avenue to enhance
                      cognition.},
      keywords     = {Mice / Animals / Dendrites: physiology / Hippocampus:
                      physiology / Acetamides: metabolism / Pyramidal Cells:
                      metabolism / Epilepsy: metabolism / Action Potentials:
                      physiology / calcium imaging (Other) / cognitive
                      comorbidities (Other) / dendritic integration (Other) /
                      dendritic spike (Other) / epilepsy (Other) / ICA-121431 (NLM
                      Chemicals) / Acetamides (NLM Chemicals)},
      cin          = {AG Henneberger},
      ddc          = {610},
      cid          = {I:(DE-2719)1013029},
      pnm          = {351 - Brain Function (POF4-351) / 352 - Disease Mechanisms
                      (POF4-352)},
      pid          = {G:(DE-HGF)POF4-351 / G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36448426},
      pmc          = {pmc:PMC10232249},
      doi          = {10.1093/brain/awac455},
      url          = {https://pub.dzne.de/record/258241},
}