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@ARTICLE{Pothmann:141551,
      author       = {Pothmann, Leonie and Klos, Christian and Braganza, Oliver
                      and Schmidt, Sarah and Horno, Oihane and Memmesheimer,
                      Raoul-Martin and Beck, Heinz},
      title        = {{A}ltered {D}ynamics of {C}anonical {F}eedback {I}nhibition
                      {P}redicts {I}ncreased {B}urst {T}ransmission in {C}hronic
                      {E}pilepsy.},
      journal      = {The journal of neuroscience},
      volume       = {39},
      number       = {45},
      issn         = {0270-6474},
      address      = {Washington, DC},
      publisher    = {Soc.61474},
      reportid     = {DZNE-2020-07875},
      pages        = {8998-9012},
      year         = {2019},
      abstract     = {Inhibitory interneurons, organized into canonical
                      feedforward and feedback motifs, play a key role in
                      controlling normal and pathological neuronal activity. We
                      demonstrate prominent quantitative changes in the dynamics
                      of feedback inhibition in a rat model of chronic epilepsy
                      (male Wistar rats). Systematic interneuron recordings
                      revealed a large decrease in intrinsic excitability of
                      basket cells and oriens-lacunosum moleculare interneurons in
                      epileptic animals. Additionally, the temporal dynamics of
                      interneuron recruitment by recurrent feedback excitation
                      were strongly altered, resulting in a profound loss of
                      initial feedback inhibition during synchronous CA1 pyramidal
                      activity. Biophysically constrained models of the complete
                      feedback circuit motifs of normal and epileptic animals
                      revealed that, as a consequence of altered feedback
                      inhibition, burst activity arising in CA3 is more strongly
                      converted to a CA1 output. This suggests that altered
                      dynamics of feedback inhibition promote the transmission of
                      epileptiform bursts to hippocampal projection
                      areas.SIGNIFICANCE STATEMENT We quantitatively characterized
                      changes of the CA1 feedback inhibitory circuit in a model of
                      chronic temporal lobe epilepsy. This study shows, for the
                      first time, that dynamic recruitment of inhibition in
                      feedback circuits is altered and establishes the cellular
                      mechanisms for this change. Computational modeling revealed
                      that the observed changes are likely to systematically alter
                      CA1 input-output properties leading to (1) increased seizure
                      propagation through CA1 and (2) altered computation of
                      synchronous CA3 input.},
      keywords     = {Action Potentials / Animals / CA1 Region, Hippocampal:
                      physiopathology / Epilepsy: physiopathology / Feedback,
                      Physiological / Interneurons: physiology / Male / Models,
                      Neurological / Neural Inhibition / Pyramidal Cells:
                      physiology / Rats / Rats, Wistar},
      cin          = {U Preclinical Researchers - Bonn},
      ddc          = {610},
      cid          = {I:(DE-2719)7000005},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342)},
      pid          = {G:(DE-HGF)POF3-342},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:31519822},
      pmc          = {pmc:PMC6832680},
      doi          = {10.1523/JNEUROSCI.2594-18.2019},
      url          = {https://pub.dzne.de/record/141551},
}