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Research Articles, Neurobiology of Disease

Selective Silencing of Hippocampal Parvalbumin Interneurons Induces Development of Recurrent Spontaneous Limbic Seizures in Mice

Meinrad Drexel, Roman A. Romanov, James Wood, Stefan Weger, Regine Heilbronn, Peer Wulff, Ramon O. Tasan, Tibor Harkany and Günther Sperk
Journal of Neuroscience 23 August 2017, 37 (34) 8166-8179; DOI: https://doi.org/10.1523/JNEUROSCI.3456-16.2017
Meinrad Drexel
1Department of Pharmacology, Medical University Innsbruck, 6020 Innsbruck, Austria,
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Roman A. Romanov
2Department of Molecular Neurosciences, Center for Brain Research, Medical University Vienna, 1090 Vienna, Austria,
3Immanuel Kant Baltic Federal University, Kaliningrad 236041, Russia,
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James Wood
1Department of Pharmacology, Medical University Innsbruck, 6020 Innsbruck, Austria,
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Stefan Weger
4Institute for Virology, Charité-Universitätsmedizin Berlin, 12203 Berlin, Germany,
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Regine Heilbronn
4Institute for Virology, Charité-Universitätsmedizin Berlin, 12203 Berlin, Germany,
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Peer Wulff
5Institute of Physiology, Christian-Albrechts-University, 24098 Kiel, Germany, and
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Ramon O. Tasan
1Department of Pharmacology, Medical University Innsbruck, 6020 Innsbruck, Austria,
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Tibor Harkany
2Department of Molecular Neurosciences, Center for Brain Research, Medical University Vienna, 1090 Vienna, Austria,
6Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden
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Günther Sperk
1Department of Pharmacology, Medical University Innsbruck, 6020 Innsbruck, Austria,
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Abstract

Temporal lobe epilepsy (TLE) is the most frequent form of focal epilepsies and is generally associated with malfunctioning of the hippocampal formation. Recently, a preferential loss of parvalbumin (PV) neurons has been observed in the subiculum of TLE patients and in animal models of TLE. To demonstrate a possible causative role of defunct PV neurons in the generation of TLE, we permanently inhibited GABA release selectively from PV neurons of the ventral subiculum by injecting a viral vector expressing tetanus toxin light chain in male mice. Subsequently, mice were subjected to telemetric EEG recording and video monitoring. Eighty-eight percent of the mice presented clusters of spike-wave discharges (C-SWDs; 40.0 ± 9.07/month), and 64% showed spontaneous recurrent seizures (SRSs; 5.3 ± 0.83/month). Mice injected with a control vector presented with neither C-SWDs nor SRSs. No neurodegeneration was observed due to vector injection or SRS. Interestingly, mice that presented with only C-SWDs but no SRSs, developed SRSs upon injection of a subconvulsive dose of pentylenetetrazole after 6 weeks. The initial frequency of SRSs declined by ∼30% after 5 weeks. In contrast to permanent silencing of PV neurons, transient inhibition of GABA release from PV neurons through the designer receptor hM4Di selectively expressed in PV-containing neurons transiently reduced the seizure threshold of the mice but induced neither acute nor recurrent seizures. Our data demonstrate a critical role for perisomatic inhibition mediated by PV-containing interneurons, suggesting that their sustained silencing could be causally involved in the development of TLE.

SIGNIFICANCE STATEMENT Development of temporal lobe epilepsy (TLE) generally takes years after an initial insult during which maladaptation of hippocampal circuitries takes place. In human TLE and in animal models of TLE, parvalbumin neurons are selectively lost in the subiculum, the major output area of the hippocampus. The present experiments demonstrate that specific and sustained inhibition of GABA release from parvalbumin-expressing interneurons (mostly basket cells) in sector CA1/subiculum is sufficient to induce hyperexcitability and spontaneous recurrent seizures in mice. As in patients with nonlesional TLE, these mice developed epilepsy without signs of neurodegeneration. The experiments highlight the importance of the potent inhibitory action mediated by parvalbumin cells in the hippocampus and identify a potential mechanism in the development of TLE.

  • basket cell
  • epilepsy
  • epileptogenesis
  • feedforward inhibition
  • parvalbumin
  • subiculum
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The Journal of Neuroscience: 37 (34)
Journal of Neuroscience
Vol. 37, Issue 34
23 Aug 2017
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Selective Silencing of Hippocampal Parvalbumin Interneurons Induces Development of Recurrent Spontaneous Limbic Seizures in Mice
Meinrad Drexel, Roman A. Romanov, James Wood, Stefan Weger, Regine Heilbronn, Peer Wulff, Ramon O. Tasan, Tibor Harkany, Günther Sperk
Journal of Neuroscience 23 August 2017, 37 (34) 8166-8179; DOI: 10.1523/JNEUROSCI.3456-16.2017

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Selective Silencing of Hippocampal Parvalbumin Interneurons Induces Development of Recurrent Spontaneous Limbic Seizures in Mice
Meinrad Drexel, Roman A. Romanov, James Wood, Stefan Weger, Regine Heilbronn, Peer Wulff, Ramon O. Tasan, Tibor Harkany, Günther Sperk
Journal of Neuroscience 23 August 2017, 37 (34) 8166-8179; DOI: 10.1523/JNEUROSCI.3456-16.2017
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Keywords

  • basket cell
  • epilepsy
  • epileptogenesis
  • feedforward inhibition
  • parvalbumin
  • subiculum

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  • RE: Statistical Power considerations in Drexel et al. 2017
    Masoumeh Gholami and Seyed Reza Khatibi
    Published on: 16 January 2019
  • Published on: (16 January 2019)
    Page navigation anchor for RE: Statistical Power considerations in Drexel et al. 2017
    RE: Statistical Power considerations in Drexel et al. 2017
    • Masoumeh Gholami, assistant professor, Neuroscience Research Center, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran.
    • Other Contributors:
      • Seyed Reza Khatibi

    In Figure 2 panels H and I of this paper, Prof. Drexel and colleagues analyzed mEPSC and mIPSC amplitudes and frequencies in subiculum pyramidal neurons from Pvalb tm1(cre) Arbr mice injected with AAV-GFP (n= 10 cells for mEPSC recordings; n= 9 cells for mIPSC recordings) and AAV-TeLC ( n= 11 cells for mEPSC recordings; n 10 cells for mIPSC recordings). They stated that data are not significantly different between the two experimental groups. We would like to make two points about the article:
    First, it would be better if the authors reported Mean±SEM for Fig 2.
    Second, based on the data shown in Figure 2 H,I we estimated mean and SEM, and calculated power as follows:
    For Fig 2H:
    Amplitude, GFP: 12±22, Telc: 11±5; power = 0.072
    Frequency, GFP: 2.5±3.5, Telc: 1.5±1; power = 0.78
    For FIg 2I:
    Amplitude, GFP: 18±2, Telc: 18±2.5; power = 0.05
    Frequency GFP: 2.5±1.5, Telc: 2.5±1; power = 0.05

    It has been demonstrated that low-powered studies (an adequate power is equal or more than 80%) produce more false negatives than high-powered studies. When studies in a given field are designed with a power of 20%, it means that if there are 100 genuine non-null effects to be discovered in that field, these studies are expected to discover only 20 of them (Button, 2013; Sterne & Smith, 2001). Thus, based on our calculation of statistical power, one cannot be sure that there is no difference between the two groups. A larger number...

    Show More

    In Figure 2 panels H and I of this paper, Prof. Drexel and colleagues analyzed mEPSC and mIPSC amplitudes and frequencies in subiculum pyramidal neurons from Pvalb tm1(cre) Arbr mice injected with AAV-GFP (n= 10 cells for mEPSC recordings; n= 9 cells for mIPSC recordings) and AAV-TeLC ( n= 11 cells for mEPSC recordings; n 10 cells for mIPSC recordings). They stated that data are not significantly different between the two experimental groups. We would like to make two points about the article:
    First, it would be better if the authors reported Mean±SEM for Fig 2.
    Second, based on the data shown in Figure 2 H,I we estimated mean and SEM, and calculated power as follows:
    For Fig 2H:
    Amplitude, GFP: 12±22, Telc: 11±5; power = 0.072
    Frequency, GFP: 2.5±3.5, Telc: 1.5±1; power = 0.78
    For FIg 2I:
    Amplitude, GFP: 18±2, Telc: 18±2.5; power = 0.05
    Frequency GFP: 2.5±1.5, Telc: 2.5±1; power = 0.05

    It has been demonstrated that low-powered studies (an adequate power is equal or more than 80%) produce more false negatives than high-powered studies. When studies in a given field are designed with a power of 20%, it means that if there are 100 genuine non-null effects to be discovered in that field, these studies are expected to discover only 20 of them (Button, 2013; Sterne & Smith, 2001). Thus, based on our calculation of statistical power, one cannot be sure that there is no difference between the two groups. A larger number of cells would be required to make this judgment.

    References:
    Button KS, Ioannidis JP, Mokrysz C, Nosek BA, Flint J, Robinson ES, et al. Power failure: why small sample size undermines the reliability of neuroscience. Nature Reviews Neuroscience. 2013;14(5):365.
    Sterne JA, Smith GD. Sifting the evidence—what's wrong with significance tests? Physical Therapy. 2001;81(8):1464-9.

    Show Less
    Competing Interests: None declared.

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