Hippocampal low-frequency stimulation prevents seizure generation in a mouse model of mesial temporal lobe epilepsy

  1. Enya Paschen  Is a corresponding author
  2. Claudio Elgueta
  3. Katharina Heining
  4. Diego M Vieira
  5. Piret Kleis
  6. Catarina Orcinha
  7. Ute Häussler
  8. Marlene Bartos
  9. Ulrich Egert
  10. Philipp Janz
  11. Carola A Haas  Is a corresponding author
  1. Medical Center - University of Freiburg, Faculty of Medicine, Germany
  2. University of Freiburg, Germany
  3. Faculty of Engineering, University of Freiburg, Germany

Abstract

Mesial temporal lobe epilepsy (MTLE) is the most common form of focal, pharmacoresistant epilepsy in adults and is often associated with hippocampal sclerosis. Here, we established the efficacy of optogenetic and electrical low-frequency stimulation (LFS) in interfering with seizure generation in a mouse model of MTLE. Specifically, we applied LFS in the sclerotic hippocampus to study the effects on spontaneous subclinical and evoked generalized seizures. We found that stimulation at 1 Hz for one hour resulted in an almost complete suppression of spontaneous seizures in both hippocampi. This seizure-suppressive action during daily stimulation remained stable over several weeks. Furthermore, LFS for 30 min before a pro-convulsive stimulus successfully prevented seizure generalization. Finally, acute slice experiments revealed a reduced efficacy of perforant path transmission onto granule cells upon LFS. Taken together, our results suggest that hippocampal LFS constitutes a promising approach for seizure control in MTLE.

Data availability

The LFP dataset is available on Open Science Framework: https://osf.io/uk94m/. The source code files for the seizure detection algorithm is accessible at Zenodo (DOI: 10.5281/zenodo.4110614). The source code for the seizure detection algorithm (Heining et al., 2019) was developed using previously published LFP data (Froriep et al., 2012; Janz et al., 2017b).

The following data sets were generated

Article and author information

Author details

  1. Enya Paschen

    Experimental Epilepsy Research, Dept. of Neurosurgery, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
    For correspondence
    enya.paschen@uniklinik-freiburg.de
    Competing interests
    The authors declare that no competing interests exist.
  2. Claudio Elgueta

    Institute for Physiology I, University of Freiburg, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Katharina Heining

    Laboratory for Biomicrotechnology, Dept. of Microsystems Engineering, University of Freiburg, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Diego M Vieira

    Biomicrotechnology, Dept. of Microsystems Engineering - IMTEK, Faculty of Engineering, University of Freiburg, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8005-134X
  5. Piret Kleis

    Experimental Epilepsy Research, Dept. of Neurosurgery, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Catarina Orcinha

    Experimental Epilepsy Research, Dept. of Neurosurgery, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Ute Häussler

    Experimental Epilepsy Research, Dept. of Neurosurgery, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Marlene Bartos

    Institute for Physiology I, University of Freiburg, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9741-1946
  9. Ulrich Egert

    Biomicrotechnology, Dept. of Microsystems Engineering - IMTEK, Faculty of Engineering, University of Freiburg, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4583-0425
  10. Philipp Janz

    Experimental Epilepsy Research, Dept. of Neurosurgery, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  11. Carola A Haas

    Experimental Epilepsy Research, Dept. of Neurosurgery, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
    For correspondence
    carola.haas@uniklinik-freiburg.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7022-4136

Funding

Deutsche Forschungsgemeinschaft (EXC 1086)

  • Ute Häussler
  • Marlene Bartos
  • Ulrich Egert
  • Carola A Haas

Deutsche Forschungsgemeinschaft (HA 1443/11-1)

  • Carola A Haas

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal procedures were carried out in accordance with the guidelines of the European Community's Council Directive of 22 September 2010 (2010/63/EU) and were approved by the regional council (Regierungspräsidium Freiburg).

Reviewing Editor

  1. John R Huguenard, Stanford University School of Medicine, United States

Publication history

  1. Received: December 17, 2019
  2. Accepted: December 13, 2020
  3. Accepted Manuscript published: December 22, 2020 (version 1)
  4. Version of Record published: January 11, 2021 (version 2)

Copyright

© 2020, Paschen et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,873
    Page views
  • 350
    Downloads
  • 10
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Enya Paschen
  2. Claudio Elgueta
  3. Katharina Heining
  4. Diego M Vieira
  5. Piret Kleis
  6. Catarina Orcinha
  7. Ute Häussler
  8. Marlene Bartos
  9. Ulrich Egert
  10. Philipp Janz
  11. Carola A Haas
(2020)
Hippocampal low-frequency stimulation prevents seizure generation in a mouse model of mesial temporal lobe epilepsy
eLife 9:e54518.
https://doi.org/10.7554/eLife.54518

Further reading

    1. Neuroscience
    Arefeh Sherafati et al.
    Research Article Updated

    Cochlear implants are neuroprosthetic devices that can restore hearing in people with severe to profound hearing loss by electrically stimulating the auditory nerve. Because of physical limitations on the precision of this stimulation, the acoustic information delivered by a cochlear implant does not convey the same level of acoustic detail as that conveyed by normal hearing. As a result, speech understanding in listeners with cochlear implants is typically poorer and more effortful than in listeners with normal hearing. The brain networks supporting speech understanding in listeners with cochlear implants are not well understood, partly due to difficulties obtaining functional neuroimaging data in this population. In the current study, we assessed the brain regions supporting spoken word understanding in adult listeners with right unilateral cochlear implants (n=20) and matched controls (n=18) using high-density diffuse optical tomography (HD-DOT), a quiet and non-invasive imaging modality with spatial resolution comparable to that of functional MRI. We found that while listening to spoken words in quiet, listeners with cochlear implants showed greater activity in the left prefrontal cortex than listeners with normal hearing, specifically in a region engaged in a separate spatial working memory task. These results suggest that listeners with cochlear implants require greater cognitive processing during speech understanding than listeners with normal hearing, supported by compensatory recruitment of the left prefrontal cortex.

    1. Neuroscience
    Mohammad Ali Salehinejad et al.
    Research Article Updated

    Sleep strongly affects synaptic strength, making it critical for cognition, especially learning and memory formation. Whether and how sleep deprivation modulates human brain physiology and cognition is not well understood. Here we examined how overnight sleep deprivation vs overnight sufficient sleep affects (a) cortical excitability, measured by transcranial magnetic stimulation, (b) inducibility of long-term potentiation (LTP)- and long-term depression (LTD)-like plasticity via transcranial direct current stimulation (tDCS), and (c) learning, memory, and attention. The results suggest that sleep deprivation upscales cortical excitability due to enhanced glutamate-related cortical facilitation and decreases and/or reverses GABAergic cortical inhibition. Furthermore, tDCS-induced LTP-like plasticity (anodal) abolishes while the inhibitory LTD-like plasticity (cathodal) converts to excitatory LTP-like plasticity under sleep deprivation. This is associated with increased EEG theta oscillations due to sleep pressure. Finally, we show that learning and memory formation, behavioral counterparts of plasticity, and working memory and attention, which rely on cortical excitability, are impaired during sleep deprivation. Our data indicate that upscaled brain excitability and altered plasticity, due to sleep deprivation, are associated with impaired cognitive performance. Besides showing how brain physiology and cognition undergo changes (from neurophysiology to higher-order cognition) under sleep pressure, the findings have implications for variability and optimal application of noninvasive brain stimulation.