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Corticohippocampal circuit dysfunction in a mouse model of Dravet syndrome

Joanna Mattis, Ala Somarowthu, Kevin M. Goff, Jina Yom, Nathaniel P. Sotuyo, Laura M. McGarry, Huijie Feng, Keisuke Kaneko, View ORCID ProfileEthan M. Goldberg
doi: https://doi.org/10.1101/2021.05.01.442271
Joanna Mattis
1Department of Neurology, The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104, USA
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Ala Somarowthu
2Division of Neurology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, 19104 USA
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Kevin M. Goff
3Neuroscience Graduate Group, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104 USA
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Jina Yom
4College of Arts and Sciences, The University of Pennsylvania, Philadelphia, PA, 19104 USA
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Nathaniel P. Sotuyo
3Neuroscience Graduate Group, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104 USA
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Laura M. McGarry
2Division of Neurology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, 19104 USA
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Huijie Feng
2Division of Neurology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, 19104 USA
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Keisuke Kaneko
2Division of Neurology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, 19104 USA
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Ethan M. Goldberg
1Department of Neurology, The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104, USA
2Division of Neurology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, 19104 USA
5Department of Neuroscience, The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104, USA
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  • ORCID record for Ethan M. Goldberg
  • For correspondence: goldberge@email.chop.edu
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Abstract

Dravet syndrome (DS) is a neurodevelopmental disorder defined by treatment-resistant epilepsy, autism spectrum disorder, and sudden death, due to pathogenic variants in SCN1A encoding the Nav1.1 sodium channel subunit. Convergent data suggest hippocampal dentate gyrus (DG) pathology. We found that optogenetic stimulation of entorhinal cortex was ictogenic in DS (Scn1a+/-) but not wild-type mice in vivo. Two-photon calcium imaging in brain slice demonstrated profound impairment in filtering of perforant path input by DG in young adult Scn1a+/- mice due to enhanced excitatory input to granule cells. Excitability of parvalbumin interneurons (PV-INs) was near-normal and selective activation of PV-INs rescued circuit impairments. This demonstrates developmental reorganization of hippocampal circuitry that can be modulated by recruitment of functional PV-INs, suggesting potential therapeutic approaches towards seizure modulation. The identified circuit abnormality mirrors that seen in models of chronic temporal lobe epilepsy, suggesting convergent mechanisms linking genetic and acquired causes of temporal lobe-onset seizures.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • J.M. and E.M.G. designed the experimental study. J.M. conducted all imaging experiments. A.S. performed analysis of the imaging data. J.M., K.M.G., L.M.M., and K.K. conducted the slice physiology experiments. J.M. and K.M.G. performed analysis of the slice physiology data. J.M., N.S., and H.F. conducted the in vivo experiments. J.Y. assisted with animal husbandry and viral injections. J.M. and E.M.G. wrote the manuscript.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 01, 2021.
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Corticohippocampal circuit dysfunction in a mouse model of Dravet syndrome
Joanna Mattis, Ala Somarowthu, Kevin M. Goff, Jina Yom, Nathaniel P. Sotuyo, Laura M. McGarry, Huijie Feng, Keisuke Kaneko, Ethan M. Goldberg
bioRxiv 2021.05.01.442271; doi: https://doi.org/10.1101/2021.05.01.442271
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Corticohippocampal circuit dysfunction in a mouse model of Dravet syndrome
Joanna Mattis, Ala Somarowthu, Kevin M. Goff, Jina Yom, Nathaniel P. Sotuyo, Laura M. McGarry, Huijie Feng, Keisuke Kaneko, Ethan M. Goldberg
bioRxiv 2021.05.01.442271; doi: https://doi.org/10.1101/2021.05.01.442271

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