Corticohippocampal circuit dysfunction in a mouse model of Dravet syndrome
Dravet syndrome (DS) is a neurodevelopmental disorder due to pathogenic variants in SCN1A encoding the Nav1.1 sodium channel subunit, characterized by treatment-resistant epilepsy, temperature-sensitive seizures, developmental delay/intellectual disability with features of autism spectrum disorder,...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-02-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/69293 |
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| author | Joanna Mattis Ala Somarowthu Kevin M Goff Evan Jiang Jina Yom Nathaniel Sotuyo Laura M Mcgarry Huijie Feng Keisuke Kaneko Ethan M Goldberg |
| author_facet | Joanna Mattis Ala Somarowthu Kevin M Goff Evan Jiang Jina Yom Nathaniel Sotuyo Laura M Mcgarry Huijie Feng Keisuke Kaneko Ethan M Goldberg |
| author_sort | Joanna Mattis |
| collection | DOAJ |
| description | Dravet syndrome (DS) is a neurodevelopmental disorder due to pathogenic variants in SCN1A encoding the Nav1.1 sodium channel subunit, characterized by treatment-resistant epilepsy, temperature-sensitive seizures, developmental delay/intellectual disability with features of autism spectrum disorder, and increased risk of sudden death. Convergent data suggest hippocampal dentate gyrus (DG) pathology in DS (Scn1a+/-) mice. We performed two-photon calcium imaging in brain slice to uncover a profound dysfunction of filtering of perforant path input by DG in young adult Scn1a+/- mice. This was not due to dysfunction of DG parvalbumin inhibitory interneurons (PV-INs), which were only mildly impaired at this timepoint; however, we identified enhanced excitatory input to granule cells, suggesting that circuit dysfunction is due to excessive excitation rather than impaired inhibition. We confirmed that both optogenetic stimulation of entorhinal cortex and selective chemogenetic inhibition of DG PV-INs lowered seizure threshold in vivo in young adult Scn1a+/- mice. Optogenetic activation of PV-INs, on the other hand, normalized evoked responses in granule cells in vitro. These results establish the corticohippocampal circuit as a key locus of pathology in Scn1a+/- mice and suggest that PV-INs retain powerful inhibitory function and may be harnessed as a potential therapeutic approach toward seizure modulation. |
| first_indexed | 2024-04-12T09:44:09Z |
| format | Article |
| id | doaj.art-31cb96e7bcb84203b9d4601d65b25be7 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T09:44:09Z |
| publishDate | 2022-02-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-31cb96e7bcb84203b9d4601d65b25be72022-12-22T03:37:59ZengeLife Sciences Publications LtdeLife2050-084X2022-02-011110.7554/eLife.69293Corticohippocampal circuit dysfunction in a mouse model of Dravet syndromeJoanna Mattis0https://orcid.org/0000-0003-0341-1270Ala Somarowthu1Kevin M Goff2https://orcid.org/0000-0001-5862-0219Evan Jiang3Jina Yom4Nathaniel Sotuyo5Laura M Mcgarry6Huijie Feng7Keisuke Kaneko8https://orcid.org/0000-0002-5071-0057Ethan M Goldberg9https://orcid.org/0000-0002-7404-735XDepartment of Neurology, The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, United StatesDivision of Neurology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, United StatesNeuroscience Graduate Group, The University of Pennsylvania Perelman School of Medicine, Philadelphia, United StatesDivision of Neurology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, United StatesCollege of Arts and Sciences, The University of Pennsylvania, Philadelphia, United StatesNeuroscience Graduate Group, The University of Pennsylvania Perelman School of Medicine, Philadelphia, United StatesDivision of Neurology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, United StatesDivision of Neurology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, United StatesDivision of Neurology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, United StatesDepartment of Neurology, The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, United States; Division of Neurology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, United States; Department of Neuroscience, The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, United StatesDravet syndrome (DS) is a neurodevelopmental disorder due to pathogenic variants in SCN1A encoding the Nav1.1 sodium channel subunit, characterized by treatment-resistant epilepsy, temperature-sensitive seizures, developmental delay/intellectual disability with features of autism spectrum disorder, and increased risk of sudden death. Convergent data suggest hippocampal dentate gyrus (DG) pathology in DS (Scn1a+/-) mice. We performed two-photon calcium imaging in brain slice to uncover a profound dysfunction of filtering of perforant path input by DG in young adult Scn1a+/- mice. This was not due to dysfunction of DG parvalbumin inhibitory interneurons (PV-INs), which were only mildly impaired at this timepoint; however, we identified enhanced excitatory input to granule cells, suggesting that circuit dysfunction is due to excessive excitation rather than impaired inhibition. We confirmed that both optogenetic stimulation of entorhinal cortex and selective chemogenetic inhibition of DG PV-INs lowered seizure threshold in vivo in young adult Scn1a+/- mice. Optogenetic activation of PV-INs, on the other hand, normalized evoked responses in granule cells in vitro. These results establish the corticohippocampal circuit as a key locus of pathology in Scn1a+/- mice and suggest that PV-INs retain powerful inhibitory function and may be harnessed as a potential therapeutic approach toward seizure modulation.https://elifesciences.org/articles/69293Dravet syndromeSCN1ANav1.1gabaergic interneuronsdentate gyrus |
| spellingShingle | Joanna Mattis Ala Somarowthu Kevin M Goff Evan Jiang Jina Yom Nathaniel Sotuyo Laura M Mcgarry Huijie Feng Keisuke Kaneko Ethan M Goldberg Corticohippocampal circuit dysfunction in a mouse model of Dravet syndrome eLife Dravet syndrome SCN1A Nav1.1 gabaergic interneurons dentate gyrus |
| title | Corticohippocampal circuit dysfunction in a mouse model of Dravet syndrome |
| title_full | Corticohippocampal circuit dysfunction in a mouse model of Dravet syndrome |
| title_fullStr | Corticohippocampal circuit dysfunction in a mouse model of Dravet syndrome |
| title_full_unstemmed | Corticohippocampal circuit dysfunction in a mouse model of Dravet syndrome |
| title_short | Corticohippocampal circuit dysfunction in a mouse model of Dravet syndrome |
| title_sort | corticohippocampal circuit dysfunction in a mouse model of dravet syndrome |
| topic | Dravet syndrome SCN1A Nav1.1 gabaergic interneurons dentate gyrus |
| url | https://elifesciences.org/articles/69293 |
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