Vasoactive intestinal peptide-expressing interneurons are impaired in a mouse model of Dravet syndrome
Dravet Syndrome (DS) is a severe neurodevelopmental disorder caused by pathogenic loss of function variants in the gene SCN1A which encodes the voltage gated sodium (Na+) channel subunit Nav1.1. GABAergic interneurons expressing parvalbumin (PV-INs) and somatostatin (SST-INs) exhibit impaired excita...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2019-07-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/46846 |
| _version_ | 1811236794455293952 |
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| author | Kevin M Goff Ethan M Goldberg |
| author_facet | Kevin M Goff Ethan M Goldberg |
| author_sort | Kevin M Goff |
| collection | DOAJ |
| description | Dravet Syndrome (DS) is a severe neurodevelopmental disorder caused by pathogenic loss of function variants in the gene SCN1A which encodes the voltage gated sodium (Na+) channel subunit Nav1.1. GABAergic interneurons expressing parvalbumin (PV-INs) and somatostatin (SST-INs) exhibit impaired excitability in DS (Scn1a+/-) mice. However, the function of a third major class of interneurons in DS – those expressing vasoactive intestinal peptide (VIP-IN) –is unknown. We recorded VIP-INs in brain slices from Scn1a+/-mice and wild-type littermate controls and found prominent impairment of irregular spiking (IS), but not continuous adapting (CA) VIP-INs, in Scn1a+/- mice. Application of the Nav1.1-specific toxin Hm1a rescued the observed deficits. The IS vs. CA firing pattern is determined by expression of KCNQ channels; IS VIP-INs switched to tonic firing with both pharmacologic blockade of M-current and muscarinic acetylcholine receptor activation. These results show that VIP-INs express Nav1.1 and are dysfunctional in DS, which may contribute to DS pathogenesis. |
| first_indexed | 2024-04-12T12:14:14Z |
| format | Article |
| id | doaj.art-1867578a712a4604986bef67d5bb3645 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T12:14:14Z |
| publishDate | 2019-07-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
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| spelling | doaj.art-1867578a712a4604986bef67d5bb36452022-12-22T03:33:28ZengeLife Sciences Publications LtdeLife2050-084X2019-07-01810.7554/eLife.46846Vasoactive intestinal peptide-expressing interneurons are impaired in a mouse model of Dravet syndromeKevin M Goff0https://orcid.org/0000-0001-5862-0219Ethan M Goldberg1https://orcid.org/0000-0002-7404-735XDepartment of Neuroscience, The University of Pennsylvania Perelman School of Medicine, Philadelphia, United States; The Medical Scientist Training Program, The University of Pennsylvania Perelman School of Medicine, Philadelphia, United StatesDepartment of Neuroscience, The University of Pennsylvania Perelman School of Medicine, Philadelphia, United States; Division of Neurology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, United States; Department of Neurology, The University of Pennsylvania Perelman School of Medicine, Philadelphia, United StatesDravet Syndrome (DS) is a severe neurodevelopmental disorder caused by pathogenic loss of function variants in the gene SCN1A which encodes the voltage gated sodium (Na+) channel subunit Nav1.1. GABAergic interneurons expressing parvalbumin (PV-INs) and somatostatin (SST-INs) exhibit impaired excitability in DS (Scn1a+/-) mice. However, the function of a third major class of interneurons in DS – those expressing vasoactive intestinal peptide (VIP-IN) –is unknown. We recorded VIP-INs in brain slices from Scn1a+/-mice and wild-type littermate controls and found prominent impairment of irregular spiking (IS), but not continuous adapting (CA) VIP-INs, in Scn1a+/- mice. Application of the Nav1.1-specific toxin Hm1a rescued the observed deficits. The IS vs. CA firing pattern is determined by expression of KCNQ channels; IS VIP-INs switched to tonic firing with both pharmacologic blockade of M-current and muscarinic acetylcholine receptor activation. These results show that VIP-INs express Nav1.1 and are dysfunctional in DS, which may contribute to DS pathogenesis.https://elifesciences.org/articles/46846epilepsyNav1.1SCN1Aelectrophysiologyion channels |
| spellingShingle | Kevin M Goff Ethan M Goldberg Vasoactive intestinal peptide-expressing interneurons are impaired in a mouse model of Dravet syndrome eLife epilepsy Nav1.1 SCN1A electrophysiology ion channels |
| title | Vasoactive intestinal peptide-expressing interneurons are impaired in a mouse model of Dravet syndrome |
| title_full | Vasoactive intestinal peptide-expressing interneurons are impaired in a mouse model of Dravet syndrome |
| title_fullStr | Vasoactive intestinal peptide-expressing interneurons are impaired in a mouse model of Dravet syndrome |
| title_full_unstemmed | Vasoactive intestinal peptide-expressing interneurons are impaired in a mouse model of Dravet syndrome |
| title_short | Vasoactive intestinal peptide-expressing interneurons are impaired in a mouse model of Dravet syndrome |
| title_sort | vasoactive intestinal peptide expressing interneurons are impaired in a mouse model of dravet syndrome |
| topic | epilepsy Nav1.1 SCN1A electrophysiology ion channels |
| url | https://elifesciences.org/articles/46846 |
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