Interneuron FGF13 regulates seizure susceptibility via a sodium channel-independent mechanism
Developmental and epileptic encephalopathies (DEEs), a class of devastating neurological disorders characterized by recurrent seizures and exacerbated by disruptions to excitatory/inhibitory balance in the brain, are commonly caused by mutations in ion channels. Disruption of, or variants in, FGF13...
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eLife Sciences Publications Ltd
2025-01-01
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| Online Access: | https://elifesciences.org/articles/98661 |
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| author | Susan Lin Aravind R Gade Hong-Gang Wang James E Niemeyer Allison Galante Isabella DiStefano Patrick Towers Jorge Nunez Maiko Matsui Theodore H Schwartz Anjali Rajadhyaksha Geoffrey S Pitt |
| author_facet | Susan Lin Aravind R Gade Hong-Gang Wang James E Niemeyer Allison Galante Isabella DiStefano Patrick Towers Jorge Nunez Maiko Matsui Theodore H Schwartz Anjali Rajadhyaksha Geoffrey S Pitt |
| author_sort | Susan Lin |
| collection | DOAJ |
| description | Developmental and epileptic encephalopathies (DEEs), a class of devastating neurological disorders characterized by recurrent seizures and exacerbated by disruptions to excitatory/inhibitory balance in the brain, are commonly caused by mutations in ion channels. Disruption of, or variants in, FGF13 were implicated as causal for a set of DEEs, but the underlying mechanisms were clouded because FGF13 is expressed in both excitatory and inhibitory neurons, FGF13 undergoes extensive alternative splicing producing multiple isoforms with distinct functions, and the overall roles of FGF13 in neurons are incompletely cataloged. To overcome these challenges, we generated a set of novel cell-type-specific conditional knockout mice. Interneuron-targeted deletion of Fgf13 led to perinatal mortality associated with extensive seizures and impaired the hippocampal inhibitory/excitatory balance while excitatory neuron-targeted deletion of Fgf13 caused no detectable seizures and no survival deficits. While best studied as a voltage-gated sodium channel (Nav) regulator, we observed no effect of Fgf13 ablation in interneurons on Navs but rather a marked reduction in K+ channel currents. Re-expressing different Fgf13 splice isoforms could partially rescue deficits in interneuron excitability and restore K+ channel current amplitude. These results enhance our understanding of the molecular mechanisms that drive the pathogenesis of Fgf13-related seizures and expand our understanding of FGF13 functions in different neuron subsets. |
| format | Article |
| id | doaj-art-c203d883eca346739222aa0f6d7675a4 |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | eLife Sciences Publications Ltd |
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| spelling | doaj-art-c203d883eca346739222aa0f6d7675a42025-01-08T15:27:59ZengeLife Sciences Publications LtdeLife2050-084X2025-01-011310.7554/eLife.98661Interneuron FGF13 regulates seizure susceptibility via a sodium channel-independent mechanismSusan Lin0https://orcid.org/0000-0001-9344-6594Aravind R Gade1Hong-Gang Wang2James E Niemeyer3Allison Galante4Isabella DiStefano5Patrick Towers6Jorge Nunez7Maiko Matsui8https://orcid.org/0000-0001-9706-8244Theodore H Schwartz9Anjali Rajadhyaksha10Geoffrey S Pitt11https://orcid.org/0000-0003-2246-0289Cardiovascular Research Institute, Weill Cornell Medicine, New York City, United StatesCardiovascular Research Institute, Weill Cornell Medicine, New York City, United StatesCardiovascular Research Institute, Weill Cornell Medicine, New York City, United StatesDepartment of Neurological Surgery and Brain and Mind Research Institute, Weill Cornell Medicine of Cornell University, New York Presbyterian Hospital, New York, United StatesCardiovascular Research Institute, Weill Cornell Medicine, New York City, United StatesCardiovascular Research Institute, Weill Cornell Medicine, New York City, United StatesCardiovascular Research Institute, Weill Cornell Medicine, New York City, United StatesCardiovascular Research Institute, Weill Cornell Medicine, New York City, United StatesCardiovascular Research Institute, Weill Cornell Medicine, New York City, United StatesDepartment of Neurological Surgery and Brain and Mind Research Institute, Weill Cornell Medicine of Cornell University, New York Presbyterian Hospital, New York, United StatesDepartment of Pediatrics, Division of Pediatric Neurology, Weill Cornell Medicine, New York City, United States; Brain and Mind Research Institute, Weill Cornell Medicine, New York, United StatesCardiovascular Research Institute, Weill Cornell Medicine, New York City, United StatesDevelopmental and epileptic encephalopathies (DEEs), a class of devastating neurological disorders characterized by recurrent seizures and exacerbated by disruptions to excitatory/inhibitory balance in the brain, are commonly caused by mutations in ion channels. Disruption of, or variants in, FGF13 were implicated as causal for a set of DEEs, but the underlying mechanisms were clouded because FGF13 is expressed in both excitatory and inhibitory neurons, FGF13 undergoes extensive alternative splicing producing multiple isoforms with distinct functions, and the overall roles of FGF13 in neurons are incompletely cataloged. To overcome these challenges, we generated a set of novel cell-type-specific conditional knockout mice. Interneuron-targeted deletion of Fgf13 led to perinatal mortality associated with extensive seizures and impaired the hippocampal inhibitory/excitatory balance while excitatory neuron-targeted deletion of Fgf13 caused no detectable seizures and no survival deficits. While best studied as a voltage-gated sodium channel (Nav) regulator, we observed no effect of Fgf13 ablation in interneurons on Navs but rather a marked reduction in K+ channel currents. Re-expressing different Fgf13 splice isoforms could partially rescue deficits in interneuron excitability and restore K+ channel current amplitude. These results enhance our understanding of the molecular mechanisms that drive the pathogenesis of Fgf13-related seizures and expand our understanding of FGF13 functions in different neuron subsets.https://elifesciences.org/articles/98661sodium channelsepilepsyinhibitory interneuron |
| spellingShingle | Susan Lin Aravind R Gade Hong-Gang Wang James E Niemeyer Allison Galante Isabella DiStefano Patrick Towers Jorge Nunez Maiko Matsui Theodore H Schwartz Anjali Rajadhyaksha Geoffrey S Pitt Interneuron FGF13 regulates seizure susceptibility via a sodium channel-independent mechanism eLife sodium channels epilepsy inhibitory interneuron |
| title | Interneuron FGF13 regulates seizure susceptibility via a sodium channel-independent mechanism |
| title_full | Interneuron FGF13 regulates seizure susceptibility via a sodium channel-independent mechanism |
| title_fullStr | Interneuron FGF13 regulates seizure susceptibility via a sodium channel-independent mechanism |
| title_full_unstemmed | Interneuron FGF13 regulates seizure susceptibility via a sodium channel-independent mechanism |
| title_short | Interneuron FGF13 regulates seizure susceptibility via a sodium channel-independent mechanism |
| title_sort | interneuron fgf13 regulates seizure susceptibility via a sodium channel independent mechanism |
| topic | sodium channels epilepsy inhibitory interneuron |
| url | https://elifesciences.org/articles/98661 |
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