Journal Article

Interneuron FGF13 regulates seizure susceptibility via a sodium channel-independent mechanism

Rajadhyaksha, Anjali, Wang, Hong-Gang, Towers, Patrick, Gade, Aravind R, Nunez, Jorge, Pitt, Geoffrey S, DiStefano, Isabella, Schwartz, Theodore H, Niemeyer, James E, Galante, Allison, Lin, Susan, Matsui, Maiko

2025

Overview

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 (Na v ) regulator, we observed no effect of Fgf13 ablation in interneurons on Na v s 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.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Animals / Brain / Child development / Convulsions & seizures / Epilepsy / Fibroblast growth factors / Fibroblast Growth Factors - genetics / Fibroblast Growth Factors - metabolism / Fibroblasts / Growth factors / Immunohistochemistry / inhibitory interneuron / Interneurons - metabolism / Interneurons - physiology / Kinases / Mice / Mice, Knockout / Nervous system diseases / Neurons / Neuroscience / Postpartum period / Seizures / Seizures (Medicine) / Seizures - genetics / Seizures - metabolism / Sodium / sodium channels / Sodium Channels - genetics / Sodium Channels - metabolism