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

Abstract

AbstractDevelopmental 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,FGF13were implicated as causal for a set of DEEs, but the underlying mechanisms were clouded becauseFGF13is expressed in both excitatory and inhibitory neurons,FGF13undergoes 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 ofFgf13led to perinatal mortality associated with extensive seizures and impaired the hippocampal inhibitory/excitatory balance while excitatory neuron-targeted deletion ofFgf13caused no detectable seizures and no survival deficits. While best studied as a voltage-gated sodium channel (Nav) regulator, we observed no effect ofFgf13ablation in interneurons on Navs but rather a marked reduction in K+channel currents. Re-expressing differentFgf13splice 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 ofFgf13-related seizures and expand our understanding of FGF13 functions in different neuron subsets.