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

Abstract

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, <i>FGF13</i> were implicated as causal for a set of DEEs, but the underlying mechanisms were clouded because <i>FGF13</i> is expressed in both excitatory and inhibitory neurons, <i>FGF13</i> 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 <i>Fgf13</i> led to perinatal mortality associated with extensive seizures and impaired the hippocampal inhibitory/excitatory balance while excitatory neuron-targeted deletion of <i>Fgf13</i> 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 <i>Fgf13</i> ablation in interneurons on Na_vs but rather a marked reduction in K⁺ channel currents. Re-expressing different <i>Fgf13</i> 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 <i>Fgf13-</i>related seizures and expand our understanding of FGF13 functions in different neuron subsets.