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_vs 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.

It has been well validated that chronic psychological stress leads to bone loss, but the underlying mechanism remains unclarified. In this study, we established and analyzed the chronic unpredictable mild stress (CUMS) mice to investigate the miRNA-related pathogenic mechanism involved in psychological stress-induced osteoporosis. Our result found that these CUMS mice exhibited osteoporosis phenotype that is mainly attributed to the abnormal activities of osteoclasts. Subsequently, miRNA sequencing and other analysis showed that miR-335-3p, which is normally highly expressed in the brain, was significantly downregulated in the nucleus ambiguous, serum, and bone of the CUMS mice. Additionally, in vitro studies detected that miR-335-3p is important for osteoclast differentiation, with its direct targeting site in Fos. Further studies demonstrated FOS was upregulated in CUMS osteoclast, and the inhibition of FOS suppressed the accelerated osteoclastic differentiation, as well as the expression of osteoclastic genes, such as Nfatc1, Acp5, and Mmp9, in miR-335-3p-restrained osteoclasts. In conclusion, this work indicated that psychological stress may downregulate the miR-335-3p expression, which resulted in the accumulation of FOS and the upregulation of NFACT1 signaling pathway in osteoclasts, leading to its accelerated differentiation and abnormal activity. These results decipher a previously unrecognized paradigm that miRNA can act as a link between psychological stress and bone metabolism.