Mosaic and non-mosaic pcdh19 mutation leads to neuronal hyperexcitability in zebrafish

Abstract Epilepsy is one of the most common neurological disorders. The X-linked gene PCDH19 is associated with sporadic and familial epilepsy in humans, typically with early-onset clustering seizures and intellectual disability in females but not in so-called ‘carrier’ males, suggesting that mosaic PCDH19 expression is required to produce epilepsy. To characterize the role of loss of PCDH19 function in epilepsy, we generated zebrafish with truncating pcdh19 variants. We observed hyperexcitability phenotypes in both mosaic and non-mosaic pcdh19+/- and -/- mutant larvae, indicating that Pcdh19 cellular mosaicism is not required for network hyperexcitability in zebrafish. Further, zebrafish with non-mosaic pcdh19 mutation display reduced numbers of inhibitory interneurons and transcriptional down-regulation of key inhibitory synapse components, suggesting a potential cellular basis for the observed hyperexcitability. Our findings in both mosaic and non-mosaic pcdh19 mutant zebrafish challenge the prevailing theory that mosaicism governs all PCDH19-related phenotypes and point to interneuron-mediated mechanisms underlying these phenotypes.