Mosaic and non-mosaic protocadherin 19 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.

The IDM and THDMa -- current constraints and future prospects

“…We here report on results of a scan that allows all of the above novel parameters float in specific predefined ranges [36]. In such a scenario, it is not always straightforward to display bounds from specific constraints in 2-dimensional planes.…”

“…Finally, we can investigate which cross-section values would still be feasible for points that fulfill all constraints [36] at e + e − colliders. We are specifically interested in signatures that include missing energy and therefore do not exist in a THDM without a portal to the dark sector.…”

“…We see that there is a non-negligible number of points where the second channel is dominant. A "best" point with a large rate for t t + / E ⊥ has been presented in [36].…”

“…Color coding refers to m H + m A (left) and M H + 0.5 × (m A + m a ) (right). Figures taken from[36].…”

“…The typical resonance-enhanced relic density annihilation is clearly visible. Figures taken from[36].…”