Mosaic and non-mosaic protocadherin 19 mutation leads to neuronal hyperexcitability in zebrafish

Barbara K Robens; Xinzhu Yang; Christopher M McGraw; Laura H Turner; Carsten Robens; Summer Thyme; Alexander Rotenberg; Annapurna Poduri

doi:10.1016/j.nbd.2022.105738

Mosaic and non-mosaic protocadherin 19 mutation leads to neuronal hyperexcitability in zebrafish

Neurobiol Dis. 2022 Jul:169:105738. doi: 10.1016/j.nbd.2022.105738. Epub 2022 Apr 20.

Authors

Barbara K Robens¹, Xinzhu Yang¹, Christopher M McGraw², Laura H Turner¹, Carsten Robens³, Summer Thyme⁴, Alexander Rotenberg⁵, Annapurna Poduri⁶

Affiliations

¹ Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital - Harvard Medical School, Boston, MA, USA; Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital - Harvard Medical School, Boston, MA, USA.
² Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital - Harvard Medical School, Boston, MA, USA; Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital - Harvard Medical School, Boston, MA, USA.; Department of Neurology, Harvard Medical School, Boston, MA, USA; Division of Epilepsy, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
³ MIT-Harvard Center for Ultracold Atoms, Research Laboratory of Electronics, and Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁴ Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA.
⁵ Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital - Harvard Medical School, Boston, MA, USA; Department of Neurology, Harvard Medical School, Boston, MA, USA; Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
⁶ Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital - Harvard Medical School, Boston, MA, USA; Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital - Harvard Medical School, Boston, MA, USA.; Department of Neurology, Harvard Medical School, Boston, MA, USA; Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, MA, USA. Electronic address: Annapurna.Poduri@childrens.harvard.edu.

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. Evaluating zebrafish larvae for electrophysiological abnormalities, we observed hyperexcitability phenotypes in both mosaic and non-mosaic pcdh19^+/- and pcdh19^-/- mutant larvae. Thus, we demonstrate that the key feature of epilepsy-network hyperexcitability-can be modeled effectively in zebrafish, even though overt spontaneous seizure-like swim patterns were not observed. Further, zebrafish with non-mosaic pcdh19 mutation displayed reduced numbers of inhibitory interneurons 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.

Keywords: Anxiety; Epilepsy; Girls clustering epilepsy; Hyperexcitability; Inhibitory neurons; Learning and memory; Mosaicism; PCDH19; X-linked; Zebrafish.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Cadherins / genetics
Epilepsy* / genetics
Female
Male
Mutation / genetics
Protocadherins
Zebrafish*

Substances

Cadherins
Protocadherins

Abstract

Publication types

MeSH terms

Substances

Grants and funding