Disrupted Excitatory Synaptic Contacts and Altered Neuronal Network Activity Underpins the Neurological Phenotype in PCDH19-Clustering Epilepsy (PCDH19-CE)

Stefka Mincheva-Tasheva, Alvaro F. Nieto Guil, Claire C. Homan, Jozef Gecz, Paul Q. Thomas

Research output: Contribution to journalArticlepeer-review


PCDH19-Clustering Epilepsy (PCDH19-CE) is an infantile onset disorder caused by mutation of the X-linked PCDH19 gene. Intriguingly, heterozygous females are affected while hemizygous males are not. While there is compelling evidence that this disorder stems from the coexistence of WT and PCDH19-null cells, the cellular mechanism underpinning the neurological phenotype remains unclear. Here, we investigate the impact of Pcdh19 WT and KO neuron mosaicism on synaptogenesis and network activity. Using our previously established knock-in and knock-out mouse models, together with CRISPR-Cas9 genome editing technology, we demonstrate a reduction in excitatory synaptic contacts between PCDH19-expressing and PCDH19-null neurons. Significantly altered neuronal morphology and neuronal network activities were also identified in the mixed populations. In addition, we show that in Pcdh19 heterozygous mice, where the coexistence of WT and KO neurons naturally occurs, aberrant contralateral axonal branching is present. Overall, our data show that mosaic expression of PCDH19 disrupts physiological neurite communication leading to abnormal neuronal activity, a hallmark of PCDH19-CE.

Original languageEnglish
JournalMolecular Neurobiology
Publication statusAccepted/In press - 1 Jan 2021


  • Epilepsy
  • PCDH19
  • PCDH19-Clustering Epilepsy (PCDH19-CE)
  • Protocadherin 19
  • Synapses

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

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