Disrupted Excitatory Synaptic Contacts and Altered Neuronal Network Activity Underpins the Neurological Phenotype in
Stefka Mincheva-Tasheva1,2, Alvaro F Nieto Guil1,2, Claire C Homan1
1Adelaide Medical School and Robinson Research Institute, University of Adelaide, Adelaide, South Australia, 5005, Australia.
Insights
PCDH19-Clustering Epilepsy (PCDH19-CE) results from mosaicism of PCDH19-expressing and PCDH19-null cells. This cellular imbalance disrupts neuronal connections and network activity, explaining the disorder's neurological symptoms.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- PCDH19-Clustering Epilepsy (PCDH19-CE) is an X-linked disorder caused by PCDH19 gene mutations.
- Heterozygous females are affected, while hemizygous males are typically asymptomatic.
- The underlying cellular mechanisms of PCDH19-CE, particularly concerning cell mosaicism, are not fully understood.
Purpose of the Study:
- To investigate the impact of PCDH19 wild-type (WT) and knockout (KO) neuron mosaicism on synaptogenesis and network activity.
- To elucidate the cellular basis of the neurological phenotype in PCDH19-CE.
Main Methods:
- Utilized established knock-in and knock-out mouse models for Pcdh19.
- Employed CRISPR-Cas9 genome editing technology to create mixed neuronal populations.
- Analyzed synaptogenesis, neuronal morphology, and network activity in mosaic conditions.
Main Results:
- Demonstrated a reduction in excitatory synaptic contacts between PCDH19-expressing and PCDH19-null neurons.
- Identified significantly altered neuronal morphology and network activities in mixed neuronal populations.
- Observed aberrant contralateral axonal branching in heterozygous Pcdh19 mice with natural WT/KO neuron coexistence.
Conclusions:
- Mosaic expression of PCDH19 disrupts physiological neurite communication.
- Aberrant neuronal communication and activity are key features of PCDH19-CE.
- Findings provide cellular insights into the neurological phenotype of PCDH19-Clustering Epilepsy.
Abstract:
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.
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