A rat model of a focal mosaic expression of PCDH19 replicates human brain developmental abnormalities and behaviours
Andrzej W Cwetsch1,2,3, Ilias Ziogas1,2, Roberto Narducci1
1Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, Via Morego 30, Genova 16163, Italy.
Insights
Protocadherin 19 clustering epilepsy, a severe infantile epilepsy, involves protocadherin 19 protein loss. This study reveals protocadherin 19
Area of Science:
- Neuroscience
- Genetics
- Epilepsy Research
Background:
- Protocadherin 19 clustering epilepsy (PCDH19-EC) is an X-linked infantile epilepsy syndrome.
- It causes variable psychiatric, sensory, and cognitive impairments.
- Affected females exhibit mosaicism due to X-chromosome inactivation, complicating disease modeling.
Purpose of the Study:
- To investigate the role of protocadherin 19 (PCDH19) in brain development and function.
- To develop a more accurate model for PCDH19-EC research.
- To understand the mechanisms underlying PCDH19-EC related deficits.
Main Methods:
- Utilized *in utero* electroporation in rats to induce focal mosaicism of PCDH19 expression.
- Examined effects on neuronal migration, seizure susceptibility, behavior, and cognitive function.
Main Results:
- Focal PCDH19 deficiency impacts neuronal migration in specific brain regions.
- PCDH19 signaling is crucial for regulating heat-induced epileptic seizures.
- Altered PCDH19 expression is linked to autism-related behaviors and cognitive deficits.
Conclusions:
- PCDH19 plays a critical role in neuronal development and network function.
- This rat model offers new avenues for studying PCDH19-EC pathogenesis and treatment.
- Targeting PCDH19 signaling may hold therapeutic potential for epilepsy and related disorders.
Abstract:
Protocadherin 19 gene-related epilepsy or protocadherin 19 clustering epilepsy is an infantile-onset epilepsy syndrome characterized by psychiatric (including autism-related), sensory, and cognitive impairment of varying degrees. Protocadherin 19 clustering epilepsy is caused by X-linked protocadherin 19 protein loss of function. Due to random X-chromosome inactivation, protocadherin 19 clustering epilepsy-affected females present a mosaic population of healthy and protocadherin 19-mutant cells. Unfortunately, to date, no current mouse model can fully recapitulate both the brain histological and behavioural deficits present in people with protocadherin 19 clustering epilepsy. Thus, the search for a proper understanding of the disease and possible future treatment is hampered. By inducing a focal mosaicism of protocadherin 19 expression using in utero electroporation in rats, we found here that protocadherin 19 signalling in specific brain areas is implicated in neuronal migration, heat-induced epileptic seizures, core/comorbid behaviours related to autism and cognitive function.
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