Abstract
The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons. In vivo, PCDH19 downregulation impairs migration, orientation and dendritic arborization of CA1 hippocampal neurons and increases rat seizure susceptibility. In sum, these data indicate a role for PCDH19 in GABAergic transmission as well as migration and morphological maturation of neurons.
Highlights
Mutations in the PCDH19 gene on chromosome X (Xp22.1) cause a female-limited epilepsy (PCDH19 Female Epilepsy, PCDH19-FE; OMIM # 300088) that is frequently associated with intellectual disability and autistic features [1,2]
Our study stems from the finding that PCDH19 is able to bind GABAA receptor (GABAAR) both in heterologous cells and in rat neurons
Immunocytochemistry (ICC) experiments revealed PCDH19-alpha 1 colocalization, which was most evident in the perinuclear region, likely the endoplasmic reticulum (ER), when alpha was the only overexpressed GABAAR subunit, and in vesicle-like structures when alpha 1 was coexpressed with the other receptor subunits (Fig. 1A)
Summary
Mutations in the PCDH19 gene on chromosome X (Xp22.1) cause a female-limited epilepsy (PCDH19 Female Epilepsy, PCDH19-FE; OMIM # 300088) that is frequently associated with intellectual disability and autistic features [1,2]. Since the discovery of its involvement in PCDH19-FE in 2008, PCDH19 has rapidly become the second most clinically relevant gene in epilepsy after the Dravet syndrome causative gene SCN1A [3]. PCDH19 encodes protocadherin-19 (PCDH19), a calciumdependent cell-adhesion molecule belonging to the nonclustered delta2-protocadherin subclass of the cadherin superfamily [4,5].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
