22.09.2017 - 06:34
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Understanding pathophysiological mechanisms underlying PCDH19
September 22, 2017 11:00
Speaker: Maria Passafaro (Neuroscience Institute, CNR, Milan)
Talk at the Department of Evolutionary Genetics

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Seminar Area Genetics

Mutations in the PCDH19 gene on chromosome X (Xp22.1) cause a female-limited epilepsy (PCDH19 Female Epilepsy, PCDH19-FE) that is frequently associated with intellectual disability and autism.
Epilepsy affects heterozygous females and spares hemizygous males, with the exception of few mosaic males. PCDH19 encodes for rotocadherin-19 (PCDH19) that is a calcium-dependent cell-adhesion molecule belonging to the non-clustered elta2-protocadherin subclass of the cadherin superfamily. PCDH19 has six conserved extracellular cadherin repeats, a transmembrane region and an intracellular C-terminus (CT). We found that PCDH19 is expressed at both excitatory and inhibitory synapses of hippocampal neurons and regulates neuronal excitability via two distinct mechanisms: by modulating GABAAR transmission at synapses and gene expression in the nucleus.
Our data indicate that PCDH19 CT interacts with the GABAAR alpha subunits; upon PCDH19 shRNA-mediated downregulation, GABAAR surface expression is reduced and fast GABAergic transmission impaired. Since PCDH19 expression increases throughout embryonic development and peaks in the first postnatal days when GABA signaling orchestrates neuronal migration and arborization, we downregulated PCDH19 via shRNA in utero electroporation in rat hippocampus. Consistently with an impairment of GABAergic transmission, PCDH19 downregulation during brain development affects the migration and morphological maturation of pyramidal neurons and increases rat’s seizure susceptibility.
In addition, upon sustained NMDAR activation, PCDH19 CT is cleaved by gamma sectetase and enters the nucleus. In the nucleus, PCDH19 CT associates with the CoREST complex and represses the transcription of immediate early genes (IEGs), which are key regulators of neuronal plasticity and excitability. Conversely, PCDH19 shRNA-mediated downregulation increases IEGs transcripts. Notably, PCDH19 cleavage occurs in vivo upon epileptogenic stimuli, as demonstrated by CT generation in hippocampal homogenates from mice that experienced pilocarpine induced-seizures. We hypothesize that PCDH19 cleavage might represents a homeostatic mechanism in response to strong neuronal activation that prevents IEGs overactivation.
Finally, we generated a conditional PCDH19 KO mouse model by using LoxP-Cre technology. Our preliminary data suggest that Cre-mediated PCDH19 inactivation is associated with an epileptic phenotype that we will investigate in detail with a focus on mosaic PCDH19 expression and its role on PCDH19-FE pathogenesis.
Altogether, PCDH19 emerges as a new GABAAR binding partner that controls GABAergic transmission and simultaneously exerts a homeostatic control of excitability via IEGs expression regulation, thus suggesting new pathogenic mechanisms for PCDH19-FE.

Viola Mittag
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E-mail: mittag[>>> Please replace the brackets with an AT sign! <<<]eva.mpg.de
Website: http://www.eva.mpg.de/genetics