<EM>​</EM>CHARACTERIZING THE ROLE OF PCDH19 INTRACELLULAR DOMAIN IN DENDRITIC SPINES

Protocadherin-19 is a cell-adhesion protein from the cadherin superfamily that can be found at synapses in CNS neurons. Mosaic mutations in PCDH19 have been linked to epileptic seizures and cognitive impairment, whereas a complete absence of functional protein does not cause any significant symptoms. The biological roles of PCDH19 are still being investigated, but it is known that this protein undergoes activity-dependent proteolytic processing, releasing an intracellular domain (ICD) that can translocate to the nucleus. We have previously found that in vivo overexpression of PCDH19 ICD in mouse upper layer cortical neurons results in a decrease in dendritic spine density at postnatal day 60 (P60). This change is mediated by Xlr3 genes, which are linked to dendritic spine instability. We now aim to get a better understanding of how this phenotype is brought about and of the way in which PCDH19 and PCDH19ICD regulate spine dynamics. To this end, we have characterised PCDH19 processing in the cortex at different time points via western blot and we are analysing the effect of ICD overexpression on dendritic spine density at different postnatal stages through in utero electroporation. Interestingly, PCDH19-ICD overexpression seems to increase dendritic spine density at P10, when synaptogenesis is under way. However, the effect is completely reversed by P20, when spine density is already significantly lower in overexpressing neurons.