Developmental and Epileptic Encephalopathy 9 (DEE9) is a debilitating neurological condition with no effective cure characterized by epilepsy, intellectual disability and autism. DEE9 is due to mutations in the X-chromosome gene PCDH19 that encodes protocadherin-19 (PCDH19), a cell adhesion molecule. We recently reported that PCDH19 undergoes an activity-dependent proteolytic cleavage that generates a cytosolic C-terminal fragment (CTF), which goes in the nucleus and regulates the expression of a subset of immediate early genes in primary hippocampal neurons.The aim of this project is to investigate ex vivo the role of PCDH19 in the regulation of gene expression.Therefore, we are exploiting the conditional KO (cKO) mouse model for Pcdh19 recently characterized and that recapitulates key aspects of DEE9.We found that in hippocampus PCDH19 CTF is produced and peaks in the first postnatal period, when synaptogenesis and neuronal circuits refinement occur.Moreover, through fractionation and sequential salt extraction assay, we proved that PCDH19 CTF localizes in nuclei and associates with the chromatin.Single nucleus RNA sequencing analysis of hippocampal cells from the DEE9 model and the control counterpart revealed the presence of broad alterations occurring in key pathways involved in synaptic transmission, cell adhesion, cytoskeleton organization, energy metabolism and regulation of translation, some being cell-type specific, while others shared across multiple cell types.Overall, we provide for the first time a systematic analysis carried out at single cell resolution aimed at dissecting the complex mechanisms responsible for the onset of the DEE9 disorder and at identifying new potential therapeutic targets.