Investigating the role of parvalbumin positive interneurons in PCDH19-related Developmental and Epileptic Encephalopathy-9 (DEE9)

Developmental and epileptic encephalopathy 9 (DEE9) is a syndrome that occurs exclusively in females, marked by seizure onset in infancy and a broad spectrum of intellectual disabilities, ranging from mild to severe. The disorder stems from mutations in PCDH19 gene, an X-linked gene encoding for protocadherin-19, a cell-adhesion molecule crucial for establishment and maintenance of synapses in the central nervous system. This study investigates the hypothesis that dysfunction in parvalbumin-positive interneurons (PVIs), resulting from PCDH19 loss, contributes to the etiology of DEE9. To explore this, a mouse model with PCDH19 expression is selectively knocked out in PVIs is employed. This model exhibits altered cortical activity along with behavioral alterations that mirror those observed in the human condition. Conventional transmission electron microscopy is used to examine potential ultrastructural alterations in synapses within the prefrontal cortex. Additionally, a volume correlative light and electron microscopy approach, combined with near infrared branding, is implemented to gain insights into the dendritic complexity of PVIs and the spatial organization of neuronal inputs converging onto them.