Abstract
OBJECTIVE: Protocadherin-19 (PCDH19)-clustering epilepsy (PCE) is a severe genetic epilepsy that manifests with early-onset cluster seizures often triggered by fever, intellectual disability, autistic features, and later neuropsychiatric risk. PCDH19 is an X-linked gene critical for brain development. PCE predominantly affects females and rare mosaic males, but not hemizygous males, likely due to cellular mosaicism arising from random X-inactivation and resultant segregation of wild-type and mutant neurons (so-called cellular interference) during development. We generated a novel PCE mouse model and explored neuronal segregation, seizure susceptibility and cortical interneuron distributions. METHODS: Female Pcdh19 (+/-) mice were crossed with X-GFP males to visualize random X-inactivation patterns. Seizure susceptibility was assessed in juvenile mice using hyperthermia and flurothyl exposure. Behavioral testing evaluated cognitive domains. Interneuron distribution in hippocampus and cortex was examined histologically by immunolabeling and crosses with parvalbumin reporter mice. RESULTS: Juvenile Pcdh19 (+/-) females lacked spontaneous seizures but displayed lower seizure thresholds and more severe seizures during hyperthermia. Seizure susceptibility did not differ from controls after flurothyl exposure. Pcdh19 (+/-) females also exhibited segregation of GFP+ cells in the cortex, hippocampal CA1 region and medial ganglionic eminence, with a marked reduction of parvalbumin-positive interneurons in the CA1 hippocampal region. Although parvalbumin interneuron density was unchanged in the Pcdh19 (+/-) female cortex overall, localized decreases arose in GFP- ( Pcdh19 knockout) cortical stripes. INTERPRETATION: Juvenile PCE mice exhibit seizure susceptibility to hyperthermia and disrupted the distribution of parvalbumin-expressing interneurons in the hippocampus and cortex. These findings suggest focal parvalbumin interneuron alterations may contribute to PCE pathophysiology.