Leveraging Mice with GABAergic Deletion of Ube3a to Study Seizure Histopathology in Angelman Syndrome

Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by a host of symptoms, chief among which are recurrent, treatment-refractory seizures that affect >90% of individuals. AS is caused by loss of the maternal copy of UBE3A, which is sufficient to eliminate nearly all UBE3A production in neurons. Little is known about the mechanisms by which neuronal UBE3A loss leads to persistent seizure phenotypes in AS. However, the dentate gyrus of the hippocampus is one region of mechanistic interest, as AS model mice show prominent histopathology in this region following repeated seizures induced by the convulsant flurothyl. This research examines the relationship between epileptogenesis (induced by flurothyl kindling) and hippocampal histopathology with the goal of elucidating the mechanism by which the loss of neuronal UBE3A enhances seizure susceptibility. We screened mice with maternal allele deletion of Ube3a from three major subclasses of forebrain GABAergic neurons for seizure behavior using a flurothyl kindling paradigm, and assessed brain sections from these mice for changes in two types of seizure-relevant pathologies: hippocampal perineuronal net distribution and astrogliosis. Deletion of Ube3a from parvalbumin (PV)-expressing inhibitory neurons enhanced seizure susceptibility in the flurothyl kindling paradigm similar to that of AS model mice, and caused the same post-kindling markers of histopathology as AS mice. To explore the efficacy of genetic reinstatement of Ube3a in inhibitory neurons, we performed flurothyl kindling on mice with inhibitory neuron-specific reinstatement of Ube3a and assessed the relevant histopathological markers. Reinstatement in PV neurons partially rescued the epileptogenic phenotype, without noticeable rescue of histopathology. Our results suggest that PV+ neurons play a key role in seizures of AS mice and potentially AS individuals. Correlation analysis of seizure threshold and histopathology suggest an inverse relationship between these elements, suggesting dentate gyrus pathology likely contributes to epileptogenic phenotypes, but may act in conjunction with other circuit changes. Further elucidation of the complex relationship between histopathology and epileptogenesis will inform future therapeutic treatments for AS.