Abstracts

Rationale: X-linked inheritance is an increasingly recognized pattern of intellectual disability (ID) in humans, constituting ~10% of all cases; over 90 genes on the X chromosome are associated with intellectual disability. X-linked ID is often accompanied by epilepsy. Experimental models of epilepsy and ID provide an opportunity to investigate disease pathomechanisms. In this study, we aim to investigate the mechanisms of epilepsy in a novel mouse model of epilepsy due to a 1.1 Mb microdeletion of chromosome Xq22.1. This region in mouse is syntenic to the deleted region in human Xq22.1 deletion syndrome, which is characterized by developmental delay/ID, epilepsy, dysmorphic features, and an X-linked pattern of inheritance. Interestingly, the deleted region includes multiple members of the G-protein coupled receptor (GPCR) associated protein (GPRASP, or GASP) family, which regulate the trafficking of various GPCRs. Methods: To investigate the mechanism of epilepsy in these mice, employed a combination of techniques, including 6-channel continuous electroencephalography (EEG) with video monitoring, immunohistochemistry, biochemistry, and voltage senstiive dye imaging. Results: Males harboring the deleted region of Xq22.1 exhibited respiratory failure, cleft palate, and neonatal lethality. Heterozygous females exhibited cleft palate and growth retardation; many (~75% of) females died in the first 3-4 weeks of life. Females surviving to post-natal day 30 exhibited epilepsy, including handling and stress-induced seizures as well as spontaneous seizures. EEG showed that adult heterozygous females had, on average, 0.5 ± 0.2 seizures per 24 hours. Electrographic seizures appeared to initiate from the hippocampus. Histological analysis revealed normal anatomy and layering of the neocortex and hippocampus. Voltage sensitive dye imaging in brain slices prepared from heterozygous female mice revealed hyperexcitability in dentate gyrus in response to perforant path stimulation. Conclusions: Deletion of a 1.1 Mb region of Xq22.1 reproduces the salient features seen in patients harboring this deletion. Epilepsy in these mice may be due to dysfunctional trafficking of G-protein coupled receptors leading to hyperexcitability in cortical networks. While Xq22.1 deletion syndrome is a rare cause of epilepsy and ID, analysis of the mouse model may yield important insights into a more general role of GASP/GPRASPs in cortical excitability and mechanisms of epilepsy.