Abstracts

Rationale: Epilepsy is a common co-morbidity in a number of developmental disorders including autism, is particularly associated with the occurrence of developmental regression, and seizures are often the most disrupting symptom of these disorders for the patient, pediatricians and family. Epilepsy is represented in the great majority of girls heterozygous for mutations in the X-linked gene MECP2 associated with the developmental disorder Rett Syndrome (RTT). RTT shares many symptoms with autism, and other developmental disorders, including a developmentally complex emergence of symptoms over the lifetime of the individual. These symptoms include a broad developmental regression triggering diagnosis between 12 to 18 months of age; yet seizures typically began 3 to 6 years later and interestingly remit in adulthood. To understand the pathogenesis of epilepsy in RTT and its resolution in adulthood we measured differences in electrically-evoked seizure thresholds between heterozygous MeCP2 knockout mice (MeCP2+/-, female) and wildtype littermates (C57BL/6J background) over adult development.Methods: The electroconvulsive shock threshold (ECT) for generalized and maximal seizures was measured in separate groups of mice starting at 10, 20 and 36 weeks of age and shocks were delivered at constant current via auricular electrodes. ECTs were determined using a ramping procedure in which mice were tested once per day. The starting current was 20 mA and the daily current increment was 2 mA. The ECT for generalized seizure (GECT) was taken as the current level at which mice first displayed loss of posture and bilateral limb clonus. The value at which mice displayed tonic extension of the hind limbs was scored as a maximal seizure (MECT). Results: Results showed significant effects of age (P = 0.006) and genotype (P=0.0005) on GECT as well as a significant interaction between these two parameters (P=0.045, 2-way ANOVA). A significant effect of age was also noted for MECT (P=0.004) with results showing that older mice have a lower threshold; however, there was no effect of genotype. A trend towards an interaction effect on MECT between age and genotype was noted (P=0.07) suggesting that a differential effect of age on wild type compared to knockout mice may also emerge as the study continues. Current results demonstrate differential effects of age on seizure susceptibility in mice genocopying MeCP2-null mutations in RTT. These interactions are primarily driven by a decrease in seizure susceptibility with increasing age when measured by GECT. Conclusions: These mice may reflect the complex development of epilepsy in RTT and our findings may provide insight into other developmental disorders where epileptogenesis occurs in later stages childhood. Furthermore this work provides an important and novel model for understanding interactions between development and genetics in the pathogenesis of epilepsy.