Genetic background influences in a mouse model of absence epilepsy
Category: Current
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Recently, a mutation was found to be linked to a generalised epilepsy syndrome with Childhood Absence Epilepsy (CAE) in a large Victorian family. Absence seizures are defined as seizures which result in sudden onset of brief periods of unconsciousness. These occurrence of these seizures commonly decline after 6 years of age. Interestingly, a mouse model incorporating this mutation developed by our group recapitulated this epileptic condition, confirming the causal role of this mutation in CAE. Previously, we have demonstrated that the mutation results in impaired GABAA receptor trafficking, which results in a deficit in cortical inhibition. Our lab now focuses on relevant neuronal networks and in vivo in order to relate these molecular deficits with the clinical pathology of the disease. In families harbouring the GABAA receptor g2 (R43Q) mutation, the presence of the mutation is linked to Childhood Absence Epilepsy. However, there is a strong clinical heterogeneity and not all subjects with the mutation exhibit an epileptic phenotype. In order to investigate the influence of genetic background on the final phenotype of this mutation, the mutation was bred into two different genetic backgrounds; the C57/B6 and the DBA/2J mice strains. At a young age, the mutation resulted in spontaneous absence seizures in both strains. Similarly to the clinical condition, the frequency of seizures continuously declined with age in both strains, unlike other commonly studied rat models of absence epilepsy, which actually develop seizures as the animals mature. The genetic background of the animal harbouring the mutation also exerted a strong influence on the epileptic phenotype. Mutant C57/B6 mice only exhibited 4-10 seizures per hour with each seizure lasting only 0.5-1s. In contrast, mutant mice in the DBA/2J background exhibited 40-150 seizures per hour with each seizure lasting 1-3s. To investigate the physiological difference between these two strains responsible for contrasting seizure susceptibility, a technique called Patch Clamp recording was used to record synaptic signals in brain slices to characterize how different cells communicate with each other. We focused our efforts on the cortex and the thalamus, two large brain regions known to play an important role in Absence epilepsy. Interestingly, the DBA strain showed a large increase in synaptic inhibition in the thalamus but not the cortex. Inhibition in the thalamus is essential in driving this region of the brain into synchronized epileptic activity. This inherent difference between the mice strains may therefore responsible for the different seizure severity they develop as a result of the mutation. This suggests that although a single mutation may be a primary cause for the development of epilepsy, other genetic factors strongly influence the final clinical outcome.
