Anatomical focus of absence seizures

Anatomical focus of absence seizures assessed by precision stereotaxic activation of mutant gene expression

The pathophysiology of absence epilepsy is still a matter of debate. Several brain regions have been implicated in absence seizure initiation, e.g. primary thalamic relay nuclei, reticular thalamus and a cortical focus in the perioral region of the somatosensory cortex. We want to investigate the role of these regions in epiletogenesis by activating mutant gene expression in a spatially and temporally controlled manner. We will use the R43Q mouse model of human childhood absence epilepsy (CAE). In a large Australian family, febrile seizures and childhood absence epilepsy (CAE) were linked to a R43Q mutation in the 2-subunit of GABAA receptor (GABRG2). R43Q knock-in mice display frequent absence seizures, closely resembling the human phenotype.

We will specifically activate GABRG2(R43Q) expression in each of the brain nuclei listed above. To this end, stereotaxic in vivo injection of adenoassociated virus (AAV) expressing cre-recombinase will be applied in transgenic mice that carry the GABRG2(R43Q) mutation interrupted by a floxed neo cassette. Injections will be performed in both juvenile and adult mice to examine the precise regions and developmental time points involved in absence seizure initiation. Rodent EEG and tetrode recording as well as behavioural and electrophysiological techniques will demonstrate whether and/or when the expression of mutant receptors in a certain region is sufficient to induce generalized seizures. These experiments will yield important information about the origin and temporal genesis of absence epilepsy.