One (1) widely accepted benchmark in epilepsy research is to achieve a cure for an inherited form of epilepsy by developing a therapy that is based on understanding the effects of the causative mutation. Towards this end, we have genetically engineered mutant mouse strains that genocopy a human disorder known as autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Patients with this idiopathic partial epilepsy syndrome become symptomatic during the second decade of life. Audiovisual monitoring and polysomnography reveals brief clusters of hyperkinetic motor seizures and vocalizations that begin during non-rapid eye movement sleep. Currently, several mutations have been linked to ADNFLE, all of which map to the pore-forming domain of the nicotinic acetylcholine receptor (nAChR) a4 or B2 subunit genes. We have created 2 lines of 'knockin' mice that contain ADNFLE mutations in the nAChR a4 subunit gene. The principal objective of this proposal is to establish the degree to which these mutant mice phenocopy human ADNFLE and thereby validate this animal model of inherited partial epilepsy.
In Specific Aim 1, we propose experiments that seek to characterize recurrent seizure activity in ADNFLE mice. In particular, we will determine the age of seizure onset, estimate penetrance, and evaluate seizure semiology and frequency. Combined video-polysomnographic and electroencephalographic (EEC) analyses will be used to measure ictal and interictal EEG patterns, localize the neuroanatomical origin of epileptiform activity, and explore the relationship between sleep and seizure onset.
In Specific Aim 2, we outline studies using mouse brain slices and electrophysiology to test the hypothesis that mutant a4B2 nAChRs alter y-aminobutyric acid-mediated events leading to disinhibition of excitatory, glutamatergic systems and seizures. The objective of these experiments is to examine possible synaptic mechanisms underlying epileptogenesis and to determine the effects of ADNFLE mutations on a4a2receptor-mediated function in vivo.
|Vetter, Douglas E; Katz, Eleonora; Maison, Stephane F et al. (2007) The alpha10 nicotinic acetylcholine receptor subunit is required for normal synaptic function and integrity of the olivocochlear system. Proc Natl Acad Sci U S A 104:20594-9|