Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is an idiopathic epileptic disorder characterized by nocturnal seizures localized within the frontal lobe arising during stage 2 sleep. Mutations within the putative pore-lining M2 helix of ionotropic neuronal nicotinic acetylcholine receptor alpha4 (CHRNA4) and beta2(CHRNAB2) subunits have been linked to ADNFLE. When expressed in heterologous expression systems ADNFLE associated mutant receptors have altered channel properties compared to wild-type, suggesting that malfunctioning nicotinic receptors are responsible for the disease phenotype. Despite the molecular identification and characterization of nAChR mutations that may underlie some cases of ADNFLE, many questions remain regarding the pathophysiology of the disease. For example: Why are seizures localized to the frontal lobe of the neocortex? Why do seizures arise only during sleep? In general, what is the mechanism by which mutant acetylcholine receptors induce epileptiform activity? It is the goal of the proposed experiments to address these question by 1) establishing an ADNFLE mutant nAChR a4 knock-in mouse colony derived from our existing chimeric mice as an in vivo model for ADNFLE 2) assessing both spontaneous and nicotine-induced epileptiform activity using EEG recording and 3) characterizing the ADNFLE mutant knock-in mouse line, via intracellular recordings from neocortical and hippocampal cultures. Characterization of mutant mice on a behavioral, neuronal, cellular and molecular level should provide valuable insights into the pathogenic mechanism and pathophysiology of ADNFLE, as well as the role of alpha4beta2 acetylcholine receptors in the forebrain.
