title: Mice expressing the ADNFLE valine 287 leucine mutation of the Β2 nicotinic acetylcholine receptor subunit display increased sensitivity to acute nicotine administration and altered presynaptic nicotinic receptor function.
abstract: Several mutations in α4 or β2 nicotinic receptor subunits are linked to autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). One such missense mutation in the gene encoding the β2 neuronal nicotinic acetylcholine receptor (nAChR) subunit (CHRNB2) is a valine-to-leucine substitution in the second transmembrane domain at position 287 (β2VL). Previous studies indicated that the β2VL mutation in mice alters circadian rhythm consistent with sleep alterations observed in ADNFLE patients (Xu et al., 2011). The current study investigates changes in nicotinic receptor function and expression that may explain the behavioral phenotype of β2VL mice. No differences in β2 mRNA expression were found between wild-type (WT) and heterozygous (HT) or homozygous mutant (MT) mice. However, antibody and ligand binding indicated that the mutation resulted in a reduction in receptor protein. Functional consequences of the β2VL mutation were assessed biochemically using crude synaptosomes. A gene-dose dependent increase in sensitivity to activation by acetylcholine and decrease in maximal nAChR-mediated [(3)H]-dopamine release and (86)Rb efflux were observed. Maximal nAChR-mediated [(3)H]-GABA release in the cortex was also decreased in the MT, but maximal [(3)H]-GABA release was retained in the hippocampus. Behaviorally both HT and MT mice demonstrated increased sensitivity to nicotine-induced hypolocomotion and hypothermia. Furthermore, WT mice display only a tonic-clonic seizure (EEG recordable) 3 min after injection of a high dose of nicotine, while MT mice also display a dystonic arousal complex (non-EEG recordable) event 30s after nicotine injection. Data indicate decreases in maximal response for certain measures are larger than expected given the decrease in receptor expression.
authors.affiliation: Institute for Behavioral Genetics, 447 UCB, University of Colorado, Boulder, CO 80309, USA. heidi.oneill@colorado.edu
authors.forename: Heidi C
authors.initials: HC
authors.lastname: O'Neill
authors.forename: Duncan C
authors.initials: DC
authors.lastname: Laverty
authors.forename: Natalie E
authors.initials: NE
authors.lastname: Patzlaff
authors.forename: Bruce N
authors.initials: BN
authors.lastname: Cohen
authors.forename: Carlos
authors.initials: C
authors.lastname: Fonck
authors.forename: Sheri
authors.initials: S
authors.lastname: McKinney
authors.forename: J Michael
authors.initials: JM
authors.lastname: McIntosh
authors.forename: Jon M
authors.initials: JM
authors.lastname: Lindstrom
authors.forename: Henry A
authors.initials: HA
authors.lastname: Lester
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Grady
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Marks
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001831:Body Temperature / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D059333:Central Nervous System Sensitization / Q000235:genetics / Q000502:physiology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004421:Dystonia / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology; D055879:Gene Knock-In Techniques; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D020125:Mutation, Missense / Q000235:genetics; D009538:Nicotine / Q000008:administration & dosage / Q000494:pharmacology*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000502:physiology*; D011869:Radioligand Assay / Q000379:methods; D011978:Receptors, Nicotinic / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012414:Rubidium Radioisotopes; D012640:Seizures / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000109:Acetylcholine; D004298:Dopamine; D009538:Nicotine; D011978:Receptors, Nicotinic; D012414:Rubidium Radioisotopes; D005680:gamma-Aminobutyric Acid