Deletion of lynx1 reduces the function of α6*nicotinic receptors

The alpha 6 nicotinic acetylcholine receptor (nAChR) subunit is an attractive drug target for treating nicotine addiction because it is present at limited sites in the brain including the reward pathway. Lynx1 modulates several nAChR subtypes; lynx1-nAChR interaction sites could possibly provide drug targets. We found that dopaminergic cells from the substantia nigra pars compacta (SNc) express lynx1 mRNA transcripts and, as assessed by co-immunoprecipitation, alpha 6 receptors form stable complexes with lynx1 protein, although co-transfection with lynx1 did not affect nicotine-induced currents from cell lines transfected with alpha 6 and beta 2. To test whether lynx1 is important for the function of alpha 6 nAChRs in vivo, we bred transgenic mice carrying a hypersensitive mutation in the alpha 6 nAChR subunit (alpha 6L90S) with lynx1 knockout mice, providing a selective probe of the effects of lynx1 on alpha 6* nAChRs. Lynx1 removal reduced the alpha 6 component of nicotine-mediated rubidium efflux and dopamine (DA) release from synaptosomal preparations with no effect on numbers of alpha 6 beta 2 binding sites, indicating that lynx1 is functionally important for alpha 6* nAChR activity. No effects of lynx1 removal were detected on nicotine-induced currents in slices from SNc, suggesting that lynx1 affects presynaptic alpha 6* nAChR function more than somatic function. In the absence of agonist, lynx1 removal did not alter DA release in dorsal striatum as measured by fast scan cyclic voltammetry. Lynx1 removal affected some behaviors, including a novel-environment assay and nicotine-stimulated locomotion. Trends in 24-hour home-cage behavior were also suggestive of an effect of lynx1 removal. Conditioned place preference for nicotine was not affected by lynx1 removal. The results show that some functional and behavioral aspects of alpha 6nAChRs are modulated by lynx1.