Natural genetic variability of the neuronal nicotinic acetylcholine receptor subunit genes in mice: Consequences and confounds

Abstract

Recent human genetic studies have identified genetic variants in multiple nicotinic acetylcholine receptor (nAChR) subunit genes that are associated with risk for nicotine dependence and other smoking-related measures. Genetic variability also exists in the nAChR subunit genes in mice. Most studies on mouse nAChR subunit gene variability to date have focused on Chrna4, the gene that encodes the α4 nAChR subunit and Chrna7, the gene that encodes the α7 nAChR subunit. However, genetic variability exists for all nAChR genes in mice. In this review, we will describe what is known about nAChR subunit gene polymorphisms in mice and how it relates to variability in nAChR expression and function in brain. The relationship between nAChR genetic variability in mice and the effects of nicotine on several behavioral and physiological measures also will be discussed. In addition, an overview of the contribution of other genetic variation to nicotine sensitivity in mice will be provided. Finally, the potential for natural genetic variability to confound and/or modify the results of studies that utilize genetically engineered mice will be considered. As an example of the ability of a natural genetic variant to modify the effect of an engineered mutation, data will be presented that demonstrate that the effect of Chrna5 deletion on oral nicotine intake is dependent upon naturally occurring variant alleles of Chrna4.

Molecular Mechanisms Associated with Nicotine Pharmacology and Dependence

“…Similar observations occurred in the nicotine CPP paradigm where α5 knockout mice exhibited a maintained nicotine preference at higher doses not maintained by α5 wild-type mice (Jackson et al 2010). In addition, in mice expressing the α5 human mutation, an increase in nicotine self-administration was reported (Wilking and Stitzel 2015). Furthermore, using rats carrying the α5 human mutation, Forget et al (2018) found greater nicotine intake in the SNP-expressing mutant rats compared with wild-type rats, as well as an increase in nicotine motivation mutant rats.…”

Human Genetics of Addiction: New Insights and Future Directions

“…Independent of rs16969968, noncoding CHRNA5 SNPs have been found to tag cis -expression quantitative trait loci ( cis -eQTL) and cis -methylation QTL ( cis -meQTL) variants that regulate CHRNA5 RNA expression (rs588765 [48] and rs880395 [49]) and DNA methylation (rs11636753 [50]), respectively, in postmortem human PFC. Consistent with these findings, mouse models have indicated that genetically altered CHRNA5 RNA expression profoundly influences behavioral traits characteristic of nicotine dependence [51–53].…”

The nicotinic acetylcholine receptor: From molecular biology to cognition

“…Using rodent models, Wilking and Stitzel (2015) apply gene targeting to study genetic polymorphisms and review what is known about nAChR subunit variation in mice and how it relates to changes in nAChR expression and function in the brain.…”