so it remains possible that reduced neuronal expression of α5 may contribute to the observed nicotine sensitivity. This would agree with results from Chrna5 knockout mouse models as well, where reduced α5 subunit caused substantial behavioral effects910. Observations of the increased neuronal activity triggered by nicotine, supported by the increased basal frequency of PSCs and the predicted pathway changes revealed by RNAseq, leads us to conclude that the N398 variant produces neurons with increased responsiveness to nicotine followed by desensitization to subsequent exposure. This difference in response occurs at nicotine concentrations typical of heavy smokers (0.025–0.5 μM), potentially contributing to the increased risk of nicotine addiction50.
