Allelic Variation of Calsyntenin 2 (CLSTN2) Modulates the Impact of Developmental Tobacco Smoke Exposure on Mnemonic Processing in Adolescents

Background: Exposure to nicotine in tobacco smoke during development has been linked to subsequent deficits inattention and memory. The present study tested for evidence that genetic variation may contribute to individual differences in vulnerability to the effects of developmental exposure to tobacco smoke on memory and medial temporal lobe function in adolescents. Methods: Verbal and visuospatial memory were assessed and functional magnetic resonance imaging (fMRI) data were acquired in 101 adolescents systematically characterized for prenatal and adolescent exposure to tobacco smoke, while they performed an encoding and recognition memory task. The impact of allelic variation at loci within CLSTN2 (encoding synaptic protein calsyntenin 2) and KIBRA, shown previously to modulate early and delayed recall of words, on the dependent measures was examined. Results: KIBRA genotype did not exert significant main or interacting effects with prenatal or adolescent exposure to tobacco smoke on verbal or visuospatial memory. Previous observations of a beneficial effect of the CLSTN2 C allele on verbal recall were replicated. Adolescent exposure to tobacco smoke reversed this beneficial effect and was associated with increased activation of parahippocampal gyrus during early and delayed recognition in CLTSN2 C allele carriers. While the CLSTN2 C allele conferred enhanced functional connectivity between brain regions subserving accurate verbal recognition, adolescent exposure to tobacco smoke reversed this effect. Conclusions: These findings extend previous work demonstrating that calsyntenins play an essential role in learning and indicate that this role is modulated both by CLSTN2 genotype and, during adolescent development, by exposure to tobacco smoke.