Genetic Association Study of Spatial Working Memory

GENETIC ASSOCIATION STUDY OF SPATIAL WORKING MEMORY Mingkuan Lin, Ph.D. George Mason University, 2009 Dissertation Director: Dr. Karl J. Fryxell Working memory (WM) is a collection of cognitive pr ocesses that include short term storage of task related information and manipu lation of this information to facilitate the transformation of memory to action immediately. Age-related declines in WM performance have been attributed to dysfunction in dopamine and cholinergic neurotransmission. In this study, we applied a gene tic approach to investigate how normal variation in genes controlling monoamine expression in PFC is linked to age-related decline in working memory. One well-studied source of genetic variation in dop amine neurotransmission occurs in the gene controlling the enzyme CatecholO-Methyltransferase (COMT). A well-studied 158 G/A polymorphism in the COMT gene (rs4680) is non-synonymous and results in a valine-to-methionine substitution. The m thionine variant is associated with a 3-4 fold lower level of enzyme activity, compared t o its valine counterpart. We analyzed two measures of performance (accuracy and reaction time measures) in terms of the influence of two biological parameters (age and COM T genotype) and two spatial WM parameters (distance between the target and the pro be d t, and memory load). For accuracy measures, a significant interaction of mem ory load x COMT x age in the “Match” task conditions was observed. For accuracy measures, we showed a significant memory load x COMT x age interaction in “match” tas k conditions and the age effect was most prominent in “non-match” short distance ta sk conditions. For reaction time measures, the older val/val homozygotes showed long er reaction times than the met/met and val/met subjects. Taken together, our results s pport the idea that different levels of COMT enzyme activity may be optimal for different t asks and heritability of COMT becomes increasingly important in cognitive perform ance with advancing age. The muscarinic cholinergic M2 receptor (CHRM2) belo ngs to the superfamily of Gprotein coupled receptors, whose roles include m odulation of cholinergic transmission, neuronal excitability, synaptic plasticity and feed back regulation of acetylcholine release. The CHRM2 A1890T polymorphism (rs8191992) which loc ated in the 3’ untranslated region has been repeatedly reported to be correlate d to intelligence quotient (IQ). In this study, we also analyzed two measures of performance (a curacy and reaction time measures) in terms of the influence of two biologic al parameters (age and CHRM2 genotype) and two spatial WM parameters (distance b etween the target and the probe dot, and memory load). For the accuracy measures, we sho wed a significant memory load x CHRM2 x age interaction in the match task condition s. This interaction showed improved accuracies for CHRM2 AT heterozygotes in high memor y loads. For reaction time measures, a significant CHRM2 x age interaction was also observed. This interaction showed that the young AA homozygotes used shorter r eaction times than the young AT heterozygotes and the TT homozygotes, while the old r AA homozygotes used longer reaction times than the older AT heterozygotes and the TT homozygotes. The CHRM2 A1890T polymorphism also showed increased effects i n non-match task conditions for older adults. Taken together, our results support t he idea that the CHRM2 A1890T polymorphism associated with the performance of spa tial working memory at different ages. The increased genetic effects were observed i n ol er adults. In this study, we showed the influence of normal ge ne variability on working memory. We also showed the increased gene effects i n older adults. However, the cellular mechanism of how did these polymorphisms effect the neuronal activity is still not clear. Muscarinic neurotransmission has been implicated to play an important role in learning, attention and in Alzheimer’s disease. Thus, further research is needed in this area. Cellular and molecular studies of rs8191992 may hel p to elucidate the molecular mechanism of this SNP.