Dissertation Defense Announcement
To:  The George Mason University Community

Candidate: Ramya Sundararajan
Program:    PhD Biosciences

Date:   Tuesday August 7, 2012
Time:   10:00 a.m.
Place:  George Mason University
           Bull Run Hall #248
           Prince William Campus
 
Dissertation Director/Committee Chair: Dr. Karl J. Fryxell
Committee members: Dr. Ancha Baranova, Dr. Daniel N. Cox, Dr. Pamela Greenwood

Title: "Effect of DBH, DRD2 and ADRA2A Gene Variants on Human Working Memory"

The dissertation is on reserve in the Johnson Center Library, Fairfax campus.
The doctoral project will not be read at the meeting, but should be read in advance.

All members of the George Mason University community are invited to attend.


ABSTRACT:

Study of the genetic basis of cognitive aging is a relatively new field. A few genes including those that encode catechol-O-methyltransferase (COMT), dopamine b-hydroxylase (DBH), brain-derived neurotrophic factor (BDNF), dopamine transporter (DAT), dopamine receptors D1 (DRD1), D2 (DRD2), D4 (DRD4) and alpha2A adrenergic receptor (ADRA2A) have been found to be associated with cognitive traits and/or complex diseases. Studies with the CHRNA4, CHRM2, DBH, BDNF and COMT gene variants in our laboratory have shown associations between gene variants and working memory accuracy and/or visuospatial attention in normal healthy adults. We hypothesized that variation in genes involved in the dopaminergic and noradrenergic systems affect working memory performance, particularly in older adults. We investigated the effects of the SNPs DBH rs1611115 (–1021C/T), DBH rs1108580 (444G/A), ADRA2A rs553668, DRD2 rs1800497 and Age on a spatial working memory task in healthy individuals. The genetic effects on working memory performance were modulated by Age in all the SNPs studied. DBH rs1108580 AG performed better than the two homozygotes and older adults benefitted from carrying the DBH rs1611115 T allele. The combination of alleles associated with low DBH enzyme activity (DBH rs1611115 TT + DBH rs1108580 AA), and hence more dopamine, were the best performers in match trials. Participants with the combined genotype of DBH rs1108580 AA+DRD2 rs1800497 CC had better accuracy. These findings lead us to conclude that the beneficial effect of lower DBH activity is due to increased release of dopamine that diffuses out of adrenergic synapses, binds to extracellular D2 receptors and enhances working memory functions. For the ADRA2A gene, participants with ADRA2A rs553668 T allele generally performed poorly. ADRA2A T+ had better performance only in the lowest load condition. The T+ allele might influence the ability to shift attention in older adults, causing a bigger drop in performance compared to young adults as load increased. Older adults with combined genotypes associated with lower noradrenaline and lower adrenoreceptors (DBH rs1108580 AA+ADRA2A rs553668 T-) or higher noradrenaline and higher adrenoreceptors (DBH rs1108580 GG+ADRA2A rs553668 T+) had better working memory performance. No interactions were found between ADRA2A rs553668 and DRD2 rs1800497 or DBH rs1611115. Our results suggest that both dopamine D2 and alpha 2A adrenergic signaling were beneficial for working memory. These results supported our hypothesis that variation in DBH, ADRA2A and DRD2 genes contribute to individual differences in working memory, and the genotypic effects were more pronounced in older adults than in young adults.

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