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 
<http://www.gmu.edu/resources/welcome/Directions-to-GMU.html>
 
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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