The Influence of the Interaction and Allelic Location of the C957T and SNP19 Polymorphisms of the Dopamine Receptor-2 Gene on Feedback-Based Learning
Anfal Ahmad Saleh Abu-Hilal
أنفال أحمد صالح أبو هلال
People vary in their cognitive performance. Multiple factors can perturb learning and forming associations. It has been shown that the neurotransmitter dopamine is an essential factor in modulating feedback-based learning. Dopamine exerts its effects via two families of postsynaptic receptors, type 1 and type 2. The release of dopamine is regulated by presynaptic dopamine type 2 receptors (DRD2). In this project, we pursued a multidisciplinary approach to examine the molecular and cognitive aspects of naturally-occurring variations in the dopamine system. We investigated feedback-based learning under the influence of two naturally occurring polymorphisms in the DRD2 gene, the C957T, which regulates binding affinity in postsynaptic DRD2 receptors; and SNP19, which modulates the number of presynaptic DRD2 autoreceptors. After using polymerase chain reaction (PCR), we utilized restriction fragment length polymorphism (RFLP) to identify the polymorphism variants. Further, we developed a PCR based technique to test whether the two polymorphisms are on the same allele or not. Our aim was two-fold: (1) to study the interaction between the C957T and SNP19 in modulating cognitive function, and (2) to investigate the cognitive effects of allelic location of C957T and SNP19 on cognitive performance. All heterozygotes for the two polymorphisms underwent amplification refractory mutation system (ARMS) PCR followed by ARMS to examine the allelic location of the two polymorphisms. We recruited a sample of 476 healthy undergraduate students at Al-Quds University, Palestine. All subjects completed a probabilistic categorical feedback-based learning task that differentiates learning from positive and negative feedback. Our results showed a gene dose effect, in which the T allele of C957T that is related to low expression of D2 postsynaptically is linked to the G allele of SNP19 that is related to high expression presynaptically. Also, we found that subjects with the lowest DRD2 postsynaptic affinity (CC-homozygotes for C957T) alongside the highest concentration of presynaptic DRD2 autoreceptors (GG- homozygotes for SNP-19) learned significantly better after receiving positive feedback or being in a potentially-positive state. These results are in line with previous findings that highlight the role of DRD2 in modulating tonic dopamine signaling. To our knowledge, this is the first project to examine the cognitive effects of the interaction of the C957T and SNP19 polymorphisms and their allelic locations. These results will further our understanding of the dopaminergic system and its regulation of cognition and involvement in a myriad of neurological and psychiatric disorders.