Roxanne A. Vaughan, Ph.D., Professor
Project: Dopamine Transporter Regulation
Mentor: Roxanne A. Vaughan, Ph.D., Professor
Location: Department of Biomedical Sciences, School of Medicine & Health Sciences
Description: The dopamine transporter (DAT) is a synaptic protein that drives reuptake of dopamine (DA) from the synapse into the presynaptic neuron, and is the major mechanism for regulation of DA neurotransmission. The activity of DAT is highly regulated by post-translational modifications including phosphorylation and the lipid modification palmitoylation that serve to coordinate the clearance of DA with physiological needs. Several mood and psychiatric disorders including attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and schizophrenia (SCZ) are associated with elevated levels of DA that could result from dysregulated uptake, but the mechanisms have not been elucidated. Our lab previously showed that the palmitoylation enzyme DHHC8 enhances palmitoylation of DAT, which leads to enhance DA uptake velocity, which would be predicted to result in more rapid clearance of DA and lower transmitter levels in the brain. In this study, we will examine the potential dysregulation of DAT palmitoylation and transport in the brain using a mouse model of schizophrenia. Transgenic mice were generated to contain a chromosomal deletion that mimics the human disorder 22q11.2 Deletion Syndrome, also called DiGeorge Syndrome, which causes a spectrum of serious abnormalities and in is strongly associated with development of SCZ. One of the genes lost in this microdeletion is DHHC8, and we hypothesize that the loss of this enzyme results in reduced levels of DAT palmitoylation and corresponding reductions in DA reuptake. If this occurs, the dysregulated reuptake could result in hyperdopaminergia that might underlie some elements of the SCZ phenotype. Our research project will be to assist in characterizing various aspects of DAT in these mice, including assessment of DAT palmitoylation, total DAT expression, and analysis of DA transport function. The results will indicate if these DAT functions are impacted in this mouse model and may be mechanistically connected to a hyperdopaminergic phenotype. This project is suitable for execution by an undergraduate student as all assay procedures are well characterized feasible, and the questions to be answered are scientifically important. The study will introduce a student to many pharmacological principles related to DAT and dopaminergic disorders, as well as to basic scientific principles in experimental methodology.
