Regulation of Monoamine Transporters in Tourette Syndrome

Grant Type
Grant Year
Institution Location
Institution Organization Name
Emory University
Investigators Name
Ciliax, Brian, PhD

The goal of this TSA-sponsored project is to determine whether the amount or distributions of transporter proteins for dopamine and serotonin are altered in postmortem brain tissue from Tourette Syndrome (TS) patients. These proteins include the plasma membrane transporters selective for dopamine (DAT) or serotonin (SERT), as well as the vesicular monoamine transporter (VMAT2), which is present in both dopamine and serotonin neurons. DAT and SERT directly regulate the levels of dopamine and serotonin available for neurotransmission by uptake of the neurotransmitters from the extracellular space into their respective cells. VMAT2 indirectly facilitates this process since it transports the monoamines from the intracellular compartment into vesicles and thereby maintains a high concentration gradient (i.e. driving force) across the plasma membrane. Thus, these transporter proteins act in concert to regulate the extracellular concentration of dopamine and serotonin. Several lines of evidence suggest that altered function of dopamine and serotonin circuits may underlie the symptoms of TS. For example, dopamine and serotonin metabolite levels are altered in TS. In addition, dopamine blockers reduce symptoms whereas dopamine stimulants worsen symptoms. Finally, DAT binding sites are increased in TS striatum. These findings have lead to the hypoth¬esis that TS symptoms are due to excess monoamine activity, which might be related to altered protein levels of monoamine transporters. Although striatal DAT binding sites increase in TS, changes in DAT protein levels have not been directly measured, nor have those of SERT or VMAT2. In addition, the regional distributions of such changes have not been determined. We hypothesize that protein levels of monoamine transporters are altered in TS and that these changes are regionally specific. To test these hypotheses, we will measure DAT, SERT and VMAT2 protein levels in TS brain tissue using antibodies that specifically recognize each transporter. Sampled areas will include brain stem regions containing dopamine and serotonin neurons and the areas to which these neurons project, specifically the striatum and nucleus accumbens. Furthermore, we will determine whether there are changes in the distribution of these transporter proteins in TS brain tissue sections. The tissue to be used for this study will come from those harvested through the TSA Brain Bank Program. Until this valuable program was established, these studies were not possible because pathological changes specific to TS cannot be verified with animal studies. This research should provide new insights into the dysfunctional regulation of monoaminergic neurotransmission that occurs in TS, and possibly lead to new treatments and prevention. Brian J. Ciliax, Ph.D., Gary W. Miller, Ph.D. Emory University School of Medicine Atlanta, GA Award: $37,700 Tourette Association of America Inc. – Research Grant Award 1997