Dopaminergic Transmission and Striatal Long Term Synaptic Depression

Grant Type
Grant Year
Institution Location
Institution Organization Name
Vanderbilt University
Investigators Name
Lovinger, David, PhD

A wealth of experimental evidence suggests that the brain region known as the striatum plays an important role in causing Tourette Syndrome (TS). Furthermore, there is some evidence pointing to a dysfunction of the neurotrans¬mitter dopamine. Pharmaceutical agents designed to alter the function of this neurotransmitter are used in the treatment of TS. Dopamine is known to be abundant in the striatum. However, the exact role of this neurotransmitter in regulating synaptic communication between nerve cells within the striatum is unclear. Our aim is to clarify the role of dopamine and the different receptor proteins that mediate dopamine actions in the striatum. Investigators have discovered that dopamine strongly interacts with another neurotransmitter (glutamate) within the striatum. The interaction of these two neurotransmitters is a key feature of the way in which nerve cells in the striatum coordinate the activity of the cerebral cortex and ultimately shape movements and other behaviors such as speech patterns. Recent experiments indicate that dopamine plays a critical role in reducing the level at which glutamate excites striatal nerve cells. This reduction of the glutamate’s actions, which is called Long Term Synaptic Depression, appears to be an important mechanism for setting proper levels of neural activity to ensure proper movement and other activities. In addition, our recent studies indicate that Long Term Synaptic Depression in the striatum may play a key role in the development of proper neural communication within the striatum in pre-adolescent to adolescent animals. This finding suggests that learning proper movement patterns may depend on the function of dopamine in the striatum. Too much dopamine-mediated synaptic communication in striatum may lead to unwanted movement and speech. As a part of this project we will examine the molecular mecha¬nisms by which dopamine regulates Long Term Synaptic Depression. We believe that dopamine works by regulating the concentration of the ion calcium within striatal nerve cells. Calcium is known to act as a “messenger molecule” inside cells that can set into motion other molecular signals that alter nerve cell function. Dopamine, acting through its protein receptors, may increase the amount of calcium that enters a striatal nerve cell, and this appears to be a necessary step in the generation of Long Term Synaptic Depression. We will examine the actions of dopamine by selectively activating dopamine-containing neurons and dopamine receptor proteins within the striatum. We will measure the effects of these treatments on levels of calcium in striatal nerve cells, and we will relate the changes in calcium concentration to the generation of Long Term Synaptic Depression. We hypothesize that our studies will show that dopamine actions that increase calcium levels in these nerve cells are a key step in the regulation of neuronal communication in the striatum. A better understanding of the consequences of dopamine actions in the striatum will greatly aid in the development of new therapies for the control and amelioration of Tourette Syndrome symptoms. These therapies could include specific drugs aimed at molecules important for the actions of dopamine or aimed at molecular targets that are acted upon by dopamine. David M. Lovinger, Ph.D. Vanderbilt University Medical School Nashville, TN Award: $37,445 Tourette Association of America Inc. – Research Grant Award 1997