A Transgenic Approach to Dopaminergic Neurophysiology

Grant Type
Grant Year
Institution Location
Institution Organization Name
University of Minnesota
Investigators Name
Burton, Frank, PhD

We are using synthetic genes as drugs to alter neuron activity. This emerging discipline, which we call “transgenic pharmacology” has the potential to create animal modelS of neurological disorders and to treat human disorders. The advantage of transgenic pharmacology over traditional pharmacology is that traditional drugs often cause side-effects because they act on more neuron subtypes than just those causing the disorder. In contrast, transgenes can be made to turn on only in desired neuron subtypes, and thus can be specific in their action. Our scientific goal is to understand how behavior is regulated by the different neuron subtypes that recognize the neurotransmitter dopamine. Functional errors in these neuron subtypes are suspected to cause varying disorders like Tourette Syndrome, obsessive-compulsive disorder, Parkinson’s and Huntington’s disease and schizophrenia. To achieve this goal, we created a novel transgene that can stimulate the physiological output of a cell. When combined with genetic material that turns the transgene on only within one subtype of dopamine-responsive neuron, we can stimulate neurotransmission more selectively than can be achieved using traditional drugs. The transgene works by increasing the amount of a molecule called cyclic AMP (cAMP) within the neuron. Cyclic AMP is one of the most basic chemicals in living cells, acting as a messenger that tells the cell to respond to signals coming from other cells or from the microenvironment. Preliminary studies indicate we can induce psychomotor disorders in mice by expressing this cAMP-elevating trans-gene either generally in all mature neurons, or more specifically in neurons carrying the D1 receptor — one of the five known receptors for dopamine. The latter mice exhibit psychostimulation, reminiscent of some aspects of Tourette Syndrome. We plan to further examine the different behavioral effects of expressing the cAMP-elevating trans-gene in these neuron subtypes, as well as in two other dopamine-responsive neuron subtypes that express the D2 and D5 dopamine receptors. These studies may help us understand how D1, D2 and D5 neurons differ in their function, and how different types of psychomotor disease in humans may involve separate parts of the dopaminergic system. What one type of transgene can activate, another type of transgene may be able to suppress. We hope to further investigate the potential of using cAMP-elevating and cAMP-depressing transgenes as one-time injectable drugs to permanently correct abnormal neuronal activity which likely underlies psychomotor diseases such as Tourette Syndrome. At the same time, the generation of mouse models for these disorders will allow us to test hypotheses about the cause or symptoms of these disorders in humans, as well as give us test subjects to evaluate the effectiveness of future pharmacological drugs. Frank H. Burton, Ph.D., Department of Pharmacology The University of Minnesota, Minneapolis, MN Award $25,000 Tourette Association of America Inc. – Research Grant Award 1994