The research in our lab revolves around the question of how neuromodulators shape the excitability of basal ganglia neurons. The basal ganglia is a richly interconnected set of nuclei that regulate motor and cognitive behaviors. Disorders in basal ganglia function underlie a wide variety of psychomotor disorders including Parkinson's disease, dystonia, Huntington's disease, schizophrenia and Tourette's syndrome. In many of these diseases, the principal defect appears to involves an alteration in dopaminergic signaling. For example, the symptoms of Parkinson's disease are a consequence of the death of dopaminergic neurons that innervate one of the basal ganglia nuclei, the striatum.

One of our major goals has been to determine how dopamine modulates the excitability of striatal neurons. Unlike classical neurotransmitters, neuromodulators like dopamine influence neuronal activity by altering the properties of voltage-dependent and ligand-gated membrane channels. This is accomplished by G-protein coupled receptors that activate intracellular signaling cascades targeting ion channels. There are several obstacles to the characterization of these pathways and their cellular consequences. One is the tremendous molecular heterogeneity of participating proteins. Another is the difficulty in gaining a quantitative description of changes in channel behavior. To overcome these obstacles, we use a combination of electrophysiological, biochemical and molecular strategies. Patch-clamp techniques are used to quantitatively characterize the impact of receptor activation on ion channels. Biochemical techniques are used to identify the enzymes and signaling molecules linking receptor and channel. Molecular techniques, such as single cell mRNA amplification, are used to 'fingerprint' neurons subjected to electrophysiological and biochemical analyses. These single cell mRNA profiles allow us not only to determine the molecular identity of elements in a particular signaling cascade but also to determine the broader functional class to which a studied neuron belongs. The combination of these techniques has enabled us to make great strides in understanding the impact of neuromodulators, like dopamine, on basal ganglia function and, hopefully, will lead to new therapeutic strategies for basal ganglia disorders.