Parkinson disease can be caused by loss of dapaminergic neurons in the substantia nigra. There are two major populations of neurons in the striatum that respond to dopamine. Their roles in movement disorders are the subjuct of ongoing research.
I previously mentioned the article “Distinct subclasses of medium spiny neurons differentially regulate striatal motor behaviors” which describes experiments in mice that test the current model of how the basal ganglia control movement.
In current models of motor control by the basal ganglia, a distinction is made between a population of type 2 dopamine receptor (D2R) expressing neurons and a population of D1R expressing neurons (see the figure, above right).
By using the gene expression control regions of the D2 and D1 receptors, Bateup et al. were able to selectively disrupt expression of DARPP-32 in either the D2R- or D1R-expressing striatal neurons of mice. DARPP-32 is an important protein for many of the normal actions of dopamine in the brain, including those in the striatum. When DARPP-32 levels were reduced selectively in the D2R-expressing striatal neurons, the mice showed increased locomotor activity. Reduced DARPP-32 in D1R-expressing striatal neurons resulted in reduced basal locomotor activity, consistent with the standard model in which the direct pathway normally exerts a stimulatory effect on locomotion.
Such “proof of concept” experiments in mice raise hope for future interventions that might allow selective modulation of the direct and indirect pathways in humans. This might help solve problems such as development of dyskinesias following long-term use of L-DOPA or cell transplant therapy in Parkinson disease patients.