ALTERED STRIATAL FUNCTION IN A MUTANT MOUSE LACKING D-1A DOPAMINE-RECEPTORS

Of the five known dopamine receptors, D-1A and D-2 represent the major subtypes expressed in the striatum of the adult brain. Within the str iatum, these two subtypes are differentially distributed in the two ma in neuronal populations that provide direct and indirect pathways betw een the striatum and the output nuclei of the basal ganglia. Movement disorders, including Parkinson disease and various dystonias, are thou ght to result from imbalanced activity in these pathways. Dopamine reg ulates movement through its differential effects on D-1A receptors exp ressed by direct output neurons and D-2 receptors expressed by indirec t output neurons. To further examine the interaction of D-1A and D-2 n euronal pathways in the striatum, we used homologous recombination to generate mutant mice lacking functional D-1A receptors (D-1A-/-) D-1a- /- mutants are growth retarded and die shortly after weaning age unles s their diet is supplemented with hydrated food. With such treatment t he mice gain weight and survive to adulthood. Neurologically, D-1A-/- mice exhibit normal coordination and locomotion, although they display a significant decrease in rearing behavior. Examination of the striat um revealed changes associated with the altered phenotype of these mut ants. D-1A receptor binding was absent in striatal sections from D-1A- /- mice. Striatal neurons normally expressing functional D-1A receptor s are formed and persist in adult homozygous mutants. Moreover, substa nce P mRNA, which is colocalized specifically in striatal neurons with D-1A receptors, is expressed at a reduced level. In contrast, levels of enkephalin mRNA, which is expressed in striatal neurons with D-2 re ceptors, are unaffected. These findings show that D-1A-/- mice exhibit selective functional alterations in the striatal neurons giving rise to the direct striatal output pathway.