Altered Striatal Function in a Mutant Mouse Lacking D1ADopamine Receptors

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 91; no. 26; pp. 12564 - 12568
• Main Authors: Drago, John, Gerfen, Charles R., Lachowicz, Jean E., Steiner, Heinz, Hollon, Tom R., Love, Paul E., Ooi, Guck T., Grinberg, Alexander, Lee, Eric J., Huang, Sing Ping, Bartlett, Perry F., Jose, Pedro A., Sibley, David R., Westphal, Heiner
• Format: Journal Article
• Language: English
• Published: National Academy of the Sciences of the United States of America 20.12.1994
• Subjects: Alleles; Brain; DNA probes; Dopamine receptors; Genomics; Locomotion; Messenger RNA; Mice; Neurons; Receptors
• ISSN: 0027-8424; 1091-6490

Of the five known dopamine receptors, D1Aand D2represent the major subtypes expressed in the striatum of the adult brain. Within the striatum, these two subtypes are differentially distributed in the two main neuronal populations that provide direct and indirect pathways between the striatum and the output nuclei of the basal ganglia. Movement disorders, including Parkinson disease and various dystonias, are thought to result from imbalanced activity in these pathways. Dopamine regulates movement through its differential effects on D1Areceptors expressed by direct output neurons and D2receptors expressed by indirect output neurons. To further examine the interaction of D1Aand D2neuronal pathways in the striatum, we used homologous recombination to generate mutant mice lacking functional D1Areceptors (D1A-/-). D1A-/- mutants are growth retarded and die shortly after weaning age unless their diet is supplemented with hydrated food. With such treatment the mice gain weight and survive to adulthood. Neurologically, D1A-/- mice exhibit normal coordination and locomotion, although they display a significant decrease in rearing behavior. Examination of the striatum revealed changes associated with the altered phenotype of these mutants. D1Areceptor binding was absent in striatal sections from D1A-/- mice. Striatal neurons normally expressing functional D1Areceptors are formed and persist in adult homozygous mutants. Moreover, substance P mRNA, which is colocalized specifically in striatal neurons with D1Areceptors, is expressed at a reduced level. In contrast, levels of enkephalin mRNA, which is expressed in striatal neurons with D2receptors, are unaffected. These findings show that D1A-/- mice exhibit selective functional alterations in the striatal neurons giving rise to the direct striatal output pathway.