Late direct and transneuronal effects in mice with targeted expression of a toxin gene to D1 dopamine receptor neurons

Detailed analysis of a novel transgenic model of basal,ganglia disease has been undertaken. In this model the expression of an attenuated form of the diphtheria toxin gene was tightly controlled by D1 dopamine receptor regula tory domains. The behavioral and both direct toxin-mediated and transneuron al effects observed in pups in the first postnatal week have been described . Although younger pups are bradykinetic, older pups have a hyperkinetic sy ndrome with gait abnormality, postural instability and myoclonic jerks typi cal of human basal ganglia diseases such as Huntington's disease. As expect ed, striatal D1 dopamine receptor, dynorphin and substance P transcripts we re not detected by in situ hybridization but there was a 27% increase in st riatal D2 dopamine receptor messenger RNA and a 65% increase in enkephalin messenger RNA expression. Receptor autoradiographic studies confirmed the l ack of D1-class binding in the mutant striatum and in contrast to young pup s, a substantial increase in striatal D2-class binding. Autoradiographic qu antitation also showed a 30% increase in striatal dopamine transporter bind ing. In addition to the changes described in the striatopallidal and nigros triatal pathways, up-regulated dynorphin and substance P messenger RNA expr ession was also seen in the cortex. The capacity of the developing brain for neurochemical adaptation following injury is dramatic. The results show that primary loss of D1 dopamine rece ptor-positive striatonigral pathway neurons is sufficient to generate a hyp erkinetic phenotype. (C) 1999 IBRO. Published by Elsevier Science Ltd.