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 regulatory domains. The behavioral and both direct toxin-mediated and transneuronal effects observed in pups in the first postnatal week have been described. Although younger pups are bradykinetic, older pups have a hyperkinetic syndrome with gait abnormality, postural instability and myoclonic jerks typical of human basal ganglia diseases such as Huntington's disease. As expected, striatal D1 dopamine receptor, dynorphin and substance P transcripts were not detected by in situ hybridization but there was a 27% increase in striatal D2 dopamine receptor messenger RNA and a 65% increase in enkephalin messenger RNA expression. Receptor autoradiographic studies confirmed the lack of D1-class binding in the mutant striatum and in contrast to young pups, a substantial increase in striatal D2-class binding. Autoradiographic quantitation also showed a 30% increase in striatal dopamine transporter binding. In addition to the changes described in the striatopallidal and nigrostriatal pathways, up-regulated dynorphin and substance P messenger RNA expression 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 receptor-positive striatonigral pathway neurons is sufficient to generate a hyperkinetic phenotype.
Wong
J Y
JY
Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.
Padungchaichot
P
P
Massalas
J S
JS
Drago
J
J
D000818:Animals; D000831:Animals, Newborn; D001345:Autoradiography; D002352:Carrier Proteins / Q000378:metabolism; D004167:Diphtheria Toxin / Q000235:genetics*; D050483:Dopamine Plasma Membrane Transport Proteins; D004399:Dynorphins / Q000235:genetics; D004745:Enkephalins / Q000235:genetics; D015870:Gene Expression; D018390:Gene Targeting; D019868:Kanamycin Kinase / Q000235:genetics; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D009043:Motor Activity / Q000502:physiology; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000235:genetics; D011976:Receptors, Muscarinic / Q000378:metabolism; D013373:Substance P / Q000235:genetics
D002352:Carrier Proteins; D004167:Diphtheria Toxin; D050483:Dopamine Plasma Membrane Transport Proteins; D004745:Enkephalins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D011976:Receptors, Muscarinic; D013373:Substance P; D004399:Dynorphins; D019868:Kanamycin Kinase