Conditional ablation of striatal neuronal types containing dopamine D2 receptor disturbs coordination of basal ganglia function.
Dopamine (DA) exerts synaptic organization of basal ganglia circuitry through a variety of neuronal populations in the striatum. We performed conditional ablation of striatal neuronal types containing DA D2 receptor (D2R) by using immunotoxin-mediated cell targeting. Mutant mice were generated that express the human interleukin-2 receptor alpha-subunit under the control of the D2R gene. Intrastriatal immunotoxin treatment of the mutants eliminated the majority of the striatopallidal medium spiny neurons and cholinergic interneurons. The elimination of these neurons caused hyperactivity of spontaneous movement and reduced motor activation in response to DA stimulation. The elimination also induced upregulation of GAD gene expression in the globus pallidus (GP) and downregulation of cytochrome oxidase activity in the subthalamic nucleus (STN), whereas it attenuated DA-induced expression of the immediate-early genes (IEGs) in the striatonigral neurons. In addition, chemical lesion of cholinergic interneurons did not alter spontaneous movement but caused a moderate enhancement in DA-induced motor activation. This enhancement of the behavior was accompanied by an increase in the IEG expression in the striatonigral neurons. These data suggest that ablation of the striatopallidal neurons causes spontaneous hyperactivity through modulation of the GP and STN activity and that the ablation leads to the reduction in DA-induced behavior at least partly through attenuation of the striatonigral activity as opposed to the influence of cholinergic cell lesion. We propose a possible model in which the striatopallidal neurons dually regulate motor behavior dependent on the state of DA transmission through coordination of the basal ganglia circuitry.
Sano
Hiromi
H
Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan.
Yasoshima
Yasunobu
Y
Matsushita
Natsuki
N
Kaneko
Takeshi
T
Kohno
Kenji
K
Pastan
Ira
I
Kobayashi
Kazuto
K
D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D001480:Basal Ganglia Diseases / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D001667:Binding, Competitive / Q000235:genetics; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D015259:Dopamine Agents / Q000494:pharmacology; D004333:Drug Administration Routes; D015870:Gene Expression; D018390:Gene Targeting; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology; D053645:Interleukin-2 Receptor alpha Subunit; D008024:Ligands; D008694:Methamphetamine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics* / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics
D015259:Dopamine Agents; C508017:IL2RA protein, human; C508018:Il2ra protein, mouse; D000922:Immunotoxins; D053645:Interleukin-2 Receptor alpha Subunit; D008024:Ligands; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D018123:Receptors, Interleukin; D008694:Methamphetamine