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The Journal of Neuroscience, October 8, 2003, 23(27):9078-9088

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Behavioral/Systems/Cognitive
Conditional Ablation of Striatal Neuronal Types Containing Dopamine D2 Receptor Disturbs Coordination of Basal Ganglia Function

Hiromi Sano,^1,2 Yasunobu Yasoshima,¹ Natsuki Matsushita,¹ Takeshi Kaneko,³ Kenji Kohno,² Ira Pastan,⁴ and Kazuto Kobayashi¹

¹Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan, ²Research and Education Center for Genetic Information, Nara Institute of Science and Technology, Ikoma 630-0101, Japan, ³Department of Morphological Brain Science, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan, and ⁴Laboratory of Molecular Biology, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892

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 -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.

Key words: motor control; dopamine; dopamine D2 receptor; striatum; medium spiny neuron; immunotoxin-mediated cell targeting

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Received July 7, 2003; revised August 15, 2003; accepted August 15, 2003.

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