Conditional Ablation of Striatal Neuronal Types Containing Dopamine D2 Receptor Disturbs Coordination of Basal Ganglia Function

Abstract

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.

Genetic Engineering of Glomerular Sclerosis in the Mouse via Control of Onset and Severity of Podocyte-Specific Injury

“…This is contrasting to the phenomenon in other transgenic mice with the LMB2-mediated cell ablation system. In those mice, LMB2 injured only the target neuronal cells that expressed hCD25 but never the adjacent cells that did not express hCD25 (21)(22)(23)(24).…”

“…In addition, LMB2 showed a major clinical response in patients with CD25-expressing malignancies in a phase I trial (20). Because of highly potent and selective cytotoxic activity, LMB2 has also been used to ablate specific cell types in transgenic mice that express hCD25 in the target cells (21)(22)(23)(24). This technology is termed immunotoxin-mediated cell targeting (21).…”

Cellular and Behavioral Outcomes of Dorsal Striatonigral Neuron Ablation: New Insights into Striatal Functions

“…Differences in the psychostimulant used or the area of the striatum targeted is unlikely to account for such a discrepancy, suggesting that our phenotype might not be the direct consequence of striatonigral damage. Interestingly, an increased sensitivity to acute cocaine has been reported after elimination of cholinergic cells in the dorsal striatum or the nucleus accumbens (Hikida et al, 2001;Sano et al, 2003), suggesting that the loss of striatal cholinergic interneurons rather than ablation of striatonigral MSNs might be responsible for the potentiation of cocaineinduced locomotor response.…”

Do Preclinical Findings of Methamphetamine-Induced Motor Abnormalities Translate to an Observable Clinical Phenotype?

“…These results implicate the indirect striatopallidal pathway because of the colocalization of enkephalin (via the mu receptor) and GABA. MA-induced locomotor hyperactivity and stereotypy require normal D2 receptor function (Sano et al, 2003;Glickstein and Schmauss, 2004). This observation suggests that MA-related hyperkinesia may be less pronounced in aged compared with younger animals.…”