期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：3
页码：893-898
DOI：10.1073/pnas.1419533112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceTic disorders, such as Tourette syndrome, are common but poorly understood. Postmortem studies have revealed the loss of a particular subset of neurons, the large cholinergic interneurons, in the caudate and putamen in severe disease. To test whether this neuronal loss leads to disease we turned to studies in mice, where questions of causality are more readily addressed. We developed a strategy for targeted ablation of these interneurons. Their disrupting in the dorsolateral striatum--roughly analogous to the putamen--produced abnormal tic-like movements after either acute stress or amphetamine treatment. This demonstrates, for the first time to our knowledge, that the loss of specific interneurons can cause behavioral changes in an animal model that resemble aspects of a movement disorder. Gilles de la Tourette syndrome (TS) is characterized by tics, which are transiently worsened by stress, acute administration of dopaminergic drugs, and by subtle deficits in motor coordination and sensorimotor gating. It represents the most severe end of a spectrum of tic disorders that, in aggregate, affect [~]5% of the population. Available treatments are frequently inadequate, and the pathophysiology is poorly understood. Postmortem studies have revealed a reduction in specific striatal interneurons, including the large cholinergic interneurons, in severe disease. We tested the hypothesis that this deficit is sufficient to produce aspects of the phenomenology of TS, using a strategy for targeted, specific cell ablation in mice. We achieved [~]50% ablation of the cholinergic interneurons of the striatum, recapitulating the deficit observed in patients postmortem, without any effect on GABAergic markers or on parvalbumin-expressing fast-spiking interneurons. Interneuron ablation in the dorsolateral striatum (DLS), corresponding roughly to the human putamen, led to tic-like stereotypies after either acute stress or D-amphetamine challenge; ablation in the dorsomedial striatum, in contrast, did not. DLS interneuron ablation also led to a deficit in coordination on the rotorod, but not to any abnormalities in prepulse inhibition, a measure of sensorimotor gating. These results support the causal sufficiency of cholinergic interneuron deficits in the DLS to produce some, but not all, of the characteristic symptoms of TS.
