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Targeted Ablation of Cholinergic Interneurons in the Dorsolateral Striatum Produces Behavioral Manifestations of Tourette Syndrome

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Targeted Ablation of Cholinergic Interneurons in the Dorsolateral Striatum Produces Behavioral Manifestations of Tourette Syndrome Targeted ablation of cholinergic interneurons in the dorsolateral striatum produces behavioral manifestations of Tourette syndrome Meiyu Xua, Andrew Kobetsa,1, Jung-Chieh Dua,2, Jessica Lenningtonb, Lina Lia, Mounira Banasra, Ronald S. Dumana,c,d, Flora M. Vaccarinob,d,e, Ralph J. DiLeonea,d,e, and Christopher Pittengera,b,d,f,3 Departments of aPsychiatry, cPharmacology, eNeurobiology, fPsychology, and the bChild Study Center and dInterdepartmental Neuroscience Program, Yale University, New Haven, CT 06519 Edited by Floyd Bloom, The Scripps Research Institute, La Jolla, CA, and approved December 15, 2014 (received for review October 10, 2014) Gilles de la Tourette syndrome (TS) is characterized by tics, which with TS, whereas abnormalities in medial networks correlated are transiently worsened by stress, acute administration of dopa- instead with comorbid obsessive-compulsive symptoms (23). minergic drugs, and by subtle deficits in motor coordination and The principal cells of the striatum, the GABAergic medium sensorimotor gating. It represents the most severe end of a spectrum spiny neurons (MSNs), are modulated by several types of in- of tic disorders that, in aggregate, affect ∼5% of the population. terneuron (24). Recent postmortem work has revealed that spe- Available treatments are frequently inadequate, and the patho- cific interneuron populations are abnormal in patients with severe, physiology is poorly understood. Postmortem studies have revealed refractory TS (25–27). Cholinergic interneurons, identified by a reduction in specific striatal interneurons, including the large cho- their expression of choline acetyltransferase (ChAT), are critical linergic interneurons, in severe disease. We tested the hypothesis regulators of striatal function, although they constitute only about that this deficit is sufficient to produce aspects of the phenomenol- 1% of all neurons in the striatum (24). They are reduced by ∼50% ogy of TS, using a strategy for targeted, specific cell ablation in mice. throughout the dorsal striatum in TS (26, 27). Abnormalities in ∼ We achieved 50% ablation of the cholinergic interneurons of the ChAT interneurons in the ventral striatum have been reported in striatum, recapitulating the deficit observed in patients postmor- schizophrenia (28), but deficits in the dorsal striatum (the caudate NEUROSCIENCE tem, without any effect on GABAergic markers or on parvalbumin- and putamen) have only been described in TS (26). expressing fast-spiking interneurons. Interneuron ablation in However, the relationship of this interneuronal deficit to the the dorsolateral striatum (DLS), corresponding roughly to the etiopathophysiology of TS remains unclear. One possibility is that human putamen, led to tic-like stereotypies after either acute stress this deficit is causally related to symptoms; ChAT interneuron or D-amphetamine challenge; ablation in the dorsomedial striatum, abnormalities in different striatal subregions may have dissociable in contrast, did not. DLS interneuron ablation also led to a deficit in contributions to symptomatology. Alternative possibilities include coordination on the rotorod, but not to any abnormalities in prepulse that the ChAT deficit observed in postmortem tissue is a com- inhibition, a measure of sensorimotor gating. These results support the causal sufficiency of cholinergic interneuron deficits in the DLS to pensation for the primary pathology, a consequence of treatment, produce some, but not all, of the characteristic symptoms of TS. or an epiphenomenon of no relevance to symptomatology. Fi- nally, the ChAT interneuron deficit may be pathophysiologically Tourette sydrome | basal ganglia | interneurons | acetylcholine | animal models Significance illes de la Tourette syndrome (TS) represents the most se- Tic disorders, such as Tourette syndrome, are common but Gvere end of a spectrum of tic disorders that, in aggregate, poorly understood. Postmortem studies have revealed the loss affect 5% of the population and produce substantial morbidity of a particular subset of neurons, the large cholinergic inter- (1). Existing treatments are of limited efficacy in severe disease neurons, in the caudate and putamen in severe disease. To test (2). The defining symptoms of TS are motor and phonic tics, whether this neuronal loss leads to disease we turned to defined as sudden, repetitive, nonrhythmic, involuntary or studies in mice, where questions of causality are more readily semiinvoluntary movements or utterances that involve discrete addressed. We developed a strategy for targeted ablation of muscle groups. Tics fluctuate and are exacerbated by stress (3– these interneurons. Their disrupting in the dorsolateral striatum— 5) and by acute challenge with prodopaminergic drugs (6). roughly analogous to the putamen—produced abnormal tic-like Individuals with TS also often have deficits in fine motor control movements after either acute stress or amphetamine treatment. (7, 8), procedural learning (9), and sensorimotor gating (10, 11). This demonstrates, for the first time to our knowledge, that the Convergent evidence implicates the corticobasal ganglia cir- loss of specific interneurons can cause behavioral changes in an cuitry in the pathophysiology of TS, although details remain animal model that resemble aspects of a movement disorder. poorly understood (12, 13). The input nucleus of the basal gan- glia, the striatum, receives glutamatergic projections from the Author contributions: M.X., M.B., R.S.D., F.M.V., R.J.D., and C.P. designed research; M.X., A.K., J.-C.D., J.L., L.L., M.B., and C.P. performed research; R.J.D. contributed new reagents/ cortex and thalamus. The striatum is reduced in volume in indi- analytic tools; M.X., J.L., and C.P. analyzed data; and M.X., R.S.D., F.M.V., R.J.D., and C.P. viduals with TS (12–14), and this reduction predicts the severity wrote the paper. and the persistence of symptoms (15). Whereas the cellular ar- The authors declare no conflict of interest. chitecture of the dorsal striatum is fairly uniform throughout its This article is a PNAS Direct Submission. – medial lateral extent, the topographic organization of cortical 1Present address: Department of Neurosurgery, Montefiore Hospital, New York, NY 10467. afferents leads to functional segregation among subregions (16– 2Present address: Department of Pediatrics, Tapei City Hospital, Zhongxiao Branch, Taipei 19). The dorsolateral striatum (DLS), which corresponds roughly 115, Taiwan; and Graduate Institute of Pharmacology, College of Medicine, National to the human putamen, has been associated with sensorimotor Taiwan University, Taipei 100, Taiwan. habits (20) and with tic-like stereotypies in rodents (21, 22). 3To whom correspondence should be addressed. Email: [email protected]. Functional neuroimaging has correlated abnormalities in these This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. lateral corticostriatal networks with tic characteristics in patients 1073/pnas.1419533112/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1419533112 PNAS Early Edition | 1of6 Downloaded by guest on October 2, 2021 important, but it may manifest only in the context of other pa- Methods), were injected into the dorsal striatum of ChAT-cre thology, such as the deficit in parvalbumin-expressing interneur- transgenic mice (www.jax.org: 006410); mice were euthanized ons that has also been documented in postmortem tissue (25, 26), 2 wk later. EGFP expression was seen throughout the striatum, or only through its secondary effects on the functions of striatal confirming the spread of the rh10 viral serotype and the utility of circuits during development. Such questions cannot readily be eGFP as a marker of viral infection. FLAG immunoreactivity addressed by observational studies in patients. was seen only in cells also immunoreactive for ChAT (Fig. 2A). Therefore, to test the hypothesis that ChAT interneuron dis- No FLAG immunoreactivity was ever seen after C06 injection ruption in the dorsal striatum is sufficient to produce tic-like (Fig. 2B) or when either virus was injected into wild-type mice. phenomenology, we turned to a mouse model. We found an To test interneuron ablation, we injected A06 virus into the immunotoxin that has been used previously to target striatal dorsal striatum on one side and C06 into the contralateral dorsal ChAT interneurons (29–32) to produce nonspecific effects (Fig. striatum in ChAT-cre transgenic mice. Two weeks later, mice S1). We therefore developed an approach to induce targeted, were injected i.p. with either DT (15 μg/kg body weight) or sa- regulated ablation of ChAT interneurons in mice. We antici- line. One week after DT injection, ChAT immunoreactive cells pated that interneuronal abnormalities in different parts of the were reduced on the A06-infected side relative to the C06 in- C circuitry might contribute differentially to the TS phenotype. We fected side (Fig. 2 ), confirming interneuron ablation. The im- targeted the ChAT interneurons of the DLS and dorsomedial age shown here is taken from the center of the virus-infused striatum (DMS) in separate experiments, achieving a ∼50% re- area, where viral infection was highest and ablation was greatest; ∼ duction, which recapitulates the degree of abnormality found we achieved 50% reduction of the density of ChAT-expressing interneurons in the dorsal striatum more broadly (see below, Fig. postmortem (26). We tested the effect of this targeted ablation B E on behavioral
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