Transcriptome Analysis of the Human Striatum in Tourette Syndrome

Lennington, Jessica B.; Coppola, Gianfilippo; Kataoka‐Sasaki, Yuko; Fernandez, Thomas; Palejev, Dean; Li, Yifan; Hüttner, Anita; Pletikos, Mihovil; Šestan, Nenad; Leckman, James F.; Vaccarino, Flora M.

doi:10.1016/j.biopsych.2014.07.018

Cited by 175 publications

(207 citation statements)

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“…Postmortem studies show a reduction in ChAT-expressing striatal interneurons in the caudate and putamen in individuals with severe, refractory disease (26,27). However, such correlational findings cannot elucidate the causal role of this cellular deficit: whether it is pathogenic, compensatory, epiphenomenomenal, or a marker of a more complex developmental disruption.…”

Section: Discussionmentioning

confidence: 98%

“…The ChAT interneurons may fail to develop or differentiate properly, fail to migrate to the striatum during development, migrate but die without integrating properly into the striatal circuitry, or develop and integrate normally but die (or dedifferentiate) at a later time. Inflammatory damage to them is an interesting possibility, given recent evidence for an elevated inflammatory state in the TS striatum (27,53), but this remains speculative. The development of preventative or disease-modifying therapeutics targeting the cholinergic deficit will be facilitated by clarification of its etiology.…”

Section: Discussionmentioning

confidence: 99%

“…Recent postmortem work has revealed that specific interneuron populations are abnormal in patients with severe, refractory TS (25)(26)(27). Cholinergic interneurons, identified by their expression of choline acetyltransferase (ChAT), are critical regulators of striatal function, although they constitute only about 1% of all neurons in the striatum (24).…”

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confidence: 99%

“…Cholinergic interneurons, identified by their expression of choline acetyltransferase (ChAT), are critical regulators of striatal function, although they constitute only about 1% of all neurons in the striatum (24). They are reduced by ∼50% throughout the dorsal striatum in TS (26,27). Abnormalities in ChAT interneurons in the ventral striatum have been reported in schizophrenia (28), but deficits in the dorsal striatum (the caudate and putamen) have only been described in TS (26).…”

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confidence: 99%

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Targeted ablation of cholinergic interneurons in the dorsolateral striatum produces behavioral manifestations of Tourette syndrome

Xu¹,

Kobets²,

Du³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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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 parvalbuminexpressing 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.Tourette sydrome | basal ganglia | interneurons | acetylcholine | animal models

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Targeted ablation of cholinergic interneurons in the dorsolateral striatum produces behavioral manifestations of Tourette syndrome

Xu¹,

Kobets²,

Du³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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148

175

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“…However, one important area that is largely missing concerns the findings from post-mortem studies of the brains of individuals with TS that have been conducted by Flora Vaccarino and her laboratory at Yale University. The most notable and highly-cited article from 2016 presents an analysis of the transcriptome of striatal tissue (caudate and putamen) from the brains of nine TS and nine matched normal control subjects (Lennington et al, 2016 1 ). The authors found 309 down-regulated and 822 up-regulated genes using a data-driven gene network analysis.…”

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confidence: 99%

Tourette syndrome research highlights from 2016

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2017

F1000Res

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Prenatal and Perinatal Risk Factors and the Promise of Birth Cohort Studies

Fernandez

Leckman

2016

JAMA Psychiatry

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Obsessive-compulsive disorder (OCD) is a developmental neuropsychiatric illness with onset typically occurring during adolescence or young adulthood. The disorder can cause substantial lifelong disability due to its severe and chronic course. As with most complex neuropsychiatric disorders, the causes and pathophysiologic mechanisms underlying OCD are not well understood. This lack of understanding limits our ability to discover new treatments and interventions that will alleviate the symptoms for the millions of people worldwide with this disorder. It is clear that there is a genetic contribution to OCD risk, with modern estimates of heritability in the range of 40% to 50%. 1 Although less frequently studied, environmental risk factors (eg, infection and trauma) have also been suggested in OCD, although causal associations are less certain. There is great hope that continued study of genetic, epigenetic, and environmental susceptibility in OCD will provide needed insights into disease mechanisms and risk factors that can be leveraged for prevention and intervention.In this issue of JAMA Psychiatry, Brander et al 2 present data from Swedish national registers to prospectively investigate several perinatal risk factors that might be associated with the subsequent development of OCD. A great strength of this study, aside from the power afforded by such a sizable cohort, is the use of within-family controls (full siblings, raised in the same family, who had a different exposure to the potential risk factor) to mitigate the effect of unmeasured environmental and genetic confounders, which would presumably be shared by siblings. This study represents a significant advancement in the field of OCD research by identifying several factors that are associated with increased disease risk after correcting for unmeasured confounders and measured covariates. These risk factors include maternal smoking of 10 or more cigarettes per day during pregnancy, cesarean section delivery, preterm birth, low birth weight, large for gestational age, breech presentation at labor, and low Apgar scores at 5 minutes after delivery. Furthermore, preterm and low birth weight associations showed dose-response associations, supporting OCD causality. As might be expected, OCD risk also rose as the number of these perinatal events increased. Indeed, the authors 2 found that fully 46.6% of all identified OCD cases had at least 1 of these risk factors (Table 4 in the article); this is a finding of clear public health significance.Judging by the effect sizes reported in the present study (hazard ratios, 1.1-1.5), 2 the effects reported for common ge-

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Transcriptome Analysis of the Human Striatum in Tourette Syndrome

Cited by 175 publications

References 69 publications

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

Tourette syndrome research highlights from 2016

Prenatal and Perinatal Risk Factors and the Promise of Birth Cohort Studies

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