Decreased number of parvalbumin and cholinergic interneurons in the striatum of individuals with Tourette syndrome

Kataoka, Yuko; Kalanithi, Paul; Grantz, Heidi; Schwartz, Michael L.; Saper, Clifford B.; Leckman, James F.; Vaccarino, Flora M.

doi:10.1002/cne.22206

Cited by 420 publications

(380 citation statements)

References 62 publications

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“…important, but it may manifest only in the context of other pathology, such as the deficit in parvalbumin-expressing interneurons that has also been documented in postmortem tissue (25,26), or only through its secondary effects on the functions of striatal circuits during development. Such questions cannot readily be addressed by observational studies in patients.…”

Section: Significancementioning

confidence: 99%

“…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).…”

mentioning

confidence: 98%

“…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).…”

mentioning

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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164

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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: Significancementioning

confidence: 99%

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confidence: 98%

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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.

Self Cite

145

164

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“…Only a small number of postmortem TS brains have been examined pathologically. Two postmortem brain studies revealed a decrease in parvalbumin positive GABA neurons and cholinergic neurons in the striatum [6,7]. Further support for a disturbance of GABA neurotransmission comes from a recent positron emission tomography study that found abnormal binding of GABA A receptor binding in patients with TS compared to normal controls [8].…”

Section: Pathogenesismentioning

confidence: 99%

Treatment of Tourette Syndrome

Kurlan

2014

Neurotherapeutics

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Tourette's syndrome (TS) consists of chronic motor and phonic tics and characteristically begins in childhood. The tics can be disabling and commonly associated behavioral comorbities such as attention deficit hyperactivity disorder (ADHD) and obsessivecompulsive disorder (OCD), can also cause problems in daily functioning. The underlying etiology and neurobiology of TS remain unknown although genetic factors appear to be important, cortical control of basal ganglia motor function appears to be disturbed and neurochemical abnormalities, particularly involving dopamine neurotransmission, are likely present. The treatment of TS involves appropriate education and support. Tics can be treated with habit reversal cognitive behavioral therapy, medications (most commonly alpha agonists and antipsychotics), local intramuscular injections of botulinum toxin and some severe, refractory cases have responded to deep brain stimulation surgery (DBS). It is important to appropriately diagnose and treat comorbid behavioral disorders that are disrupting function. OCD can be treated with cognitive behavioral therapy, selective serotonin reuptake inhibitors, and atypical antipsychotics. DBS has become a treatment option for patients with disabling OCD despite other therapies. ADHD is treated with appropriate classroom accommodations, behavioral therapy, alpha agonists, atomoxetine or methylphenidate-containing stimulant drugs.

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Deep brain stimulation for Tourette's syndrome

Wang,

Zhang,

Wang

et al. 2024

Cochrane Database of Systematic Reviews

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Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder characterized by the presence of multiple motor and vocal tics. TS usually co-occurs with one or multiple psychiatric disorders. Although behavioral and pharmacological treatments for TS are available, some patients do not respond to the available treatments. For these patients, TS is a severe, chronic, and disabling disorder. In recent years, deep brain stimulation (DBS) of basal ganglia-thalamocortical networks has emerged as a promising intervention for refractory TS with or without psychiatric comorbidities. Three major challenges need to be addressed to move the field of DBS treatment for TS forward: (1) patient and DBS target selection, (2) ethical concerns with treating pediatric patients, and (3) DBS treatment optimization and improvement of individual patient outcomes (motor and phonic tics, as well as functioning and quality of life). The Tourette Association of America and the American Academy of Neurology have recently released their recommendations regarding surgical treatment for refractory TS. Here, we describe the challenges, advancements, and promises of the use of DBS in the treatment of TS. We summarize the results of clinical studies and discuss the ethical issues involved in treating pediatric patients. Our aim is to provide a better understanding of the feasibility, safety, selection process, and clinical effectiveness of DBS treatment for select cases of severe and medically intractable TS.

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Decreased number of parvalbumin and cholinergic interneurons in the striatum of individuals with Tourette syndrome

Cited by 420 publications

References 62 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

Treatment of Tourette Syndrome

Deep brain stimulation for Tourette's syndrome

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