HOT
TOPICS
Altered Cholinergic Neurotransmission in Tourette Syndrome Xu M, Kobets A, Du JC, et al. Targeted ablation of cholinergic interneurons in the dorsolateral striatum produces behavioral manifestations of Tourette syndrome. Proc Natl Acad Sci U S A. 2015;112:893-898. Gilles de la Tourette syndrome (GTS) is a complex neuropsychiatric condition with tics as the defining feature. Several lines of research converge to indicate that structural and functional changes in cortico-striato-thalamo-cortical loops are at the epicenter of GTS pathophysiology.1 On the neurotransmitter level, the pharmacological success of anti-dopaminergic treatments propelled the hypothesis of dopaminergic dysfunction at the disorder’s core. However, more recent advances have broadened the spectrum of neurotransmitters involved in GTS pathophysiology to include gamma-aminobutyric acid (GABA), acetylcholine, glutamate, nicotine, noradrenaline and, most recently, histamine.2 For GABA and acetylcholine, two postmortem studies have reinforced their pathophysiological importance by demonstrating diminished numbers and altered distribution of inhibitory interneurons in the basal ganglia.3,4 Moreover, the role of GABA in tic generation has been further highlighted in animal experiments in which local (striatal) injection of GABA antagonists resulted in functional disinhibition of cortico-striato-thalamo-cortical loops and led to tic-like movements.5 However, the role of aberrant cholinergic neurotransmission in tic pathophysiology remains largely unexplored. A recent study by Xu et al. addressed this question and demonstrated that targeted ablation of cholinergic interneurons of the dorsolateral striatum in mice can produce repetitive behaviors with similarities to the aberrant motor output of GTS patients.6 Xu et al. designed a recombinant virus, which induced partial ablation (50%) of cholinergic interneurons in either the dorsolateral or dorsomedial striatum on systemic administration of diphtheria toxin in choline acetyltransferase transgenic adult mice. For the dorsolateral striatum, they showed that, although ablated mice largely behaved similarly to controls at baseline, the introduction of acute environmental stressors (ie, repetitive acoustic startle stimuli) or D-amphetamine induced stereotypic and fragmented motor behaviors consisting of grooming and sniffing. Conversely, cholinergic interneuronal cell ablation of the dorsomedial striatum did not produce similar or, indeed, any abnormal behaviors. Clearly, differences exist between hyperkinesias in humans defined as tics and the fragmented, stereotypic behaviors seen in mice. However, this study demonstrates for the first time that abnormal complex repetitive behaviors can be elicited by specifically inducing a cholinergic interneuronal deficit in sensorimotor areas of the striatum. Given previous work on the functional interplay between levels of striatal dopamine and acetylcholine in the pathophysiology of stereotypic behaviors,7 this is perhaps unsurprising. For instance, restoration of acetylcholine release from striatal cholinergic interneurons was associated with an arrest of stereotypic motor output.7 In this sense, the
study by Xu et al. reignites interest in the role of enhanced cholinergic neurotransmission for the treatment of tics. This is in line with previous clinical reports that demonstrated that pharmacological agents targeting cholinergic stimulation (eg, donepezil), as used in the treatment of Alzheimer’s disease, led to significant tic reduction.2 However, in most of these reports, tolerability was poor. Therefore, a more targeted approach at enhancing striatal cholinergic tone to avoid systemic side effects is warranted, as for GABA, where benzodiazepines provide partial relief from tics but usually at the price of sedation and potential addiction. Ideally, both would be combined, but this will await more institutional or industrial support for a disease that is— wrongly—still considered “rare.” Christos Ganos, MD,1,2 and Andreas Hartmann, MD3,4 1
Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, University College London, London, UK 2 Department of Neurology, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany 3 fe rence National Maladie Rare: ‘Syndrome Gilles de la Centre de Re partement de Neurologie, Po ^ le des Maladies du Tourette,’ De -Salpe ^trie`re, Paris, France Syste`me Nerveux, Groupe Hospitalier Pitie 4 Centre de Recherche de l’Institut du Cerveau et de la Moelle Epinie`re UPMC/INSERM UMR_S1127; CNRS UMR 7225, Groupe -Salpe ^trie`re, Paris, France Hospitalier Pitie
References 1.
Ganos C, Roessner V, Munchau A. The functional anatomy of Gilles de la Tourette syndrome. Neurosci Biobehav Rev 2013;37:10501062.
2.
Hartmann A. Clinical pharmacology of nondopaminergic drugs in Tourette syndrome. Int Rev Neurobiol 2013;112:351-372.
3.
Kalanithi PS, Zheng W, Kataoka Y, et al. Altered parvalbuminpositive neuron distribution in basal ganglia of individuals with Tourette syndrome. Proc Natl Acad Sci U S A 2005;102:1330713312.
4.
Kataoka Y, Kalanithi PS, Grantz H, et al. Decreased number of parvalbumin and cholinergic interneurons in the striatum of individuals with Tourette syndrome. J Comp Neurol 2010;518:277-291.
5.
Bronfeld M, Yael D, Belelovsky K, Bar-Gad I. Motor tics evoked by striatal disinhibition in the rat. Front Syst Neurosci 2013;7:50.
6.
Xu M, Kobets A, Du JC, et al. Targeted ablation of cholinergic interneurons in the dorsolateral striatum produces behavioral manifestations of Tourette syndrome. Proc Natl Acad Sci U S A 2015; 112:893-898.
7.
Aliane V, Perez S, Bohren Y, Deniau JM, Kemel ML. Key role of striatal cholinergic interneurons in processes leading to arrest of motor stereotypies. Brain 2011;134:110-118.
------------------------------------------------------------------------------------------------------------------------------*E-mail: [email protected]
Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article.
638
Movement Disorders, Vol. 30, No. 5, 2015
Received: 3 February 2015; Accepted: 8 February 2015 Published online 18 March 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.26210
TOPICS
Altered Cholinergic Neurotransmission in Tourette Syndrome Xu M, Kobets A, Du JC, et al. Targeted ablation of cholinergic interneurons in the dorsolateral striatum produces behavioral manifestations of Tourette syndrome. Proc Natl Acad Sci U S A. 2015;112:893-898. Gilles de la Tourette syndrome (GTS) is a complex neuropsychiatric condition with tics as the defining feature. Several lines of research converge to indicate that structural and functional changes in cortico-striato-thalamo-cortical loops are at the epicenter of GTS pathophysiology.1 On the neurotransmitter level, the pharmacological success of anti-dopaminergic treatments propelled the hypothesis of dopaminergic dysfunction at the disorder’s core. However, more recent advances have broadened the spectrum of neurotransmitters involved in GTS pathophysiology to include gamma-aminobutyric acid (GABA), acetylcholine, glutamate, nicotine, noradrenaline and, most recently, histamine.2 For GABA and acetylcholine, two postmortem studies have reinforced their pathophysiological importance by demonstrating diminished numbers and altered distribution of inhibitory interneurons in the basal ganglia.3,4 Moreover, the role of GABA in tic generation has been further highlighted in animal experiments in which local (striatal) injection of GABA antagonists resulted in functional disinhibition of cortico-striato-thalamo-cortical loops and led to tic-like movements.5 However, the role of aberrant cholinergic neurotransmission in tic pathophysiology remains largely unexplored. A recent study by Xu et al. addressed this question and demonstrated that targeted ablation of cholinergic interneurons of the dorsolateral striatum in mice can produce repetitive behaviors with similarities to the aberrant motor output of GTS patients.6 Xu et al. designed a recombinant virus, which induced partial ablation (50%) of cholinergic interneurons in either the dorsolateral or dorsomedial striatum on systemic administration of diphtheria toxin in choline acetyltransferase transgenic adult mice. For the dorsolateral striatum, they showed that, although ablated mice largely behaved similarly to controls at baseline, the introduction of acute environmental stressors (ie, repetitive acoustic startle stimuli) or D-amphetamine induced stereotypic and fragmented motor behaviors consisting of grooming and sniffing. Conversely, cholinergic interneuronal cell ablation of the dorsomedial striatum did not produce similar or, indeed, any abnormal behaviors. Clearly, differences exist between hyperkinesias in humans defined as tics and the fragmented, stereotypic behaviors seen in mice. However, this study demonstrates for the first time that abnormal complex repetitive behaviors can be elicited by specifically inducing a cholinergic interneuronal deficit in sensorimotor areas of the striatum. Given previous work on the functional interplay between levels of striatal dopamine and acetylcholine in the pathophysiology of stereotypic behaviors,7 this is perhaps unsurprising. For instance, restoration of acetylcholine release from striatal cholinergic interneurons was associated with an arrest of stereotypic motor output.7 In this sense, the
study by Xu et al. reignites interest in the role of enhanced cholinergic neurotransmission for the treatment of tics. This is in line with previous clinical reports that demonstrated that pharmacological agents targeting cholinergic stimulation (eg, donepezil), as used in the treatment of Alzheimer’s disease, led to significant tic reduction.2 However, in most of these reports, tolerability was poor. Therefore, a more targeted approach at enhancing striatal cholinergic tone to avoid systemic side effects is warranted, as for GABA, where benzodiazepines provide partial relief from tics but usually at the price of sedation and potential addiction. Ideally, both would be combined, but this will await more institutional or industrial support for a disease that is— wrongly—still considered “rare.” Christos Ganos, MD,1,2 and Andreas Hartmann, MD3,4 1
Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, University College London, London, UK 2 Department of Neurology, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany 3 fe rence National Maladie Rare: ‘Syndrome Gilles de la Centre de Re partement de Neurologie, Po ^ le des Maladies du Tourette,’ De -Salpe ^trie`re, Paris, France Syste`me Nerveux, Groupe Hospitalier Pitie 4 Centre de Recherche de l’Institut du Cerveau et de la Moelle Epinie`re UPMC/INSERM UMR_S1127; CNRS UMR 7225, Groupe -Salpe ^trie`re, Paris, France Hospitalier Pitie
References 1.
Ganos C, Roessner V, Munchau A. The functional anatomy of Gilles de la Tourette syndrome. Neurosci Biobehav Rev 2013;37:10501062.
2.
Hartmann A. Clinical pharmacology of nondopaminergic drugs in Tourette syndrome. Int Rev Neurobiol 2013;112:351-372.
3.
Kalanithi PS, Zheng W, Kataoka Y, et al. Altered parvalbuminpositive neuron distribution in basal ganglia of individuals with Tourette syndrome. Proc Natl Acad Sci U S A 2005;102:1330713312.
4.
Kataoka Y, Kalanithi PS, Grantz H, et al. Decreased number of parvalbumin and cholinergic interneurons in the striatum of individuals with Tourette syndrome. J Comp Neurol 2010;518:277-291.
5.
Bronfeld M, Yael D, Belelovsky K, Bar-Gad I. Motor tics evoked by striatal disinhibition in the rat. Front Syst Neurosci 2013;7:50.
6.
Xu M, Kobets A, Du JC, et al. Targeted ablation of cholinergic interneurons in the dorsolateral striatum produces behavioral manifestations of Tourette syndrome. Proc Natl Acad Sci U S A 2015; 112:893-898.
7.
Aliane V, Perez S, Bohren Y, Deniau JM, Kemel ML. Key role of striatal cholinergic interneurons in processes leading to arrest of motor stereotypies. Brain 2011;134:110-118.
------------------------------------------------------------------------------------------------------------------------------*E-mail: [email protected]
Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article.
638
Movement Disorders, Vol. 30, No. 5, 2015
Received: 3 February 2015; Accepted: 8 February 2015 Published online 18 March 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.26210
