Regular ArticleCorticostriatal interactions in the generation of tic-like behaviors after local striatal disinhibition
Introduction
Tics are involuntary stereotyped motor and vocal behaviors often associated with subjective premonitory urges; they are a defining symptom of Gilles de la Tourette syndrome (TS) and are frequently seen in other neuropsychiatric conditions. TS has childhood onset, with a prevalence among school aged children of 0.3–0.8%, and is diagnosed worldwide (Knight et al., 2012, Robertson and Stern, 1997, Scharf et al., 2012). Tics are often chronic, disruptive, and stigmatizing, producing substantial morbidity (Leckman, 2002). The pathophysiology of tic disorders is not well understood, and causative genes have proven elusive (State, 2011, Williams et al., 2013). The most effective pharmacological management of tics consists of antagonists of the dopamine (DA) D2 receptor, such as haloperidol. However, the substantial side effects of these agents limit their use, especially in children, and treatment drop-outs are common (Bloch, 2008).
Dysfunction of the cortico-basal ganglia circuitry is thought to be central to the pathophysiology of tic disorders (Leckman et al., 2010, Williams et al., 2013). Structural imaging has revealed a reduction in the size of caudate and putamen (Peterson et al., 2003) that correlates with disease persistence (Bloch et al., 2005). Functional imaging studies have similarly implicated this circuitry (Rickards, 2009). The sensorimotor cortex is thinned in children with TS, with cortical thickness negatively correlated with the severity of tic symptoms (Sowell et al., 2008). In contrast, regional volumes of dorsal prefrontal and parietal cortex are significantly increased in children with TS (Peterson et al., 2001); this may relate to compensatory responses or volitional tic suppression (Peterson et al., 1998). Structural abnormalities have also been described in the thalamus (Miller et al., 2010), cerebellum (Tobe et al., 2010), and elsewhere in the brain. Recently, post-mortem investigations have shown alterations in striatal microcircuitry in severe, refractory TS, with a reduction in the density of several populations of striatal interneuron (Kalanithi et al., 2005, Kataoka et al., 2010, Lennington et al., 2014).
It has been proposed that tics arise from foci of pathological disinhibition within the striatum (caudate–putamen) (Mink, 2001, Mink, 2003). In support of such a model, small, discrete strokes of the caudate and putamen have been observed to produce both motor and phonic tics (Kwak and Jankovic, 2002). Direct injections of GABA-A receptor antagonists into the monkey or rat striatum produce contralateral tic-like movements of the limbs and face (Bronfeld et al., 2011, Bronfeld et al., 2013, Marsden et al., 1975, McCairn et al., 2009, McCairn et al., 2013, Tarsy et al., 1978, Worbe et al., 2013), providing experimental support for this concept as well as an animal model in which the consequences of local striatal inhibition can be examined (Pittenger, 2014).
Non-human primates, in which most work on local striatal disinhibition has been performed, are well suited for electrophysiological studies, but less so for pharmacological or genetic investigations. Here we replicate the local striatal disinhibition model in mice using local striatal infusion of picrotoxin, producing phenomenology similar to that reported in non-human primates and in rats (Bronfeld et al., 2011, Bronfeld et al., 2013, McCairn et al., 2009, McCairn et al., 2013, Tarsy et al., 1978, Worbe et al., 2013). This permits pharmacological investigations of the model. Specifically, we investigated the ability of local modulation of glutamate and GABA within the corticostriatal circuitry to modulate tics produced by local striatal inhibition, to increase construct validity of the model and to probe the underlying neuronal mechanisms. Past studies of local disinhibition in non-human primates and rats have used the GABA-A antagonist bicuculline (Bronfeld et al., 2011, Bronfeld et al., 2013, McCairn et al., 2009, McCairn et al., 2013, Worbe et al., 2013). We used a more specific GABA-A receptor antagonist, picrotoxin, because bicuculline has been reported to also block calcium-activated potassium SK channels and produce epileptiform oscillations in the thalamic network (Kleiman-Weiner et al., 2009).
Section snippets
Subjects
Adult male C57Bl/6 mice, aged 2.5–5 months, were purchased from Jackson Laboratories (www.jax.org) and used in all experiments. Mice were housed under a 12/12 h light/dark cycle under controlled temperature and humidity conditions. All procedures were performed in accordance with the NIH Guide for the Use of Experimental Animals and were approved and overseen by Yale University's IACUC.
Drugs
Picrotoxin (PTX), muscimol (Musc), and (RS)-4-(phosphonomethyl)-piperazine-2-carboxylic acid (PMPA), were all
Phenomenology
Local infusion of the GABA-A antagonist bicuculline into the dorsal striatum has previously been shown to produce tic-like phenomenology in monkey and rat (Bronfeld et al., 2011, Bronfeld et al., 2013, McCairn et al., 2009, McCairn et al., 2013, Tarsy et al., 1978). We sought to replicate this effect in mice, using the more specific GABA-A antagonist picrotoxin (PTX).
In exploratory experiments, we infused 0.1 or 0.2 μg PTX into targets throughout the corticostriatal circuitry and monitored the
Discussion
Tics have been proposed to result from foci of pathological disinhibition within the striatum (Mink, 2001). This may relate to a deficit in local inhibitory tone, as suggested by a documented reduction in parvalbumin-expressing interneurons in post-mortem TS striatum (Kalanithi et al., 2005, Kataoka et al., 2010); these interneurons are a potent source of feed-forward inhibition in the striatum (Gittis et al., 2010). Additional support for this hypothesis derives from the recapitulation of
Author contributions
VP conducted all experiments, analyzed data, and wrote the manuscript. MX assisted with histological characterization of cannula placement and with data analysis. HRS assisted with EEG recordings. GFB supervised EEG recordings, analyzed data, and edited the manuscript. CP supervised all experiments and data analysis, analyzed and interpreted data, and wrote and edited the manuscript.
Acknowledgments and disclosures
The authors gratefully acknowledge S. Wilber for assistance with mouse husbandry. These experiments were supported by the Alison Family Foundation (CP), R01MH091861 (CP), and the State of Connecticut through its support of the Ribicoff Research Facilities at the Connecticut Mental Health Center (CP). These experiments received no commercial support; the authors declare no commercial conflict of interest.
References (47)
- et al.
Recent advances in Tourette syndrome research
Trends Neurosci.
(2006) Symptomatic myoclonus
Neurophysiol. Clin. Clin. Neurophysiol.
(2006)- et al.
The effect of competitive antagonist chain length on NMDA receptor subunit selectivity
Neuropharmacology
(2005) - et al.
Prevalence of tic disorders: a systematic review and meta-analysis
Pediatr. Neurol.
(2012) Tourette's syndrome
Lancet
(2002)- et al.
Theoretical and practical considerations behind the use of laboratory animals for the study of Tourette syndrome
Neurosci. Biobehav. Rev.
(2013) Basal ganglia dysfunction in Tourette's syndrome: a new hypothesis
Pediatr. Neurol.
(2001)- et al.
Electrophysiological study of dyskinesia produced by microinjection of picrotoxin into the striatum of the rat
Neurosci. Res.
(1990) - et al.
Analysis of the brain regions involved in myoclonus produced by intracerebral picrotoxin
Neuroscience
(1987) Functional neuroimaging in Tourette syndrome
J. Psychosom. Res.
(2009)
The genetics of Tourette disorder
Curr. Opin. Genet. Dev.
Cerebral hemisphere regulation of motivated behavior
Brain Res.
Myoclonus and movement disorders
Neurophysiol. Clin.
Towards a primate model of Gilles de la Tourette syndrome: anatomo-behavioural correlation of disorders induced by striatal dysfunction
Cortex
Emerging treatments for Tourette's disorder
Curr. Psychiatr. Rep.
Caudate volumes in childhood predict symptom severity in adults with Tourette syndrome
Neurology
Spatial and temporal properties of tic-related neuronal activity in the cortico-basal ganglia loop
J. Neurosci. Off. J. Soc. Neurosci.
Motor tics evoked by striatal disinhibition in the rat
Front. Syst. Neurosci.
Serotonin neurones have anti-convulsant effects and reduce seizure-induced mortality
J. Physiol.
Central serotonin neurons are required for arousal to CO2
Proc. Natl. Acad. Sci. U. S. A.
Distinct roles of GABAergic interneurons in the regulation of striatal output pathways
J. Neurosci. Off. J. Soc. Neurosci.
Muscimol as an ionotropic GABA receptor agonist
Neurochem. Res.
Altered parvalbumin-positive neuron distribution in basal ganglia of individuals with Tourette syndrome
Proc. Natl. Acad. Sci. U. S. A.
Cited by (0)
- 1
Current address: Duke University, Durham, NC, USA.
- 2
Current address: Department of Neurology, University of Iowa, IA, USA.