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Kalanithi, P. S. et al. Altered parvalbumin-positive neuron distribution in basal ganglia of individuals with Tourette syndrome. Proc. Natl Acad. Sci. USA 102, 13307-13312

Child Study Center and Department of Neurobiology, Yale University, New Haven, CT 06520.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 10/2005; 102(37):13307-12. DOI: 10.1073/pnas.0502624102
Source: PubMed

ABSTRACT

Tourette syndrome (TS) is a childhood neuropsychiatric disorder characterized by motor and vocal tics. Imaging studies found alterations in caudate (Cd) and putamen volumes. To investigate possible alterations in cell populations, postmortem basal ganglia tissue from individuals with TS and normal controls was analyzed by using unbiased stereological techniques. A markedly higher total neuron number was found in the globus pallidus pars interna (GPi) of TS. In contrast, a lower neuron number and density was observed in the globus pallidus pars externa and in the Cd. An increased number and proportion of the GPi neurons were positive for the calcium-binding protein parvalbumin in tissue from TS subjects, whereas lower densities of parvalbumin-positive interneurons were observed in both the Cd and putamen of TS subjects. This change is consistent with a developmental defect in tangential migration of some GABAergic neurons. The imbalance in striatal and GPi inhibitory neuron distribution suggests that the functional dynamics of cortico-striato-thalamic circuitry are fundamentally altered in severe, persistent TS.

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    • "In order to disrupt physiological activity in the limbic and sensorimotor networks, we injected a small amount of the GABA antagonist bicuculline into the NAc (limbic) or the putamen (sensorimotor) (Figures S1B and S1C) in five monkeys (Experimental Procedures). This pharmacological protocol was chosen, among others, because (1) tic disorders in TS are hypothesized to arise from dysfunctional, local GABAergic circuits (Kalanithi et al., 2005; Lerner et al., 2012) and (2) the effect of bicuculline is rapid, thereby bypassing concerns associated with compensatory mechanisms. Our injection protocol for the NAc successfully evoked repetitive complex vocalizations (Figure 1A). "
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    ABSTRACT: Inappropriate vocal expressions, e.g., vocal tics in Tourette syndrome, severely impact quality of life. Neural mechanisms underlying vocal tics remain unexplored because no established animal model representing the condition exists. We report that unilateral disinhibition of the nucleus accumbens (NAc) generates vocal tics in monkeys. Whole-brain PET imaging identified prominent, bilateral limbic cortico-subcortical activation. Local field potentials (LFPs) developed abnormal spikes in the NAc and the anterior cingulate cortex (ACC). Vocalization could occur without obvious LFP spikes, however, when phase-phase coupling of alpha oscillations were accentuated between the NAc, ACC, and the primary motor cortex. These findings contrasted with myoclonic motor tics induced by disinhibition of the dorsolateral putamen, where PET activity was confined to the ipsilateral sensorimotor system and LFP spikes always preceded motor tics. We propose that vocal tics emerge as a consequence of dysrhythmic alpha coupling between critical nodes in the limbic and motor networks.
    Full-text · Article · Jan 2016 · Neuron
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    • "Functional MRI of TS shows primary hyperactivity of excitatory somatosensory, insular and efferent motor output circuits, which elicits premonitory urges and tics (Bohlhalter et al., 2006; Wang et al., 2011), and secondary hypoactivity of motor-suppressing executive-control circuits (Swerdlow and Sutherland, 2005). The latter may include depleted or deficient regulatory interneuron populations, including not only cortical inhibitory interneurons but striatal cholinergic interneurons that normally excite striatal "indirect pathway" (IP) medium spiny neurons (MSN) that suppress tics and compulsions, and striatal parvalbumin-positive GABAergic fast-spiking interneurons (FSI) that normally inhibit striatal "direct pathway" (DP) MSN that activate tics and compulsions (Kalanithi et al., 2005; Kataoka et al., 2010; Burguiere et al., 2013; Xu et al., 2015a). Both TS and OCD are associated with hyperactivity of regional (somatosensory or orbitofrontal) cortical output neurons, as well as impaired sensorimotor gating evidenced by PPI (prepulse inhibition) deficits (Swedo et al., 1992; Breiter et al., 1996; Ziemann et al., 1997; Edgley and Lemon, 1999; Gilbert et al., 2004; Mantovani et al., 2006; Swerdlow and Sutherland, 2006; Ahmari et al., 2012). "
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    ABSTRACT: The brain circuits underlying tics in Tourette's syndrome (TS) are unknown but thought to involve cortico/amygdalo-striato-thalamo-cortical (CSTC) loop hyperactivity. We previously engineered a transgenic mouse "circuit model" of TS by expressing an artificial neuropotentiating transgene (encoding the cAMP-elevating, intracellular A1 subunit of cholera toxin) within a small population of dopamine D1 receptor-expressing somatosensory cortical and limbic neurons that hyperactivate cortico/amygdalostriatal glutamatergic output circuits thought to be hyperactive in TS and comorbid obsessive-compulsive (OC) disorders. As in TS, these D1CT-7 ("Ticcy") transgenic mice's tics were alleviated by the TS drugs clonidine and dopamine D2 receptor antagonists; and their chronic glutamate-excited striatal motor output was unbalanced toward hyperactivity of the motoric direct pathway and inactivity of the cataleptic indirect pathway. Here we've examined whether these mice's tics are countered by drugs that "break" sequential elements of their hyperactive cortical/amygdalar glutamatergic and efferent striatal circuit: anti-serotonoceptive and anti-noradrenoceptive corticostriatal glutamate output blockers (the serotonin 5-HT2a,c receptor antagonist ritanserin and the NE alpha-1 receptor antagonist prazosin); agmatinergic striatothalamic GABA output blockers (the presynaptic agmatine/imidazoline I1 receptor agonist moxonidine); and nigrostriatal dopamine output blockers (the presynaptic D2 receptor agonist bromocriptine). Each drug class alleviates tics in the Ticcy mice, suggesting a hyperglutamatergic CSTC "tic circuit" could exist in TS wherein cortical/amygdalar pyramidal projection neurons' glutamatergic overexcitation of both striatal output neurons and nigrostriatal dopaminergic modulatory neurons unbalances their circuit integration to excite striatothalamic output and create tics, and illuminating new TS drug strategies.
    Full-text · Article · Oct 2015 · Brain research
    • "Recent work has suggested that a deficit in cortical GABAergic inhibitory transmission may contribute to symptoms found in TS: GABA-related genes have been associated with risk for TS and with symptom severity (Fernandez et al. 2012; Tian et al. 2011); serum GABA levels are reduced in TS patients; and medication affecting the GABAergic system has been shown to reduce tics (Wang et al. 2012). Furthermore, altered GABA-A receptors and reduced density of GABAergic interneurons (Kalanithi et al. 2005; Lerner et al. 2012) have been shown in TS. GABA concentration can be measured in vivo with edited magnetic resonance spectroscopy (MRS) (Mescher et al. 1998; Puts and Edden 2012). "
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    ABSTRACT: Tourette Syndrome (TS) is characterized by the presence of chronic tics. Individuals with TS often report difficulty with ignoring (habituating to) tactile sensations and some patients perceive that this contributes to a "premonitory urge" to tic. While common, the physiological basis of impaired tactile processing in TS, and indeed tics themselves, remain poorly understood. It has been well established that GABAergic processing plays an important role in shaping the neurophysiological response to tactile stimulation. Further, there are multiple lines of evidence suggesting that a deficit in GABAergic transmission may contribute to symptoms found in TS. In this study, GABA-edited MRS was combined with a battery of vibrotactile tasks to investigate the role of GABA and atypical sensory processing in children with TS. Our results show reduced primary sensorimotor (SM1) GABA concentration in children with TS compared to healthy controls (HC), as well as patterns of impaired performance on tactile detection and adaptation tasks, consistent with altered GABAergic function. Moreover, in children with TS, SM1 GABA concentration correlated with motor tic severity, linking the core feature of TS directly to in vivo brain neurochemistry. There was an absence of the typical correlation between GABA and frequency discrimination performance in TS as was seen in HC. These data show that reduced GABA concentration in TS may contribute to both motor tics and sensory impairments in children with TS. Understanding the mechanisms of altered sensory processing in TS may provide a foundation for novel interventions to alleviate these symptoms. Copyright © 2015, Journal of Neurophysiology.
    No preview · Article · Jun 2015 · Journal of Neurophysiology
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