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Exp Neurol. 2015 Mar;265:122-8. doi: 10.1016/j.expneurol.2015.01.001. Epub 2015 Jan 15.

Corticostriatal interactions in the generation of tic-like behaviors after local striatal disinhibition.

Author information

1
Department of Psychiatry, Yale University School of Medicine, USA.
2
Department of Neurology, Yale University School of Medicine, USA.
3
Department of Psychiatry, Yale University School of Medicine, USA; Department of Psychology, Yale University School of Medicine, USA; Department of Child Study Center, Yale University School of Medicine, USA; Interdepartmental Neuroscience Program, Yale University School of Medicine, USA. Electronic address: Christopher.pittenger@yale.edu.

Abstract

The pathophysiology of the tics that define Gilles de la Tourette syndrome (TS) is not well understood. Local disinhibition within the striatum has been hypothesized to play a pathogenic role. In support of this, experimental disinhibition by local antagonism of GABA-A receptors within the striatum produces tic-like phenomenology in monkey and rat. We replicated this effect in mice via local picrotoxin infusion into the dorsal striatum. Infusion of picrotoxin into sensorimotor cortex produced similar movements, accompanied by signs of behavioral activation; higher-dose picrotoxin in the cortex produced seizures. Striatal inhibition with local muscimol completely abolished tic-like movements after either striatal or cortical picrotoxin, confirming their dependence on the striatal circuitry; in contrast, cortical muscimol attenuated but did not abolish movements produced by striatal picrotoxin. Striatal glutamate blockade eliminated tic-like movements after striatal picrotoxin, indicating that glutamatergic afferents are critical for their generation. These studies replicate and extend previous work in monkey and rat, providing additional validation for the local disinhibition model of tic generation. Our results reveal a key role for corticostriatal glutamatergic afferents in the generation of tic-like movements in this model.

KEYWORDS:

Animal model; Basal ganglia; Movement disorders; Tic; Tourette syndrome

PMID:
25597650
PMCID:
PMC4361636
DOI:
10.1016/j.expneurol.2015.01.001
[Indexed for MEDLINE]
Free PMC Article
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