title: Pathological glutamatergic neurotransmission in Gilles de la Tourette syndrome.
abstract: Gilles de la Tourette syndrome is a hereditary, neuropsychiatric movement disorder with reported abnormalities in the neurotransmission of dopamine and γ-aminobutyric acid (GABA). Spatially focalized alterations in excitatory, inhibitory and modulatory neurochemical ratios within specific functional subdivisions of the basal ganglia, may lead to the expression of diverse motor and non-motor features as manifested in Gilles de la Tourette syndrome. Current treatment strategies are often unsatisfactory thus provoking the need for further elucidation of the underlying pathophysiology. In view of (i) the close spatio-temporal synergy exhibited between excitatory, inhibitory and modulatory neurotransmitter systems; (ii) the crucial role played by glutamate (Glu) in tonic/phasic dopaminergic signalling; and (iii) the interdependent metabolic relationship exhibited between Glu and GABA via glutamine (Gln); we postulated that glutamatergic signalling is related to the pathophysiology of Gilles de la Tourette syndrome. As such, we examined the neurochemical profile of three cortico-striato-thalamo-cortical regions in 37 well-characterized, drug-free adult patients and 36 age/gender-matched healthy control subjects via magnetic resonance spectroscopy at 3 T. To interrogate the influence of treatment on metabolite concentrations, spectral data were acquired from 15 patients undergoing a 4-week treatment with aripiprazole. Test-retest reliability measurements in 23 controls indicated high repeatability of voxel localization and metabolite quantitation. We report significant reductions in striatal concentrations of Gln, Glu + Gln (Glx) and the Gln:Glu ratio, and thalamic concentrations of Glx in Gilles de la Tourette syndrome in comparison to controls. ON-treatment patients exhibited no significant metabolite differences when compared to controls but significant increases in striatal Glu and Glx, and trends for increases in striatal Gln and thalamic Glx compared to baseline measurements. Multiple regression analysis revealed a significant negative correlation between (i) striatal Gln and actual tic severity; and (ii) thalamic Glu and premonitory urges. Our results indicate that patients with Gilles de la Tourette syndrome exhibit an abnormality in the flux of metabolites in the GABA-Glu-Gln cycle, thus implying perturbations in astrocytic-neuronal coupling systems that maintain the subtle balance between excitatory and inhibitory neurotransmission within subcortical nuclei.
authors.affiliation: 1 Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany kanaan@cbs.mpg.de.|2 Clinic of Psychiatry, Socialpsychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany.
authors.forename: Ahmad Seif
authors.initials: AS
authors.lastname: Kanaan
authors.affiliation: 2 Clinic of Psychiatry, Socialpsychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Gerasch
authors.affiliation: 1 Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.
authors.forename: Isabel
authors.initials: I
authors.lastname: García-García
authors.affiliation: 1 Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.
authors.forename: Leonie
authors.initials: L
authors.lastname: Lampe
authors.affiliation: 1 Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Pampel
authors.affiliation: 1 Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.
authors.forename: Alfred
authors.initials: A
authors.lastname: Anwander
authors.affiliation: 3 Douglas Mental Health University Institute and Department of Psychiatry, McGill University, Montreal, QC, Canada.
authors.forename: Jamie
authors.initials: J
authors.lastname: Near
authors.affiliation: 1 Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.
authors.forename: Harald E
authors.initials: HE
authors.lastname: Möller
authors.affiliation: 2 Clinic of Psychiatry, Socialpsychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Müller-Vahl
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001479:Basal Ganglia / Q000000981:diagnostic imaging / Q000378:metabolism*; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008297:Male; D008875:Middle Aged; D009435:Synaptic Transmission; D013788:Thalamus / Q000000981:diagnostic imaging / Q000378:metabolism*; D005879:Tourette Syndrome / Q000000981:diagnostic imaging / Q000378:metabolism*; D055815:Young Adult
chemical_list: D005973:Glutamine; D018698:Glutamic Acid
keywords: Gilles de la Tourette syndrome; basal ganglia; glutamate; glutamine; magnetic resonance spectroscopy