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.

GABA and glutamate in children with Tourette syndrome: A 1 H MR spectroscopy study at 7 T

“…Earlier published studies of striatal glutamate or its metabolites, conducted at 3 T in samples including older children or adults with TS, showed no differences from controls (Naaijen et al, 2016), or reduced Glx (Kanaan et al, 2017). While these findings might suggest that the PMC is a primary area of abnormality associated with tics, neither the elevated glutamate levels nor GABA were significant predictors of tic severity.…”

“…Several prior 1 H MRS studies have been performed at 3 T in children and adults with TS (Kanaan et al, 2017; Naaijen et al, 2016; Puts et al, 2015; Tinaz et al, 2014); however, this report represents the first investigation to obtain 1 H MRS measurements of both glutamate and GABA at 7 T within the striatum and cortex of young children with TS (including those under age 10 years—an age range not previously studied using 7 T MRS). Overall, the scans were well tolerated by the children in this age range.…”

“…Naaijen et al (2016) reported no TS-related difference in glutamate among 8–12 year olds in dorsal striatum or anterior cingulate; while Kanaan et al (2017) showed reduced Glx in striatum and thalamus among adults with TS. Potential explanations for varying patterns of findings for both GABA and Glu include differences in sample age, sex distribution, presence of existing co-morbidities, current and prior medication use, nuances of voxel placement, and potential differences that may occur when using the J-edited spin echo difference editing method (Rothman et al, 1993) versus fitting methods such as LCModel as means of quantifying GABA.…”

“…To date, there have been two published studies assessing glutamate in TS patients, both using MRS at 3 T (Kanaan et al, 2017; Naaijen et al, 2016), also with inconsistent findings. Naaijen et al (2016) reported no TS-related difference in glutamate among 8–12 year olds in dorsal striatum or anterior cingulate; while Kanaan et al (2017) showed reduced Glx in striatum and thalamus among adults with TS.…”

Tourette syndrome research highlights from 2016

“…German researchers reported a fascinating study in 37 medication-free adults with TS and 36 controls using magnetic resonance spectroscopy (MRS) 50 . The study tested the hypothesis that GABA, glutamine (Gln) and glutamate (Glu) concentrations in striatum and thalamus would differ in people with TS.…”