Pathological glutamatergic neurotransmission in Gilles de la Tourette Syndrome

Abstract

Gilles de la Tourette syndrome (GTS) 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 functional subdivisions of the basal ganglia, may lead to the expression of diverse motor and non-motor features as manifested in GTS. Current treatment strategies are often unsatisfactory thus provoking the need for further elucidation of the underlying pathophysiology. In view of (a) the close synergy exhibited by excitatory, inhibitory and modulatory neurotransmitter systems; (b) the crucial role played by glutamate (Glu) in tonic/phasic dopaminergic signalling; and (c) the interdependent metabolic relationship exhibited between Glu and GABA via glutamine (Gln); we postulated that glutamatergic signalling is related to the pathophysiology of GTS. As such, we examined the neurochemical profile of cortico-striato-thalamo-cortical regions in 37 well-characterized, drug-free adult patients and 36 age/gender-matched healthy controls via magnetic resonance spectroscopy at 3T. To interrogate the influence of treatment on metabolite concentrations, spectral data was acquired from 15 patients undergoing a four-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 GTS 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 (a) striatal Gln and actual tic severity and (b) thalamic Glu and pre-monitory urges. Our results indicate that patients with GTS 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