Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by a severe loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and a concomitant decrease of dopamine (DA) in the striatum (Marsden 1994). The degeneration of nigrostriatal dopaminergic neurons causes dysfunction of the cortico-basal Received October 16, 2007; revised manuscript received December 3, 2007; accepted December 5, 2007. Address correspondence and reprint requests to Carine Chassain, INRA UR370 QuaPA/STIM, Clermont-Ferrand/Theix, 63122 Saint Genès Champanelle, France. E-mail: kchassin@sancy.clermont.inra.frAbbreviations used: BG, basal ganglia; DA, dopamine; GAD, glutamate decarboxylase; Gln, glutamine; Glu, glutamate; Glx, Glu + Gln; Lac, lactate; MRS, magnetic resonance spectroscopy; Myo-Ins, myoinositol; NAA, N-acetyl aspartate; PD, Parkinson's disease; PRESS, point-resolved spectroscopy; SNpc, substantia nigra pars compacta; Tau, taurine; TBS, Tris-buffered saline; tCho, total choline; tCr, total creatine; TH, tyrosine hydroxylase; TSP, 3-(trimethylsilyl)-propionic acid-D4, sodium salt; VOI, voxel of interest. AbstractParkinson's disease is a neurodegenerative disorder characterized by the progressive loss of the dopaminergic neurons in the substantia nigra pars compacta, which project to the striatum. The aim of this study was to analyze in vivo and in vitro consequences of dopamine depletion on amount of metabolites in a mouse model of Parkinson's disease using proton 1 H magnetic resonance spectroscopy (MRS). The study was performed on control mice (n = 7) and MPTP-intoxicated mice (n = 7). All the experiments were performed at 9.4 T. For in vivo MRS acquisitions, mice were anesthetized and carefully placed on an animal handling system with the head centered in birdcage coil used for both excitation and signal reception. Spectra were acquired in a voxel (8 lL) centered in the striatum, applying a point-resolved spectroscopy sequence (TR = 4000 ms, TE = 8.8 ms). After in vivo MRS acquisitions, mice were killed; successful lesion verified by tyrosine hydroxylase immunolabeling on the substantia nigra pars compacta and in vitro MRS acquisitions performed on perchloric extracts of anterior part of mice brains. In vitro spectra were acquired using a standard one-pulse experiment. The absolute concentrations of metabolites were determined using JMRUI (Lyon, France) from 1 H spectra obtained in vivo on striatum and in vitro on perchloric extracts. Glutamate (Glu), glutamine (Gln), and GABA concentrations obtained in vivo were significantly increased in striatum of MPTP-lesioned mice (Glu: 15.5 ± 2.5 vs. 12.9 ± 1.0 mmol/L, p < 0.05; Gln: 2.3 ± 0.9 vs. 1.8 ± 0.6 mmol/L, p < 0.05; GABA: 2.3 ± 0.9 vs. 1.3 ± 0.6 mmol/L, p < 0.05). The in vitro results confirmed these results, Glu (10.9 ± 2.5 vs. 7.9 ± 1.7 lmol/g, p < 0.05), Gln (6.8 ± 2.9 vs. 4.3 ± 1.0 lmol/g, p < 0.05), and GABA (2.9 ± 0.9 vs. 1.5 ± 0.4 lmol/g, p < 0.01). The present study strongly supports a hyperactivity of the glutamatergic cor...

We used in vivo proton ((1)H) Magnetic Resonance Spectroscopy (MRS) to measure the levels of the main excitatory amino acid, glutamate (Glu) and also glutamine (Gln) and GABA in the striatum and cerebral cortex in the MPTP-intoxicated mouse, a model of dopaminergic denervation, before and after dopamine (DA) replacement. The study was performed at 9.4T on control mice (n = 8) and MPTP-intoxicated mice (n = 8). In vivo spectra were acquired in a voxel (8 microL) centered in the striatum, and in the cortex (4.6 microL). Three days after basal MRS acquisitions new spectra were acquired in the striatum and cortex, after levodopa (200 mg.kg(-1)). Glu, Gln and GABA concentrations obtained in the basal state were significantly increased in the striatum of MPTP-lesioned mice (Glu: 20.2 +/- 0.8 vs 11.4 +/- 0.9 mM, p < 0.001; Gln: 5.4 +/- 1.6 vs 2.0 +/- 0.6 mM, p < 0.05; GABA: 3.6 +/- 0.8 vs 1.6 +/- 0.2 mM, p < 0.05). Levodopa lowered metabolites concentrations in the striatum of MPTP-lesioned mice (Glu: 20.2 +/- 0.8 vs 11.2 +/- 0.4 mM (+ Ldopa), p < 0.001; Gln: 5.4 +/- 1.6 vs 1.6 +/- 0.4 mM (+ Ldopa), p < 0.05; GABA: 3.6 +/- 0.8 vs 1.7 +/- 0.4 mM (+ Ldopa), p < 0.01). Metabolite levels in the striatum of MPTP-intoxicated mice + levodopa were not significantly different from those in the striatum of controls. No change was found in the cortex after DA denervation and after DA replacement between the two animals groups. These results strongly support a predominant change in striatal Glu synaptic activity in the cortico-striatal pathway. Acute levodopa administration reverses the increase of metabolites in the striatum.

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tNAA, tCr, and m-Ins were identified as putative biomarkers of Parkinson disease in the putamen of patients. tNAA and tCr levels are responsive to L-DOPA therapy.

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The long-term effects and action mechanisms of subthalamic nucleus (STN) high-frequency stimulation (HFS) for Parkinson's disease still remain poorly characterized, mainly due to the lack of experimental models relevant to clinical application. To address this issue, we performed a multilevel study in freely moving hemiparkinsonian rats undergoing 5-week chronic STN HFS, using a portable constant-current microstimulator. In vivo metabolic neuroimaging by 1 H-magnetic resonance spectroscopy (11.7 T) showed that STN HFS normalized the tissue levels of the neurotransmission-related metabolites glutamate, glutamine and GABA in both the striatum and substantia nigra reticulata (SNr), which were significantly increased in hemiparkinsonian rats, but further decreased nigral GABA levels below control values; taurine levels, which were not affected in hemiparkinsonian rats, were significantly reduced. Slice electrophysiological recordings revealed that STN HFS was, uniquely among antiparkinsonian treatments, able to restore both forms of corticostriatal synaptic plasticity, i.e. long-term depression and potentiation, which were impaired in hemiparkinsonian rats. Behavior analysis (staircase test) showed a progressive recovery of motor skill during the stimulation period. Altogether, these data show that chronic STN HFS efficiently counteracts metabolic and synaptic defects due to dopaminergic lesion in both the striatum and SNr. Comparison of chronic STN HFS with acute and subchronic treatment further suggests that the long-term benefits of this treatment rely both on the maintenance of acute effects and on delayed actions on the basal ganglia network.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an efficient neurosurgical treatment for advancedParkinson's disease. Non-invasive metabolic neuroimaging during the course of DBS in animal models may contribute to our understanding of its action mechanisms. Here, DBS was adapted to in vivo proton magnetic resonance spectroscopy at 11.7 T in the rat to follow metabolic changes in main basal ganglia structures, the striatum, and the substantia nigra pars reticulata (SNr). Measurements were repeated OFF and ON acute and subchronic (7 days) STN-DBS in control and parkinsonian (6-hydroxydopamine lesion) conditions. Acute DBS reversed the increases in glutamate, glutamine, and GABA levels induced by the dopamine lesion in the striatum but not in the SNr. Subchronic DBS normalized GABA in both the striatum and SNr, and glutamate in the striatum. Taurine levels were markedly decreased under subchronic DBS in the striatum and SNr in both lesioned and unlesioned rats. Microdialysis in the striatum further showed that extracellular taurine was increased. These data reveal that STN-DBS has duration-dependent metabolic effects in the basal ganglia, consistent with development of adaptive mechanisms. In addition to counteracting defects induced by the dopamine lesion, prolonged DBS has proper effects independent of the pathological condition.