An in vivo ultrahigh field 14.1 T ¹H‐MRS study on 6‐OHDA and α‐synuclein‐based rat models of Parkinson's disease: GABA as an early disease marker

Abstract

The detection of Parkinson's disease (PD) in its preclinical stages prior to outright neurodegeneration is essential to the development of neuroprotective therapies and could reduce the number of misdiagnosed patients. However, early diagnosis is currently hampered by lack of reliable biomarkers. 1 H magnetic resonance spectroscopy (MRS) offers a noninvasive measure of brain metabolite levels that allows the identification of such potential biomarkers. This study aimed at using MRS on an ultrahigh field 14.1 T magnet to explore the striatal metabolic changes occurring in two different rat models of the disease. Rats lesioned by the injection of 6-hydroxydopamine (6-OHDA) in the medial-forebrain bundle were used to model a complete nigrostriatal lesion while a genetic model based on the nigral injection of an adeno-associated viral (AAV) vector coding for the human a-synuclein was used to model a progressive neurodegeneration and dopaminergic neuron dysfunction, thereby replicating conditions closer to early pathological stages of PD. MRS measurements in the striatum of the 6-OHDA rats revealed significant decreases in glutamate and N-acetyl-aspartate levels and a significant increase in GABA level in the ipsilateral hemisphere compared with the contralateral one, while the aSyn overexpressing rats showed a significant increase in the GABA striatal level only. Therefore, we conclude that MRS measurements of striatal GABA levels could allow for the detection of early nigrostriatal defects prior to outright neurodegeneration and, as such, offers great potential as a sensitive biomarker of presymptomatic PD.

Progressive brain metabolic changes under deep brain stimulation of subthalamic nucleus in parkinsonian rats

“…) or increase in GABA but a decrease in Glu (Coune et al . ). Increased GABA in striatum has also been reported in patients with mild PD (Emir et al .…”

“…) and in a model of early PD based on adeno‐associated virus (AAV)‐mediated expression of human α‐synuclein (Coune et al . ), suggesting that striatal GABA levels are a sensitive marker of parkinsonism. The lack of significant changes in possible indicators of energy metabolism defect (Cr) or cell viability (NAA) in BG components is consistent with the absence of evidence for neurodegeneration within the striatum and SNr in acute animal models of PD and agrees with previous reports (Chassain et al .…”

“…; Coune et al . ). Here, we developed a stimulation procedure adapted for use in magnetic environment and coupled for the first time DBS with high‐field MRS in vivo in the rat to study the temporal evolution of STN‐DBS effects between acute (1–3 h) and subchronic (7 days) conditions in the striatum and the SNr in control and parkinsonian states.…”

Proton MR Spectroscopy for Diagnosis and Evaluation of Treatment Efficacy in Parkinson Disease

“…This current 1 H MR spectroscopic study did not observe changes in Glx pool, which converges with previous studies in PD patients (15,32) but diverges from data obtained in animal models. Indeed, MR spectroscopic studies in animal models of PD suggest that dopaminergic denervation induces hyperactivity of the glutamatergic corticostriatal pathway, where the elevated glutamate concentrations observed inside the striatum were associated with increased glutamine and g-aminobutyric acid levels, which points to modified neuron-glia interactions inside this structure after dopaminergic denervation (18,20,33). As the modifications observed are associated with an acute lesion of the nigrostriatal pathway, changes in glutamate and glutamine in animal studies might reflect a temporary glial response in the striatum in response to dopaminergic denervation (18).…”

Exposure of C. elegans eggs to a glyphosate-containing herbicide leads to abnormal neuronal morphology

“…Although GABAergic neurons are not typically associated with signs or symptoms of major neurodegenerative or neurodevelopmental diseases, recent research has demonstrated their importance in the early symptomology of Parkinson’s disease [8,17,35] and Alzheimer’s disease [39,47,54]. In our herbicide model, however, these GABAergic ventral nerve cord neurons do not appear to contribute significantly (Figure 3) to the loss of green pixels observed in the pan-neuronal::GFP studies (Figure 2).…”