Role of the atypical vesicular glutamate transporter VGLUT3 in l-DOPA-induced dyskinesia

Neurobiology of Disease

卷:87

Salah El Mestikawy¹  Marco A.M. Prado²  Monica Guzman³  Vania F. Prado⁴  Giuseppe Gangarossa⁵  Emmanuel Valjent⁶  Stephanie Daumas⁶ 

[1] Cell Biology, The University of Western Ontario, London, Ontario, Canada;

[2] Correspondence to: G. Gangarossa, CIRB, Collège de France, F-75005, Paris.;

[3] INSERM, U1191, Montpellier F-34094, France;

[4] Université de Montpellier, UMR-5203, Montpellier F-34094, France;

[5] CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier F-34094, France;

[6] Molecular Medicine, Robarts Research Institute, Departments of Physiology and Pharmacology, Anatomy &

关键词: l-DOPA;    Dyskinesia;    Striatum;    Cholinergic interneurons (TANs);    Acetylcholine;    Glutamate;   

DOI  :  

来源: DOAJ

【 摘 要 】

Parkinson's disease (PD) is characterized by the degeneration of dopaminergic neurons. The gold standard therapy relies on dopamine (DA) replacement by the administration of levodopa (l-DOPA). However, with time l-DOPA treatment induces severe motor side effects characterized by abnormal and involuntary movements, or dyskinesia. Although earlier studies point to a role of striatal cholinergic interneurons, also known as striatal tonically active neurons (TANs), in l-DOPA-induced dyskinesia (LID), the underlying mechanisms remain to be fully characterized. Here, we find that DA depletion is accompanied by increased expression of choline acetyltransferase (ChAT), the vesicular acetylcholine transporter (VAChT) as well as the atypical vesicular glutamate transporter type 3 (VGLUT3). TANs number and soma size are not changed. In dyskinetic mice, the VAChT levels remain high whereas the expression of VGLUT3 decreases. LID is attenuated in VGLUT3-deficient mice but not in mice bearing selective inactivation of VAChT in TANs. Finally, the absence of VGLUT3 is accompanied by a reduction of l-DOPA-induced phosphorylation of ERK1/2, ribosomal subunit (rpS6) and GluA1.Our results reveal that VGLUT3 plays an important role in the development of LID and should be considered as a potential and promising therapeutic target for prevention of LID.

【 授权许可】

Unknown