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

Neurobiol Dis. 2016 Mar;87:69-79. doi: 10.1016/j.nbd.2015.12.010. Epub 2015 Dec 19.

Abstract

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.

Keywords: Acetylcholine; Cell signaling; Cholinergic interneurons (TANs); Dyskinesia; Glutamate; Striatum; Vesicular acetylcholine transporter (VAChT); Vesicular glutamate transporter type 3 (VGLUT3); l-DOPA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport Systems, Acidic / genetics
  • Amino Acid Transport Systems, Acidic / metabolism*
  • Animals
  • Antiparkinson Agents / toxicity*
  • Cell Count
  • Cell Size
  • Choline O-Acetyltransferase / metabolism
  • Disease Models, Animal
  • Dyskinesia, Drug-Induced / metabolism*
  • Dyskinesia, Drug-Induced / pathology
  • Levodopa / toxicity*
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Neurons / metabolism
  • Neurons / pathology
  • Oxidopamine
  • Parkinsonian Disorders / drug therapy
  • Parkinsonian Disorders / metabolism
  • Parkinsonian Disorders / pathology
  • Phosphorylation / drug effects
  • Receptors, AMPA / metabolism
  • Ribosomal Protein S6 / metabolism
  • Vesicular Acetylcholine Transport Proteins / metabolism

Substances

  • Amino Acid Transport Systems, Acidic
  • Antiparkinson Agents
  • Receptors, AMPA
  • Ribosomal Protein S6
  • Slc18a3 protein, mouse
  • Vesicular Acetylcholine Transport Proteins
  • ribosomal protein S6, mouse
  • vesicular glutamate transporter 3, mouse
  • Levodopa
  • Oxidopamine
  • Choline O-Acetyltransferase
  • Mapk1 protein, mouse
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • glutamate receptor ionotropic, AMPA 1