NMDA receptor GluN2D subunit participates to levodopa-induced dyskinesia pathophysiology

Neurobiol Dis. 2019 Jan;121:338-349. doi: 10.1016/j.nbd.2018.09.021. Epub 2018 Sep 24.


In the striatum, specific N-methyl-d-aspartate receptor (NMDAR) subtypes are found in different neuronal cells. Spiny projection neurons (SPNs) are characterized by NMDARs expressing GluN2A and GluN2B subunits, while GluN2D is exclusively detected in striatal cholinergic interneurons (ChIs). In Parkinson's disease (PD), dopamine depletion and prolonged treatment with levodopa (L-DOPA) trigger adaptive changes in the glutamatergic transmission from the cortex to the striatum, also resulting in the aberrant function of striatal NMDARs. While modifications of GluN2A- and GluN2B-NMDARs in SPNs have been extensively documented, only few studies report GluN2D dysfunction in PD and no data are available in L-DOPA-induced dyskinesia (LID). Here we investigate the contribution of a specific NMDAR subtype (GluN2D-NMDAR) to PD and LID, and whether this receptor could represent a candidate for future pharmacological interventions. Our results show that GluN2D synaptic abundance is selectively augmented in the striatum of L-DOPA-treated male parkinsonian rats displaying a dyskinetic phenotype. This event is associated to a dramatic increase in GluN2D binding to the postsynaptic protein scaffold PSD-95. Moreover, immunohistochemistry and electrophysiology experiments reveal that GluN2D-NMDARs are expressed not only by striatal ChIs but also by SPNs in dyskinetic rats. Notably, in vivo treatment with a well-characterized GluN2D antagonist ameliorates the severity of established dyskinesia in L-DOPA-treated animals. Our findings support a role for GluN2D-NMDARs in LID, and they confirm that cell-type and subunit specific modifications of NMDARs underlie the pathophysiology of LID.

Keywords: GluN2D; Levodopa-induced dyskinesia; NMDA receptor; Parkinson's disease; Pharmacological target.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cholinergic Neurons / metabolism
  • Corpus Striatum / metabolism*
  • Disease Models, Animal
  • Disks Large Homolog 4 Protein / metabolism
  • Dyskinesia, Drug-Induced / metabolism*
  • Interneurons / metabolism
  • Levodopa / administration & dosage
  • Macaca mulatta
  • Male
  • Neurons / metabolism*
  • Parkinson Disease / metabolism*
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Synapses / metabolism


  • Disks Large Homolog 4 Protein
  • NR2D NMDA receptor
  • Receptors, N-Methyl-D-Aspartate
  • Levodopa