Persistent elevation of D-Aspartate enhances NMDA receptor-mediated responses in mouse substantia nigra pars compacta dopamine neurons

Paraskevi Krashia, Ada Ledonne, Annalisa Nobili, Alberto Cordella, Francesco Errico, Alessandro Usiello, Marcello D'Amelio, Nicola Biagio Mercuri, Ezia Guatteo, Irene Carunchio

Research output: Contribution to journalArticle

Abstract

Dopamine neurons in the substantia nigra pars compacta regulate not only motor but also cognitive functions. NMDA receptors play a crucial role in modulating the activity of these cells. Considering that the amino-acid D-Aspartate has been recently shown to be an endogenous NMDA receptor agonist, the aim of the present study was to examine the effects of D-Aspartate on the functional properties of nigral dopamine neurons. We compared the electrophysiological actions of D-Aspartate in control and D-aspartate oxidase gene (Ddo-/-) knock-out mice that show a concomitant increase in brain D-Aspartate levels, improved synaptic plasticity and cognition. Finally, we analyzed the effects of L-Aspartate, a known dopamine neuron endogenous agonist in control and Ddo-/- mice. We show that D- and L-Aspartate excite dopamine neurons by activating NMDA, AMPA and metabotropic glutamate receptors. Ddo deletion did not alter the intrinsic properties or dopamine sensitivity of dopamine neurons. However, NMDA-induced currents were enhanced and membrane levels of the NMDA receptor GluN1 and GluN2A subunits were increased. Inhibition of excitatory amino-acid transporters caused a marked potentiation of D-Aspartate, but not L-Aspartate currents, in Ddo-/- neurons. This is the first study to show the actions of D-Aspartate on midbrain dopamine neurons, activating not only NMDA but also non-NMDA receptors. Our data suggest that dopamine neurons, under conditions of high D-Aspartate levels, build a protective uptake mechanism to compensate for increased NMDA receptor numbers and cell hyper-excitation, which could prevent the consequent hyper-dopaminergia in target zones that can lead to neuronal degeneration, motor and cognitive alterations.

Original languageEnglish
Pages (from-to)69-78
Number of pages10
JournalNeuropharmacology
Volume103
DOIs
Publication statusE-pub ahead of print - Dec 17 2015

Keywords

  • D-aspartate oxidase knockout
  • Excitatory amino-acid transporter
  • L-Aspartate
  • Midbrain dopamine neuron
  • NMDA receptor
  • Substantia nigra pars compacta

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

Fingerprint Dive into the research topics of 'Persistent elevation of D-Aspartate enhances NMDA receptor-mediated responses in mouse substantia nigra pars compacta dopamine neurons'. Together they form a unique fingerprint.

  • Cite this