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

• Published in: Neuropharmacology 2016-04, Vol.103, p.69-78
• Main Authors: Krashia, Paraskevi, Ledonne, Ada, Nobili, Annalisa, Cordella, Alberto, Errico, Francesco, Usiello, Alessandro, D'Amelio, Marcello, Mercuri, Nicola Biagio, Guatteo, Ezia, Carunchio, Irene
• Format: Article
• Language: English
• Subjects: Animals; Aspartic Acid - administration & dosage; Aspartic Acid - metabolism; D-Aspartate Oxidase - genetics; D-aspartate oxidase knockout; D-Aspartic Acid - administration & dosage; D-Aspartic Acid - metabolism; Dopamine - administration & dosage; Dopaminergic Neurons - drug effects; Dopaminergic Neurons - physiology; Excitatory amino-acid transporter; Female; L-Aspartate; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Midbrain dopamine neuron; NMDA receptor; Pars Compacta - drug effects; Pars Compacta - physiology; Receptors, AMPA - physiology; Receptors, Metabotropic Glutamate - physiology; Receptors, N-Methyl-D-Aspartate - agonists; Receptors, N-Methyl-D-Aspartate - physiology; Substantia nigra pars compacta
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2015.12.013

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. •Midbrain dopamine (DA) neurons have a key role in regulating movement and cognition.•D-Asp can act as an agonist in DA cells, activating NMDA and non-NMDA receptors.•D-Asp oxidase deletion in mice does not alter intrinsic properties of DA neurons.•Ddo−/− DA neurons show enhanced levels of NMDA receptor subunits and NMDA currents.•Ddo−/− DA neurons show enhanced D-Asp-specific uptake by amino-acid transporters.