Krashia, P., Ledonne, A., Nobili, A., Cordella, A., Errico, F., Usiello, A., D'Amelio, M., Mercuri, N.B., Guatteo, E., Carunchio, I.
Persistent elevation of D-Aspartate enhances NMDA receptor-mediated responses in mouse substantia nigra pars compacta dopamine neurons
(2016) Neuropharmacology, 103, pp. 69-78.
https://www.scopus.com/inward/record.uri?eid=2-s2.0-84992268842&partnerID=40&md5=8a0e6f0d479c9bdad4fa2f1b344e4813
DOI: 10.1016/j.neuropharm.2015.12.013
AFFILIATIONS: Department of Experimental Neurology, IRCCS Santa Lucia Foundation, Rome, Italy;
Department of Medicine, Unit of Molecular Neurosciences, University Campus-Biomedico, Rome, Italy;
Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy;
Ceinge Biotecnologie Avanzate, Naples, Italy;
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy;
Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Second University of Naples (SUN), Caserta, Italy
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. © 2015 Elsevier Ltd. All rights reserved.
CORRESPONDENCE ADDRESS: Guatteo, E.; Department of Experimental Neurology, IRCCS Santa Lucia FoundationItaly; email: e.guatteo@hsantalucia.it
