giovedì 2 giugno 2016

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Krashia, P.a , Ledonne, A.a , Nobili, A.a  b , Cordella, A.a  c , Errico, F.d  e , Usiello, A.d  f , D'Amelio, M.a  b , Mercuri, N.B.a  c , Guatteo, E.a , Carunchio, I.a  c

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-s2.0-84956537527&partnerID=40&md5=4c613f1153a8de6d9b2bc10a26ff7c74
DOI: 10.1016/j.neuropharm.2015.12.013

AFFILIATIONS:
a)      Department of Experimental Neurology, IRCCS Santa Lucia Foundation, Rome, Italy;
b)      Department of Medicine, Unit of Molecular Neurosciences, University Campus-Biomedico, Rome, Italy;
c)      Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy;
d)     Ceinge Biotecnologie Avanzate, Naples, Italy;
e)    Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy;
f)       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.

http://www.sciencedirect.com/science/article/pii/S0028390815302094