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