title: Persistent elevation of D-Aspartate enhances NMDA receptor-mediated responses in mouse substantia nigra pars compacta dopamine neurons.
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.
authors.affiliation: Department of Experimental Neurology, IRCCS Santa Lucia Foundation, Rome, Italy.
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Krashia
authors.affiliation: Department of Experimental Neurology, IRCCS Santa Lucia Foundation, Rome, Italy.
authors.forename: Ada
authors.initials: A
authors.lastname: Ledonne
authors.affiliation: Department of Experimental Neurology, IRCCS Santa Lucia Foundation, Rome, Italy; Department of Medicine, Unit of Molecular Neurosciences, University Campus-Biomedico, Rome, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Nobili
authors.affiliation: Department of Experimental Neurology, IRCCS Santa Lucia Foundation, Rome, Italy; Department of Systems Medicine, University of Rome 'Tor Vergata', Rome, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Cordella
authors.affiliation: Ceinge Biotecnologie Avanzate, Naples, Italy; Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Errico
authors.affiliation: Ceinge Biotecnologie Avanzate, Naples, Italy; Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Second University of Naples (SUN), Caserta, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Usiello
authors.affiliation: Department of Experimental Neurology, IRCCS Santa Lucia Foundation, Rome, Italy; Department of Medicine, Unit of Molecular Neurosciences, University Campus-Biomedico, Rome, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: D'Amelio
authors.affiliation: Department of Experimental Neurology, IRCCS Santa Lucia Foundation, Rome, Italy; Department of Systems Medicine, University of Rome 'Tor Vergata', Rome, Italy.
authors.forename: Nicola Biagio
authors.initials: NB
authors.lastname: Mercuri
authors.affiliation: Department of Experimental Neurology, IRCCS Santa Lucia Foundation, Rome, Italy. Electronic address: e.guatteo@hsantalucia.it.
authors.forename: Ezia
authors.initials: E
authors.lastname: Guatteo
authors.affiliation: Department of Experimental Neurology, IRCCS Santa Lucia Foundation, Rome, Italy; Department of Systems Medicine, University of Rome 'Tor Vergata', Rome, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Carunchio
mesh_terms: D000818:Animals; D001224:Aspartic Acid / Q000008:administration & dosage / Q000378:metabolism*; D050804:D-Aspartate Oxidase / Q000235:genetics; D026603:D-Aspartic Acid / Q000008:administration & dosage / Q000378:metabolism*; D004298:Dopamine / Q000008:administration & dosage; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000502:physiology*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065842:Pars Compacta / Q000187:drug effects / Q000502:physiology*; D018091:Receptors, AMPA / Q000502:physiology; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000502:physiology*
chemical_list: D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D001224:Aspartic Acid; D026603:D-Aspartic Acid; D050804:D-Aspartate Oxidase; D004298:Dopamine
keywords: D-aspartate oxidase knockout; Excitatory amino-acid transporter; L-Aspartate; Midbrain dopamine neuron; NMDA receptor; Substantia nigra pars compacta