Krashia Paraskevi, Ledonne Ada, Nobili Annalisa, Cordella Alberto, Errico Francesco, Usiello Alessandro, D'Amelio Marcello, Mercuri Nicola Biagio, Guatteo Ezia, Carunchio Irene
Department of Experimental Neurology, IRCCS Santa Lucia Foundation, Rome, Italy.
Department of Experimental Neurology, IRCCS Santa Lucia Foundation, Rome, Italy; Department of Medicine, Unit of Molecular Neurosciences, University Campus-Biomedico, Rome, Italy.
Neuropharmacology. 2016 Apr;103:69-78. doi: 10.1016/j.neuropharm.2015.12.013. Epub 2015 Dec 17.
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.
黑质致密部的多巴胺能神经元不仅调节运动功能，还调节认知功能。N-甲基-D-天冬氨酸（NMDA）受体在调节这些细胞的活性中起关键作用。鉴于最近已证明氨基酸D-天冬氨酸是一种内源性NMDA受体激动剂，本研究的目的是研究D-天冬氨酸对黑质多巴胺能神经元功能特性的影响。我们比较了D-天冬氨酸在对照小鼠和D-天冬氨酸氧化酶基因（Ddo(-/-)）敲除小鼠中的电生理作用，后者脑内D-天冬氨酸水平同时升高，突触可塑性和认知能力得到改善。最后，我们分析了L-天冬氨酸（一种已知的多巴胺能神经元内源性激动剂）在对照小鼠和Ddo(-/-)小鼠中的作用。我们发现，D-天冬氨酸和L-天冬氨酸通过激活NMDA、α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）和代谢型谷氨酸受体来兴奋多巴胺能神经元。Ddo基因缺失并未改变多巴胺能神经元的内在特性或多巴胺敏感性。然而，NMDA诱导的电流增强，NMDA受体GluN1和GluN2A亚基的膜水平增加。在Ddo(-/-)神经元中，抑制兴奋性氨基酸转运体可显著增强D-天冬氨酸而非L-天冬氨酸的电流。这是第一项显示D-天冬氨酸对中脑多巴胺能神经元作用的研究，它不仅激活NMDA受体，还激活非NMDA受体。我们的数据表明，在D-天冬氨酸水平较高的情况下，多巴胺能神经元建立了一种保护性摄取机制，以补偿NMDA受体数量的增加和细胞过度兴奋，这可以防止靶区随后出现的多巴胺能亢进，而多巴胺能亢进可能导致神经元变性、运动和认知改变。
