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The Journal of Neuroscience, July 15, 2001, 21(14):5110-5120
Inhibition of Mitochondrial Complex II Induces a Long-Term
Potentiation of NMDA-Mediated Synaptic Excitation in the Striatum
Requiring Endogenous Dopamine
Paolo
Calabresi1, 2,
Paolo
Gubellini1, 3,
Barbara
Picconi1, 2,
Diego
Centonze1, 2,
Antonio
Pisani1, 2,
Paola
Bonsi1, 2,
Paul
Greengard4,
Robert A.
Hipskind5,
Emiliana
Borrelli6, and
Giorgio
Bernardi1, 2
1 Clinica Neurologica, Dipartimento di Neuroscienze,
Università di "Tor Vergata," Rome 00133, Italy,
2 Fondazione Santa Lucia IRCCS, Rome 00179, Italy,
3 Istituto di Neuroscienze e Medicina Molecolare, Consiglio
Nazionale delle Ricerche, Rome 00133, Italy, 4 Laboratory
of Molecular and Cellular Neuroscience, Rockefeller University, New
York 10021, New York, 5 Institut de Génétique
Moléculaire, Centre National de la Recherche Scientifique
(CNRS)-Unité Mixte de Recherche 5535, Montpellier 34293, France,
and 6 Institut de Génétique et de Biologie
Moléculaire et Cellulaire, CNRS-Institut National de la
Santé et de la Recherche Médicale-ULP, CU de
Strasbourg 67404, France
Abnormal involuntary movements and cognitive impairment represent
the classical clinical symptoms of Huntington's disease (HD). This
genetic disorder involves degeneration of striatal spiny neurons, but
not striatal large cholinergic interneurons, and corresponds to a
marked decrease in the activity of mitochondrial complex II [succinate
dehydrogenase (SD)] in the brains of HD patients. Here we have
examined the possibility that SD inhibitors exert their toxic action by
increasing glutamatergic transmission. We report that SD inhibitors
such as 3-nitroproprionic acid (3-NP), but not an inhibitor of
mitochondrial complex I, produce a long-term potentiation of the
NMDA-mediated synaptic excitation (3-NP-LTP) in striatal spiny neurons.
In contrast, these inhibitors had no effect on excitatory synaptic
transmission in striatal cholinergic interneurons and pyramidal
cortical neurons. 3-NP-LTP involves increased intracellular calcium and
activation of the mitogen-activated protein kinase extracellular
signal-regulated kinase and is critically dependent on endogenous
dopamine acting via D2 receptors, whereas it is negatively regulated by
D1 receptors. Thus 3-NP-LTP might play a key role in the regional and
cell type-specific neuronal death observed in HD.
Key words:
D2 dopamine receptors; Huntington's disease; striatum; succinate dehydrogenase; synaptic plasticity; excitotoxicity
Copyright © 2001 Society for Neuroscience 0270-6474/01/21145110-11$05.00/0
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