Dopamine-Dependent Long-Term Potentiation Induced by 3-Nitropropionic Acid in Striatal Medium Spiny Neurons
Part of the
Advances in Behavioral Biology
book series (ABBI, volume 53)
The classical clinical symptoms of Huntington’s disease (HD) include abnormal involuntary movements (chorea) and cognitive impairment. This genetically determined disorder selectively involves degeneration of striatal spiny neurons while sparing striatal large cholinergic interneurons.1 HD is caused by an expansion of CAG repeats near the 5′ end of the IT15 gene. IT15 encodes an ubiquitously expressed protein called huntingtin. Moreover, a remarkable decrease in the activity of mitochondrial complex II (succinate dehydrogenase, SD) has been found in brains of HD patients.2 Indeed, the link between bioenergetic defects and excitotoxic mechanisms, two pathological events which seems to play a major role in HD3,4 to the mutated huntingtin, remains unknown. The corticostriatal projection represents one of the major glutamatergic pathways in the brain and an abnormal release of glutamate from this pathway seems to play a pathogenic role in HD. The complex II inhibitors 3-nitropropionic acid (3-NP) and methylmalonic acid (MMA) mimic the pathology of HD.5,6 Thus, enhanced glutamatergic transmission may trigger neurodegeneration in neurons, the energy metabolism of which is compromised due to impaired SD activity. We studied the electrophysiological effects of the pharmacological blockade of SD by either 3-NP or MMA on glutamatergic excitatory postsynaptic potentials (EPSPs), in order to investigate the link between metabolism impairment and glutamatergic transmission both in striatal spiny neurons and cholinergic interneurons. The t-LTP might play a key role in the regional and cell-type specific neuronal death observed in HD.
KeywordsGlutamatergic Transmission Methylmalonic Acid Cholinergic Interneuron EPSP Amplitude Striatal Medium Spiny Neuron
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R.J. Ferrante, N.J. Kowall, M.F. Beal, E.P. Richardson, and J.B. Martin, Selective sparing of a class of striatal neurons in Huntington’s disease. Science
, 561–563. (1985)CrossRefGoogle Scholar
M. Gu, M.T. Gash, V.M. Mann, F. Javoy-Agid, J.M. Cooper, and A.H. Schapira, Mitochondrial defect in Huntington’s disease caudate nucleus. Ann. Neurol.
, 385–389 (1996).PubMedCrossRefGoogle Scholar
S.E. Browne, A.C. Bowling, U. MacGarvey, M.J. Baik, S.C. Berger, MMK Muqit, E.D. Bird, and M.F. Beal, Oxidative damage and metabolic dysfunction in Huntington’s disease: selective vulnerability of the basal ganglia. Ann. Neurol.
, 646–653 (1997).PubMedCrossRefGoogle Scholar
J.G. Greene, J.T. Greenamyre, Bioenergetics and glutamate excitotoxicity. Prog. Neurobiol.
, 613–634 (1996).PubMedCrossRefGoogle Scholar
U. Wullner, A.B. Young, J.B. Penney, and M.F. Beal, 3-Nitropropionic acid toxicity in the striatum. J. Neurochem.
, 1772–1781 (1994).PubMedCrossRefGoogle Scholar
J.G. Greene, R.H. Porter, R.V. Eller, and JT. Greenamyre, Inhibition of succinate dehydrogenase by malonic acid produces an “excitotoxic” lesion in rat striatum. J. Neurochem.
, 1151–1154 (1993).PubMedCrossRefGoogle Scholar
P. Calabresi, D. Centonze, P. Gubellini, GA. Marfia, A. Pisani, G. Sancesario, G. Bernardi, Synaptic transmission in the striatum: from plasticity to neurodegeneration. Prog. Neurobiol.
, 231–265 (2000).PubMedCrossRefGoogle Scholar
Y. Kawaguchi, C.J. Wilson, S.J. Augood, P.C. Emson, Striatal interneurons: chemical, physiological and morphological characterization. Trends Neurosci
, 527–535, (1995).PubMedCrossRefGoogle Scholar
G. Paxinos, and C. Watson, The rat brain in stereotaxic coordinates. Sydney, Australia: Academic.(1986).Google Scholar
A.N. Murphy, G. Fiskum, and M.F. Beal, Mitochondria in neurodegeneration: bioenergetic function in cell life and death. J. Cereb. Blood Flow Metab.
, 231–245. (1999).PubMedCrossRefGoogle Scholar
A. Antonini, K.L. Leenders, and D. Eidelberg, [11C]raclopride-PET studies of the Huntington’s disease rate of progression: relevance of the trinucleotide repeat length. Ann. Neurol.
, 253–255 (1998).PubMedCrossRefGoogle Scholar
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