Induction of corticostriatal LTP by 3-nitropropionic acid requires the activation of mGluR1/PKC pathway

Paolo Gubellini, Diego Centonze, Domenicantonio Tropepi, Giorgio Bernardi, Paolo Calabresi

Research output: Contribution to journalArticlepeer-review

Abstract

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder typically affecting individuals in midlife. HD is characterized by the selective loss of striatal spiny neurons, while large cholinergic interneurons are spared. An impaired mitochondrial complex II (succinate dehydrogenase, SD) activity is known as a prominent metabolic alteration in HD. Accordingly, chronic treatment with 3-nitropropionic acid (3-NP), an irreversible SD inhibitor, mimics motor abnormalities and pathology of HD in several animal models. We have previously shown that in vitro application of 3-NP induces a long-term potentiation (LTP) of corticostriatal synaptic transmission through NMDA glutamate receptor. Since this 3-NP-induced LTP (3-NP-LTP) is shown by striatal spiny neurons, but not by cholinergic interneurons, it might play a role in the regional and cell type-specific neuronal death observed in HD. Here we investigate the role of group I metabotropic glutamate receptors (mGluRs) in the induction of 3-NP-LTP. We report that selectively blocking mGluR1, but not mGluR5, suppresses 3-NP-LTP induction. Moreover, we show that a PKC-mediated mechanism is involved in the formation of 3-NP-LTP. Characterizing the cellular mechanisms underlying 3-NP-LTP may provide new insights to better understand the processes leading to the selective neuronal loss observed in HD.

Original languageEnglish
Pages (from-to)761-769
Number of pages9
JournalNeuropharmacology
Volume46
Issue number6
DOIs
Publication statusPublished - May 2004

Keywords

  • Electrophysiology
  • Glutamate
  • Huntington's disease
  • LY 367385
  • MPEP
  • Succinate dehydrogenase
  • Synaptic plasticity

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Drug Discovery
  • Pharmacology

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