Mechanisms underlying altered striatal synaptic plasticity in old A53T-α synuclein overexpressing mice

Alessandro Tozzi, Cinzia Costa, Sabrina Siliquini, Michela Tantucci, Barbara Picconi, Alexander Kurz, Suzana Gispert, Georg Auburger, Paolo Calabresi

Research output: Contribution to journalArticle

Abstract

The interactions between certain α-synuclein (SNCA) conformations and dopamine (DA) metabolism cause selective DA neuron degeneration in Parkinson's disease (PD). Preclinical research on PD took advantage of increasing studies involving different animal models which express different forms of mutated SNCA. Transgenic animals expressing mutant α-synucleins such as mice transgenic for A53T-SNCA (TG) are considered valuable models to assess specific aspects of the pathogenesis of synucleinopathies and PD. In this study we performed electrophysiological recordings in corticostriatal slice preparations from young TG overexpressing mice, in which extracellular striatal DA levels appeared to be normal, and in old TG mice, characterized by abnormalities in striatal DA signaling and impaired long-term depression (LTD). We report no difference in TG mice from the two groups of age of either the basal membrane properties and synaptic striatal excitability in respect to age-matched wild-type mice. Furthermore, in old TG mice, showing plastic abnormalities and motor symptoms, we investigated the mechanisms at the basis of the altered LTD. In old TG mice LTD could not be restored by treatments with acute application of DA or by subchronic treatment with L-3,4-dihydroxyphenylalanine (L-DOPA). Conversely, the application of the phosphodiesterase inhibitor zaprinast fully restored LTD to normal conditions via the stimulation of a cyclic guanosine monophosphate (GMP)-protein kinase G-dependent intracellular signaling pathway. These results suggest that, in addition to the dopaminergic alterations reported in this genetic model of PD, other signal transduction pathways linked to striatal synaptic plasticity are altered in an age-dependent manner.

Original languageEnglish
Pages (from-to)1792-1799
Number of pages8
JournalNeurobiology of Aging
Volume33
Issue number8
DOIs
Publication statusPublished - Aug 2012

Keywords

  • A53T-SNCA mutation
  • Alpha-synuclein
  • Dopamine
  • L-DOPA
  • Long-term depression
  • Parkinson's disease
  • Phosphodiesterase
  • PKG

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)
  • Ageing
  • Developmental Biology
  • Geriatrics and Gerontology

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