Motor learning and metaplasticity in striatal neurons: Relevance for Parkinson's disease

Paolo Calabresi, Nadia Giordano, Attilio Iemolo, Maria Mancini, Fabrizio Cacace, Maria De Risi, Emanuele Claudio Latagliata, Veronica Ghiglieri, Gian Carlo Bellenchi, Stefano Puglisi-Allegra, Barbara Picconi, Elvira De Leonibus

Risultato della ricerca: Contributo in rivistaArticolo in rivista

23 Citazioni (Scopus)

Abstract

Nigro-striatal dopamine transmission is central to a wide range of neuronal functions, including skill learning, which is disrupted in several pathologies such as Parkinson's disease. The synaptic plasticity mechanisms, by which initial motor learning is stored for long time periods in striatal neurons, to then be gradually optimized upon subsequent training, remain unexplored. Addressing this issue is crucial to identify the synaptic and molecular mechanisms involved in striatal-dependent learning impairment in Parkinson's disease. In this study, we took advantage of interindividual differences between outbred rodents in reaching plateau performance in the rotarod incremental motor learning protocol, to study striatal synaptic plasticity ex vivo. We then assessed how this process is modulated by dopamine receptors and the dopamine active transporter, and whether it is impaired by overexpression of human α-synuclein in the mesencephalon; the latter is a progressive animal model of Parkinson's disease. We found that the initial acquisition of motor learning induced a dopamine active transporter and D1 receptors mediated long-Term potentiation, under a protocol of long-Term depression in striatal medium spiny neurons. This effect disappeared in animals reaching performance plateau. Overexpression of human α-synuclein reduced striatal dopamine active transporter levels, impaired motor learning, and prevented the learning-induced long-Term potentiation, before the appearance of dopamine neuronal loss. Our findings provide evidence of a reorganization of cellular plasticity within the dorsolateral striatum that is mediated by dopamine receptors and dopamine active transporter during the acquisition of a skill. This newly identified mechanism of cellular memory is a form of metaplasticity that is disrupted in the early stage of synucleinopathies, such as Parkinson's disease, and that might be relevant for other striatal pathologies, such as drug abuse.
Lingua originaleEnglish
pagine (da-a)505-520
Numero di pagine16
RivistaBRAIN
Volume141
DOI
Stato di pubblicazionePubblicato - 2018

Keywords

  • Animals
  • Benzazepines
  • Corpus Striatum
  • Dopamine Antagonists
  • Dopamine Plasma Membrane Transport Proteins
  • Dopamine Uptake Inhibitors
  • Green Fluorescent Proteins
  • Learning
  • Long-Term Potentiation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Motor Activity
  • Motor Skills
  • Neuronal Plasticity
  • Neurons
  • Piperazines
  • Reaction Time
  • Synapsins
  • Synaptophysin
  • Tyrosine 3-Monooxygenase
  • alpha-Synuclein
  • alpha-synucleinopathy
  • dopamine active transporter
  • long-Term depression and potentiation
  • motor learning
  • striatal plasticity

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