Cognitive impairment and dentate gyrus synaptic dysfunction in experimental Parkinsonism

Alessandra Bonito-Oliva, Marco Pignatelli, Giada Spigolon, Takashi Yoshitake, Stefanie Seiler, Francesco Longo, Sonia Piccinin, Jan Kehr, Nicola B. Mercuri, Robert Nisticò, Gilberto Fisone

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Parkinson's disease (PD) is characterized by the progressive degeneration of the nigrostriatal dopaminergic pathway and the emergence of rigidity, tremor, and bradykinesia. Accumulating evidence indicates that PD is also accompanied by nonmotor symptoms including cognitive deficits, often manifested as impaired visuospatial memory. Methods: We studied cognitive performance and synaptic plasticity in a mouse model of PD, characterized by partial lesion of the dopaminergic and noradrenergic inputs to striatum and hippocampus. Sham- and 6-hydroxydopamine-lesioned mice were subjected to the novel object recognition test, and long-term potentiation was examined in the dentate gyrus and CA1 regions of the hippocampus. Results: Bilateral 6-hydroxydopamine lesion reduced long-term but not short-term novel object recognition and decreased long-term potentiation specifically in the dentate gyrus. These abnormalities did not depend on the loss of noradrenaline but were abolished by the antiparkinsonian drug, L-DOPA, or by SKF81297, a dopamine D1-type receptor agonist. In contrast, activation of dopamine D2-type receptors did not modify the effects produced by the lesion. Blockade of the extracellular signal-regulated kinases prevented the ability of SKF81297 to rescue novel object recognition and long-term potentiation. Conclusions: These findings show that partial dopamine depletion leads to impairment of long-term recognition memory accompanied by abnormal synaptic plasticity in the dentate gyrus. They also demonstrate that activation of dopamine D1 receptors corrects these deficits, through a mechanism that requires intact extracellular signal-regulated kinases signaling.

Original languageEnglish
Pages (from-to)701-710
Number of pages10
JournalBiological Psychiatry
Volume75
Issue number9
DOIs
Publication statusPublished - May 1 2014

Keywords

  • Dopamine D1 receptor
  • extracellular signal-regulated kinases
  • hippocampus
  • long-term potentiation
  • mouse
  • novel object recognition
  • Parkinson's disease

ASJC Scopus subject areas

  • Biological Psychiatry
  • Medicine(all)

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