title: Cognitive impairment and dentate gyrus synaptic dysfunction in experimental parkinsonism.
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.
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bonito-Oliva
authors.affiliation: Department of Physiology and Pharmacology, University of Rome "La Sapienza", Rome, Italy; Pharmacology of Synaptic Plasticity Unit, European Brain Research Institute, Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Pignatelli
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Giada
authors.initials: G
authors.lastname: Spigolon
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoshitake
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Seiler
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Francesco
authors.initials: F
authors.lastname: Longo
authors.affiliation: Department of Physiology and Pharmacology, University of Rome "La Sapienza", Rome, Italy; Pharmacology of Synaptic Plasticity Unit, European Brain Research Institute, Rome, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Piccinin
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Kehr
authors.affiliation: Laboratory of Experimental Neurology, S. Lucia Foundation, Rome, Italy.
authors.forename: Nicola B
authors.initials: NB
authors.lastname: Mercuri
authors.affiliation: Department of Physiology and Pharmacology, University of Rome "La Sapienza", Rome, Italy; Laboratory of Experimental Neurology, S. Lucia Foundation, Rome, Italy.
authors.forename: Robert
authors.initials: R
authors.lastname: Nisticò
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. Electronic address: gilberto.fisone@ki.se.
authors.forename: Gilberto
authors.initials: G
authors.lastname: Fisone
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000503:physiopathology; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*; D003342:Corpus Striatum / Q000187:drug effects / Q000503:physiopathology; D018891:Dentate Gyrus / Q000187:drug effects / Q000503:physiopathology*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D008810:Mice, Inbred C57BL; D009434:Neural Pathways / Q000187:drug effects / Q000503:physiopathology; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
chemical_list: D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D016627:Oxidopamine
keywords: Dopamine D1 receptor; Parkinson’s disease; extracellular signal-regulated kinases; hippocampus; long-term potentiation; mouse; novel object recognition