title: Cognitive deficits associated with alteration of synaptic metaplasticity precede plaque deposition in AβPP23 transgenic mice.
abstract: Synaptic dysfunction is an early event in the development of Alzheimer's disease (AD) and relates closely to the cognitive impairment characterizing this neurodegenerative process. A causative association has been proposed, largely on the basis of in vitro studies, between memory decline, soluble amyloid-β (Aβ) oligomers and alterations of glutamatergic neurotransmission. We aimed here to characterize in vivo N-methyl-D-aspartate receptor (NMDAR)-mediated signaling, at an early stage of AD, before extracellular amyloid plaques are deposited. We assessed the functional link between cognitive abilities and NMDAR-mediated pharmacological responses of six-month-old AβPP23 transgenic mice (AβPP23tg), overexpressing the human amyloid-β protein precursor carrying the Swedish double mutation. We found evidence of cognitive impairments in these mice, indicated by deficits in the delayed-non-matching-to-place task. Alterations of NMDAR-mediated signaling in this mouse model were confirmed by the reduced sensitivity of motor-activation and working memory to pharmacological inhibition of NMDAR activity. At the molecular level, AβPP23tg mice show hippocampal alterations in the trafficking of synaptic NMDAR subunits NR2A and NR2B and at an ultrastructural analysis show Aβ oligomers intracellularly localized in the synaptic compartments. Importantly, the behavioral and biochemical alterations of NMDAR signaling are associated with the inhibition of long-term synaptic potentiation and inversion of metaplasticity at CA1 synapses in hippocampal slices from AβPP23tg mice. These results indicate a general impairment of synaptic function and learning and memory in young AβPP23tg mice with Aβ oligomers but no amyloid plaques.
authors.affiliation: Department of Neuroscience, Department of Cardiovascular Research, Mario Negri Institute for Pharmacological Research, Milan, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Balducci
authors.forename: Raffaella
authors.initials: R
authors.lastname: Tonini
authors.forename: Elisa
authors.initials: E
authors.lastname: Zianni
authors.forename: Cristiano
authors.initials: C
authors.lastname: Nazzaro
authors.forename: Fabio
authors.initials: F
authors.lastname: Fiordaliso
authors.forename: Monica
authors.initials: M
authors.lastname: Salio
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Vismara
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Gardoni
authors.forename: Monica
authors.initials: M
authors.lastname: Di Luca
authors.forename: Mirjana
authors.initials: M
authors.lastname: Carli
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Forloni
mesh_terms: D016229:Amyloid beta-Peptides / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D003072:Cognition Disorders / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000235:genetics; D010446:Peptide Fragments / Q000235:genetics*; D058225:Plaque, Amyloid / Q000235:genetics* / Q000473:pathology; D013569:Synapses / Q000235:genetics* / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments