title: AAV-mediated chronic over-expression of SNAP-25 in adult rat dorsal hippocampus impairs memory-associated synaptic plasticity.
abstract: Long-term memory is formed by alterations in glutamate-dependent excitatory synaptic transmission, which is in turn regulated by synaptosomal protein of 25 kDa (SNAP-25), a key component of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex essential for exocytosis of neurotransmitter-filled synaptic vesicles. Both reduced and excessive SNAP-25 activity has been implicated in various disease states that involve cognitive dysfunctions such as attention deficit hyperactivity disorder, schizophrenia and Alzheimer's disease. Here, we over-express SNAP-25 in the adult rat dorsal hippocampus by infusion of a recombinant adeno-associated virus vector, to evaluate the consequence of late adolescent-adult dysfunction of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor protein in the absence of developmental disruption. We report a specific and significant increase in the levels of extracellular glutamate detectable by microdialysis and a reduction in paired-pulse facilitation in the hippocampus. In addition, SNAP-25 over-expression produced cognitive deficits, delaying acquisition of a spatial map in the water maze and impairing contextual fear conditioning, both tasks known to be dorsal hippocampal dependent. The high background transmission state and pre-synaptic dysfunction likely result in interference with requisite synapse selection during spatial and fear memory consolidation. Together these studies provide the first evidence that excess SNAP-25 activity, restricted to the adult period, is sufficient to mediate significant deficits in the memory formation process.
authors.affiliation: Applied Neurotherapeutics Research Group, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland. amckee@tcd.ie
authors.forename: Alex G
authors.initials: AG
authors.lastname: McKee
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Loscher
authors.forename: Niamh C
authors.initials: NC
authors.lastname: O'Sullivan
authors.forename: Naomi
authors.initials: N
authors.lastname: Chadderton
authors.forename: Arpad
authors.initials: A
authors.lastname: Palfi
authors.forename: Laura
authors.initials: L
authors.lastname: Batti
authors.forename: Graham K
authors.initials: GK
authors.lastname: Sheridan
authors.forename: Sean
authors.initials: S
authors.lastname: O'Shea
authors.forename: Mary
authors.initials: M
authors.lastname: Moran
authors.forename: Olive
authors.initials: O
authors.lastname: McCabe
authors.forename: Alfonso Blanco
authors.initials: AB
authors.lastname: Fernández
authors.forename: Menelas N
authors.initials: MN
authors.lastname: Pangalos
authors.forename: John J
authors.initials: JJ
authors.lastname: O'Connor
authors.forename: Ciaran M
authors.initials: CM
authors.lastname: Regan
authors.forename: William T
authors.initials: WT
authors.lastname: O'Connor
authors.forename: Peter
authors.initials: P
authors.lastname: Humphries
authors.forename: G Jane
authors.initials: GJ
authors.lastname: Farrar
authors.forename: Keith J
authors.initials: KJ
authors.lastname: Murphy
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D001703:Biophysics / Q000379:methods; D002461:Cell Line, Transformed; D003214:Conditioning, Classical / Q000502:physiology; D000229:Dependovirus / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000379:methods; D005106:Exploratory Behavior / Q000502:physiology; D005434:Flow Cytometry / Q000379:methods; D005786:Gene Expression Regulation / Q000502:physiology*; D018698:Glutamic Acid / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017551:Microdialysis / Q000379:methods; D009433:Neural Inhibition / Q000502:physiology; D009473:Neuronal Plasticity / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D050825:Synaptosomal-Associated Protein 25 / Q000235:genetics / Q000378:metabolism*; D014161:Transduction, Genetic / Q000379:methods; D014162:Transfection / Q000379:methods
chemical_list: D050825:Synaptosomal-Associated Protein 25; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D018698:Glutamic Acid