AAV-mediated chronic over-expression of SNAP-25 in adult rat dorsal hippocampus impairs memory-associated synaptic plasticity.
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.
McKee
Alex G
AG
Applied Neurotherapeutics Research Group, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland. amckee@tcd.ie
Loscher
Jennifer S
JS
O'Sullivan
Niamh C
NC
Chadderton
Naomi
N
Palfi
Arpad
A
Batti
Laura
L
Sheridan
Graham K
GK
O'Shea
Sean
S
Moran
Mary
M
McCabe
Olive
O
Fernández
Alfonso Blanco
AB
Pangalos
Menelas N
MN
O'Connor
John J
JJ
Regan
Ciaran M
CM
O'Connor
William T
WT
Humphries
Peter
P
Farrar
G Jane
GJ
Murphy
Keith J
KJ
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
D050825:Synaptosomal-Associated Protein 25; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D018698:Glutamic Acid