AAV-mediated chronic over-expression of SNAP-25 in adult rat dorsal hippocampus impairs memory-associated synaptic plasticity

McKee, Alex G.; Loscher, Jennifer S.; O'Sullivan, Niamh C.; Chadderton, Naomi; Palfi, Arpad; Batti, Laura; Sheridan, Graham K.; O'Shea, Sean; Moran, Mary; McCabe, Olive; Fern�ndez, Alfonso Blanco; Pangalos, Menelas N.; O'Connor, John J.; Regan, Ciaran M.; O'Connor, William T.; Humphries, Peter; Farrar, G. Jane; Murphy, Keith J.

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 adenoassociated 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. © 2009 International Society for Neurochemistry.

Citation

McKee, A. G., Loscher, J. S., O'Sullivan, N. C., Chadderton, N., Palfi, A., Batti, L., …Murphy, K. J. (2010). AAV-mediated chronic over-expression of SNAP-25 in adult rat dorsal hippocampus impairs memory-associated synaptic plasticity. Journal of Neurochemistry, 112(4), 991-1004. https://doi.org/10.1111/j.1471-4159.2009.06516.x

• Journal Article Type: Article
• Acceptance Date: Nov 22, 2009
• Online Publication Date: Jan 20, 2010
• Publication Date: 2010-02
• Deposit Date: Aug 16, 2022
• Journal: Journal of Neurochemistry
• Print ISSN: 0022-3042
• Electronic ISSN: 1471-4159
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 112
• Issue: 4
• Pages: 991-1004
• DOI: https://doi.org/10.1111/j.1471-4159.2009.06516.x
• Public URL: https://nottingham-repository.worktribe.com/output/10076611
• Publisher URL: https://onlinelibrary.wiley.com/doi/10.1111/j.1471-4159.2009.06516.x