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

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

Research output: Contribution to journalArticle

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.
Original languageEnglish
Pages (from-to)991-1004
Number of pages14
JournalJournal of Neurochemistry
Volume112
Issue number4
DOIs
Publication statusPublished - 3 Mar 2010

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    McKee, A. G., Loscher, J. S., O'Sullivan, N. C., Chadderton, N., Palfi, A., Batti, L., Sheridan, G., O'Shea, S., Moran, M., McCabe, O., Fernandez, A. B., Pangalos, M. N., O'Connor, J. J., Regan, C. M., O'Connor, W. T., Humphries, P., Farrar, J. G., & 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