AAV-mediated overexpression of neuroserpin in the hippocampus decreases PSD-95 expression but does not affect hippocampal-dependent learning and memory

Neuroserpin is a serine protease inhibitor, or serpin, that is expressed in the nervous system and inhibits the protease tissue plasminogen activator (tPA). Neuroserpin has been suggested to play a role in learning and memory but direct evidence for such a role is lacking. Here we have used an adeno...

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Bibliographic Details
Published in:PloS one 2014-03, Vol.9 (3), p.e91050-e91050
Main Authors: Tsang, Vicky W K, Young, Deborah, During, Matthew J, Birch, Nigel P
Format: Article
Language:English
Subjects:
Animals
Anxiety - metabolism
Associative learning
Biology
Brain
Dependovirus - metabolism
Disks Large Homolog 4 Protein
Fear
Gene Expression
Genetic vectors
Genetic Vectors - metabolism
HEK293 Cells
Hippocampus - metabolism
Humans
Intracellular Signaling Peptides and Proteins - metabolism
Learning
Male
Membrane Proteins - metabolism
Memory
Neuronal Plasticity
Neuropeptides - metabolism
Neuroserpin
Plasminogen Activator Inhibitor 1 - metabolism
Protease inhibitors
Proteases
Rats, Wistar
Recombinant Fusion Proteins - metabolism
Secretory Pathway
Serpins - metabolism
Tissue plasminogen activator
Tissue Plasminogen Activator - metabolism
Transduction, Genetic
Transgenes
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Summary:Neuroserpin is a serine protease inhibitor, or serpin, that is expressed in the nervous system and inhibits the protease tissue plasminogen activator (tPA). Neuroserpin has been suggested to play a role in learning and memory but direct evidence for such a role is lacking. Here we have used an adeno-associated virus (AAV) vector expression system to investigate the effect of neuroserpin on hippocampal-dependent learning and memory in the young adult rat. A FLAG-tagged neuroserpin construct was initially characterized by in vitro transcription/translation and transfection into HEK293 cells and shown to interact with tPA and be targeted to the secretory pathway. Targeted injection of a chimeric AAV1/2 vector expressing FLAG-neuroserpin resulted in localized overexpression in the dorsal hippocampus. Neuroserpin overexpression led to the appearance of an unstable neuroserpin:tPA complex in zymographic assays consistent with interaction with endogenous tPA in vivo. Rats overexpressing neuroserpin also showed a significant decrease in the levels of postsynaptic density protein 95, a major postsynaptic scaffolding protein. Three weeks after injection, a range of behavioural tests was performed to measure spatial and associative learning and memory, as well as innate and acquired fear. These tests provided no evidence of a role for neuroserpin in hippocampal-dependent learning and memory. In summary this study does not support a role for neuroserpin in hippocampal-dependent learning and memory in young adult rats but does suggest an involvement of neuroserpin in hippocampal synaptic plasticity.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0091050