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Evidence for disrupted NMDA receptor function in tissue plasminogen activator knockout mice
Jennifer M Horwood1, Tamzin L Ripley, David N Stephens
1Laboratory of Experimental Psychology, University of Sussex, Falmer, Brighton BN1 9QG, UK.
Behavioural Brain Research
|March 23, 2004
Summary
Mice lacking tissue plasminogen activator (tPA) showed no spatial learning deficits but were more sensitive to the NMDA antagonist dizocilpine during specific learning tasks, suggesting tPA influences NMDA receptor function.
Area of Science:
- Neuroscience
- Molecular Biology
- Behavioral Science
Background:
- Tissue plasminogen activator (tPA), a serine protease, is expressed in brain regions vital for learning and memory.
- tPA cleaves the NR1 subunit of the NMDA receptor, potentiating Ca(2+) influx.
- Mice lacking tPA exhibit impaired late-phase Long-Term Potentiation (LTP) in the hippocampus.
Purpose of the Study:
- To investigate the behavioral effects of the NMDA antagonist dizocilpine in mice lacking tPA (tPA-/-) compared to wild-type (WT) controls.
- To assess the role of tPA in NMDA receptor-dependent learning and memory processes.
Main Methods:
- Behavioral testing of tPA-/- and WT mice on spatial working memory (eight-arm radial maze) and differential reinforcement of low response rate (DRL) operant tasks.
- Acute and repeated administration of dizocilpine at varying doses.
- Assessment of locomotor activity.
Main Results:
- tPA-/- and WT mice showed similar performance on the spatial working memory task.
- Acute dizocilpine impaired performance in both genotypes on the DRL task.
- Repeated dizocilpine administration during acquisition of a signalled-DRL task retarded learning specifically in tPA-/- mice.
- Locomotor activity was unaffected by the dizocilpine treatment regime.
Conclusions:
- Absence of tPA does not impair spatial learning but increases sensitivity to dizocilpine during the acquisition of a DRL task.
- These findings support a role for tPA in the modification of NMDA receptor function.
- tPA is implicated in specific forms of NMDA receptor-dependent learning.