title: Evidence for disrupted NMDA receptor function in tissue plasminogen activator knockout mice.
abstract: Tissue plasminogen activator (tPA), a serine protease immediate-early gene product expressed in brain areas important in learning and memory, has been shown to cleave the NR1 subunit of the NMDA receptor leading to a potentiated Ca(2+) influx. Mice lacking tPA (tPA-/- mice) have disrupted late phase-LTP in the hippocampus, possibly as a consequence of reduced Ca(2+) flux through NMDA receptors. In the present experiments, we investigated whether the NMDA antagonist dizocilpine might alter performance in tPA-/- mice in behavioural tasks shown to be sensitive to hippocampal lesions. tPA-/- mice and wild-type controls (WT) showed similar rates of acquisition and performance of a spatial working memory task (eight-arm radial maze). Dizocilpine (0.03-0.3 mg/kg, i.p.), given acutely, disrupted performance by increasing the number of errors equally across both genotypes. At asymptotic performance of a differential reinforcement of low response rate operant task (DRL), acute dizocilpine (0.03-0.3 mg/kg) impaired performance, but no differences between genotypes were observed. However, dizocilpine (0.1 mg/kg), given repeatedly during acquisition of a signalled-DRL15" task, retarded acquisition in tPA-/- but not WT mice. This treatment regime had no effect on locomotor activity in either genotype. tPA-/- mice showed no spatial learning deficits, but were more sensitive to dizocilpine during acquisition (though not expression) of a DRL task. This supports a role for tPA in modification of the NMDA receptor, although absence of tPA does not have consequences for all forms of NMDA-dependent mediated learning.
authors.affiliation: Laboratory of Experimental Psychology, University of Sussex, Falmer, Brighton BN1 9QG, UK.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Horwood
authors.forename: Tamzin L
authors.initials: TL
authors.lastname: Ripley
authors.forename: David N
authors.initials: DN
authors.lastname: Stephens
mesh_terms: D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D003463:Cues; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000235:genetics*; D013028:Space Perception / Q000502:physiology; D010959:Tissue Plasminogen Activator / Q000235:genetics*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D010959:Tissue Plasminogen Activator