Evidence for disrupted NMDA receptor function in tissue plasminogen activator knockout mice.

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.