Various ligands and modulators are involved in NMDA-receptor signalling, which controls crucial brain functions. Tissue-type plasminogen activator (tPA), for example, interacts with and then cleaves the NR1 subunit of the NMDA receptor, increasing receptor-mediated Ca2+ influx; however, the contribution this interaction makes to brain function and dysfunction is currently a matter of debate. Now, Karim Benchenane and co-workers demonstrate that tPA controls NMDA-receptor-mediated neurotoxicity and spatial memory (see p. 578). They developed an immunological strategy to selectively prevent tPA-NR1 interaction and NR1 cleavage to reveal the role it plays in neuronal death or survival and in behaviour. Blocking the tPA-NR1 interaction prevented permanent cerebral ischemia and reduced the severity of excitotoxic neuronal death in mouse brains. Cognitive function was also altered in some but not all behavioural tasks, indicating the tPA-NR1 interaction is not involved in all tPA-driven functions. The authors speculate that using antibody-based therapies that prevent the tPA-NR1 interaction may improve acute management of stroke patients.