Anti-NR1 N-terminal-domain vaccination unmasks the crucial action of tPA on NMDA-receptor-mediated toxicity and spatial memory
Journal of Cell Science. 2007-02-15; 120(4): 578-585
DOI: 10.1242/jcs.03354
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Fine-tuning of NMDA glutamatergic receptor signalling strategically controls
crucial brain functions. This process depends on several ligands and modulators,
one of which unexpectedly includes the serine protease tissue-type plasminogen
activator (tPA). In vitro, tPA increases NMDA-receptor-mediated calcium influx by
interacting with, and then cleaving, the NR1 subunit within its N-terminal
domain. Owing to lack of in vivo evidence of the relevance and contribution of
this mechanism in physiological and pathological brain processes, active
immunisation was developed here in mice, to allow transient and specific
prevention of the interaction of tPA with the NR1 subunit. Immunisation
significantly reduced the severity of ischemic and excitotoxic insults in the
mouse brain. Cognitive function was altered in some, but not all behavioural
tasks affected in tPA-deficient mice. Our data demonstrate that in vivo, tPA
controls neurotoxicity and the encoding of novel spatial experiences by binding
to and cleaving the NMDA receptor NR1 subunit. Interesting therapeutic
possibilities for several brain pathologies that involve excitotoxicity may now
be envisaged.