Anti-NR1 N-terminal-domain vaccination unmasks the crucial action of tPA on NMDA-receptor-mediated toxicity and spatial memory. - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Journal of Cell Science Année : 2007

Anti-NR1 N-terminal-domain vaccination unmasks the crucial action of tPA on NMDA-receptor-mediated toxicity and spatial memory.

Karim Benchenane
Rosemarie Bluthé
  • Fonction : Auteur
Monica Fernandez-Monreal
José P Lopez-Atalaya
  • Fonction : Auteur
Sabrina Butt-Gueulle
  • Fonction : Auteur
Robert Dantzer
  • Fonction : Auteur

Résumé

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.
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Dates et versions

hal-00178289 , version 1 (10-10-2007)

Identifiants

Citer

Karim Benchenane, Hervé Castel, Michel Boulouard, Rosemarie Bluthé, Monica Fernandez-Monreal, et al.. 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, 120 (Pt 4), pp.578-585. ⟨10.1242/jcs.03354⟩. ⟨hal-00178289⟩
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