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First published online 23 January 2007
doi: 10.1242/jcs.03354

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

Karim Benchenane^1,*, Hervé Castel¹, Michel Boulouard², Rosemarie Bluthé³, Monica Fernandez-Monreal^1,, Benoit D. Roussel¹, José P. Lopez-Atalaya¹, Sabrina Butt-Gueulle², Véronique Agin¹, Eric Maubert¹, Robert Dantzer³, Omar Touzani⁴, François Dauphin², Denis Vivien^1, and Carine Ali¹

¹ INSERM, INSERM-Avenir `tPA in the working brain'; Université de Caen Basse-Normandie; Cyceron; 14074 Caen Cedex, France
² Université de Caen Basse-Normandie, EA 3915, CERMN, Pharmacologie-Physiologie, UFR des Sciences Pharmaceutiques, 14032 Caen, France
³ INRA, U1244; Université de Bordeaux 2; CNRS, FRE2723, 33077 Bordeaux, France
⁴ CNRS, UMR-6185; Université de Caen Basse-Normandie; Cyceron; 14074 Caen Cedex, France

Author for correspondence (e-mail: vivien{at}cyceron.fr)

Accepted 21 November 2006

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.

Key words: Excitotoxicity, Stroke, Immunisation, NMDA receptor, Spatial memory, Tissue-type plasminogen activator

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