Anti-NR1 N-terminal-domain vaccination unmasks the crucial action of tPA on NMDA-receptor-mediated toxicity and spatial memory.
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.
Benchenane
Karim
K
INSERM, INSERM-Avenir tPA in the working brain, Université de Caen Basse-Normandie, Cyceron, 14074 Caen Cedex, France.
Castel
Hervé
H
Boulouard
Michel
M
Bluthé
Rosemarie
R
Fernandez-Monreal
Monica
M
Roussel
Benoit D
BD
Lopez-Atalaya
José P
JP
Butt-Gueulle
Sabrina
S
Agin
Véronique
V
Maubert
Eric
E
Dantzer
Robert
R
Touzani
Omar
O
Dauphin
François
F
Vivien
Denis
D
Ali
Carine
C
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005260:Female; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects*; D051379:Mice; D018448:Models, Immunological; D016202:N-Methylaspartate / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry* / Q000378:metabolism*; D010959:Tissue Plasminogen Activator / Q000172:deficiency / Q000378:metabolism*; D014611:Vaccination
D018690:Excitatory Amino Acid Agonists; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D010959:Tissue Plasminogen Activator