Abstract：
: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.
journal_name
J Cell Scijournal_title
Journal of cell scienceauthors
Benchenane K,Castel H,Boulouard M,Bluthé R,Fernandez-Monreal M,Roussel BD,Lopez-Atalaya JP,Butt-Gueulle S,Agin V,Maubert E,Dantzer R,Touzani O,Dauphin F,Vivien D,Ali Cdoi
10.1242/jcs.03354subject
Has Abstractpub_date
2007-02-15 00:00:00pages
578-85issue
Pt 4eissn
0021-9533issn
1477-9137pii
jcs.03354journal_volume
120pub_type
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