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Chronic hyperammonemia induces tonic activation of NMDA receptors in cerebellum
Author(s) -
ElMlili Nisrin,
Boix Jordi,
Ahabrach Hanan,
Rodrigo Regina,
Errami Mohammed,
Felipo Vicente
Publication year - 2010
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2009.06520.x
Subject(s) - hyperammonemia , nmda receptor , glutamate receptor , medicine , cerebellum , endocrinology , chemistry , long term depression , nitric oxide , receptor , nitric oxide synthase , biology , ampa receptor , biochemistry
J. Neurochem . (2009) 112 , 1005–1014. Abstract Reduced function of the glutamate–nitric oxide (NO)–cGMP pathway is responsible for some cognitive alterations in rats with hyperammonemia and hepatic encephalopathy. Hyperammonemia impairs the pathway in cerebellum by increasing neuronal nitric oxide synthase (nNOS) phosphorylation in Ser847 by calcium‐calmodulin‐dependent protein kinase II (CaMKII), reducing nNOS activity, and by reducing nNOS amount in synaptic membranes, which reduces its activation following NMDA receptors activation. The reason for increased CaMKII activity in hyperammonemia remains unknown. We hypothesized that it would be as a result of increased tonic activation of NMDA receptors. The aims of this work were to assess: (i) whether tonic NMDA activation receptors is increased in cerebellum in chronic hyperammonemia in vivo ; and (ii) whether this tonic activation is responsible for increased CaMKII activity and reduced activity of nNOS and of the glutamate–NO–cGMP pathway. Blocking NMDA receptors with MK‐801 increases cGMP and NO metabolites in cerebellum in vivo and in slices from hyperammonemic rats. This is because of reduced phosphorylation and activity of CaMKII, leading to normalization of nNOS phosphorylation and activity. MK‐801 also increases nNOS in synaptic membranes and reduces it in cytosol. This indicates that hyperammonemia increases tonic activation of NMDA receptors leading to reduced activity of nNOS and of the glutamate–NO–cGMP pathway.