Chronic hyperammonemia induces tonic activation of NMDA receptors in cerebellum

• Published in: Journal of neurochemistry 2010-02, Vol.112 (4), p.1005-1014
• Main Authors: ElMlili, Nisrin, Boix, Jordi, Ahabrach, Hanan, Rodrigo, Regina, Errami, Mohammed, Felipo, Vicente
• Format: Article
• Language: English
• Subjects: Aminoacid disorders; Animals; Biological and medical sciences; Brain; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; CaMKII; Central nervous system; Central neurotransmission. Neuromudulation. Pathways and receptors; Cerebellum - drug effects; Cerebellum - metabolism; cGMP; Chronic illnesses; Cyclic GMP - metabolism; Disease Models, Animal; Dizocilpine Maleate - pharmacology; Errors of metabolism; Excitatory Amino Acid Antagonists - pharmacology; Fundamental and applied biological sciences. Psychology; Glutamic Acid - metabolism; hepatic encephalopathy; hyperammonemia; Hyperammonemia - pathology; In Vitro Techniques; Male; Medical sciences; Metabolic diseases; Microdialysis - methods; neuronal nitric oxide synthase; Neurons; Nitrates - metabolism; Nitric oxide; Nitric Oxide Synthase Type I - metabolism; Nitrites - metabolism; NMDA receptor; Phosphorylation - physiology; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate - metabolism; Serine - metabolism; Statistics, Nonparametric; Subcellular Fractions - enzymology; Threonine - metabolism; Vertebrates: nervous system and sense organs
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2009.06520.x

J. Neurochem. (2009) 112, 1005-1014. 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.