Abstract
Alterations of excitatory amino acid neurotransmitters have previously been described in brain in congenital ornithine transcarbamylase (OTC) deficiency. In order to further elucidate the role of the glutamatergic neurotransmitter system in OTC deficiency, densities of binding sites for [3H]MK801, an NMDA receptor antagonist ligand were measured by quantitative receptor autoradiography in the brains of chronically hyperammonemic sparse-fur mice (spf), mutant mice with a congenital defect of OTC. [3H]MK801 binding site densities were significantly reduced by up to 57% (p<0.01) in 16 out of 17 brain regions of OTC-deficient mice. Such changes could result from either neuronal cell loss in these animals or from “down-regulation” of these sites as a consequence of exposure to increased extracellular concentrations of glutamate or quinolinic acid, two known endogenous NMDA receptor ligands previously found to be increased in brain in chronic hyperammonemic syndromes. Reduced NMDA receptor densities in congenital OTC deficiency could represent an adaptive mechanism of protection against further excitotoxic brain injury.
Similar content being viewed by others
References
Butterworth, R.F. (1994). Hepatic Encephalopathy. InThe Liver Biology and Pathobiology:Third Edition (I.M. Arias, J.L. Boyer, N. Fausto, W.B. Jakoby, D.A. Schachter, and D.A. Shafritz, eds), Raven Press, Ltd, New York, pp. 1193–1208.
DeMars, R., LeVan, S.L., Trend, B.L. and Russell, L.B. (1976) Abnormal ornithine carbamyltransferase in mice having the sparse-fur mutation.Proc. Natl. Acad. Sci. (USA) 73:1693–1697.
Dienst, S.G. (1961). An ion exchange method for plasma ammonia concentration.J. Lab. Clin. Med. 58:149–155.
Dolman, C.L., Clasen, R.A. and Dorovini-Zis, K. (1988). Severe cerebral damage in ornithine transcarbamylase deficiency.Clin. Neuropathol. 7:10–15.
Greenamyre, J.T., Olson, J.M.M., Penney, J.B., and Young, A.B. (1985). Autoradiographic characterization of N-methyl-D-aspartate-, quisqualate-, and kainate-sensitive glutamate binding sites.J. Pharmacol. Exp. Ther. 233:254–263.
Harding, B.N., Leonard, J.V., and Erdohazi, M. (1984). Ornithine carbamyltransferase deficiency. A neuropathological study.Pediatrics 141:215–220.
Lowry, O.H., Rosebrough, N.J., Farr, A.L., and Randall, R.J. (1951). Protein measurement with the folin-phenol reagent.J. Biol. Chem. 193:265–275.
Marescau, B., Qureshi, I.A., DeDeyn, P.P., Letarte, J., Ryba, R, and Lowenthal, A. (1985). Guanidino compounds in plasma, urine and cerebrospinal fluid of hyperargininemic patients during therapy.Clin. Chim. Acta. 146:21–27.
Moroni, F., Lombardi, G., Carla, V., Pellegrini, D., Carassale, G.L., Cortesini, C. (1986a). Content of quinolinic acid and other tryptophan metabolites increases in brain regions of rats used as experimental models of hepatic encephalopathy.J. Neurochem. 46:869–874.
Moroni, F., Lombardi, G., Carla, V., Lal, S., Etienne, P., Nair, N.P.V. (1986b). Increase in the content of quinolinic acid in cerebrospinal fluid and frontal cortex of patients with hepatic failure.J. Neurochem. 47:1667–1671.
Moroni, F., Riggio, O., Carla, V., Festuccia, V., Ghinelli, F., Marino, I.R., Merli, M., et al. (1987). Hepatic encephalopathy: lack of changes of γ-aminobutyric acid content in plasma and cerebrospinal fluid.Hepatology 7:816–820.
Peterson, C., Giguère, J.F., Cotman, C.W., and Butterworth R.F. (1990). Selective loss of N-methyl-D-aspartate-sensitive L-3H glutamate binding sites in rat brain following portacaval anastomosis.J. Neurochem. 55:386–390.
Qureshi, I.A., Letarte, J. and Ouellet, R. (1979). Ornithine transcarbamylase deficiency in mutant mice. 1. Studies on the characterization of enzyme defect and suitability as animal model of human disease.Pediatr. Res. 13:807–811.
Rao, V.L.R., Agrawal, A.K., and Murthy, Ch.R.K. (1991). Ammonia-induced alterations in glutamate and muscimol binding to cerebellar synaptic membranes.Neurosci. Lett. 130:251–254.
Ratnakumari, L., Qureshi, I.A., and Butterworth, R.F. (1994). Evidence for cholinergic neuronal loss in brain in congenital ornithine transcarbamylase deficiency.Neurosci. Lett. 178:63–65.
Ratnakumari, L., Qureshi, I.A., and Butterworth, R.F. (1994). Regional amino acid neurotransmitter changes in brains of spf/Y mice with congenital ornithine transcarbamylase deficiency.Metab. Brain Dis. 9:43–52.
Robinson, M.B., Anegawa, N.J., Gorry, E., Qureshi, I.A., Coyle, J.T., Lucki, I., and Batshaw, M.L. (1992). Brain serotonin2 and serotonin1A receptors are altered in the congenitally hyperammonemic sparse-fur mouse.J. Neurochem 58:1016–1022.
Sidman, R.L., Angevine, J.B., and Taber Pierce, E. (1971). Atlas of the mouse brain and spinal cord. Harvard University Press, Cambridge, Massachusetts.
Snyder, S.H., and Bredt, D.S. (1992). Biological roles of nitric oxide.Sci. Amer. (May):68–77.
Subramaniam S., and McGonigle, P. (1991). Quantitative autoradiographic characterization of the binding of (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine ([3H]MK801) in rat brain: Regional effects of polyamines.J. Pharmacol. Exp. Therap. 256:811–819.
Tossman, U., Delin, A., Eriksson, L.S., and Ungerstedt, U. (1987). Brain cortical amino acids measured by intracerebral dialysis in portacaval shunted rats.Neurochem. Res. 12:265–269. A0431005 00006 CS-SPJRNPDF [HEADSUP]
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Ratnakumari, L., Qureshi, I.A. & Butterworth, R.F. Loss of [3H]MK801 binding sites in brain in congenital ornithine transcarbamylase deficiency. Metab Brain Dis 10, 249–255 (1995). https://doi.org/10.1007/BF02081030
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02081030