LOSS OF [H-3] MK801 BINDING-SITES IN BRAIN IN CONGENITAL ORNITHINE TRANSCARBAMYLASE DEFICIENCY

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 glutamater gic neurotransmitter system in OTC deficiency, densities of binding si tes for [H-3]MK801, an NMDA receptor antagonist ligand were measured b y quantitative receptor autoradiography in the brains of chronically h yperammonemic sparse-fur mice (spf), mutant mice with a congenital def ect of OTC. [H-3]MK801 binding site densities were significantly reduc ed by up to 57% (p<0.01) in 16 out of 17 brain regions of OTC-deficien t mice. Such changes could result from either neuronal cell loss in th ese animals or from ''down-regulation'' of these sites as a consequenc e of exposure to increased extracellular concentrations of glutamate o r quinolinic acid, two known endogenous NMDA receptor ligands previous ly found to be increased in brain in chronic hyperammonemic syndromes. Reduced NMDA receptor densities in congenital OTC deficiency could re present an adaptive mechanism of protection against further excitotoxi c brain injury.