Loss of [3H]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 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.