Central muscarinic cholinergic M1 and M2 receptor changes in congenital ornithine transcarbamylase deficiency.
Congenital ornithine transcarbamylase (OTC) deficiency results in neuropathologic damage to the cerebral cortex, basal ganglia, and thalamus. However, the precise nature of the cell loss, as well as the pathophysiologic mechanisms responsible for it, have not been fully elucidated. In the present study, densities of the M1 and M2 subclasses of muscarinic cholinergic binding sites were assessed using quantitative receptor autoradiography in the brains of sparse-fur (spf) mice with congenital OTC deficiency and in age-matched CD-1 controls. Densities of binding sites for the muscarinic M1 subtype ligand [3H]pirenzepine were reduced by 24-54% (p < 0.01) in frontal cortex, caudate/ putamen, and hippocampal CA1 and CA2 areas. Since muscarinic M1 sites are localized presynaptically, their selective loss, together with a previous report of reduced activities of the presynaptic cholinergic enzyme choline acetyltransferase, confirms that loss of cholinergic neurons is an important feature of congenital OTC deficiency. Densities of binding sites for the predominantly postsynaptic muscarinic M2 subtype ligand 3H-AFDX 384 were increased by up to 60% (p < 0.01) in cerebral cortex, hippocampus, globus pallidus, as well as thalamic and hypothalamic structures of OTC-deficient mice. Increased M2 sites in the cerebral cortex, hippocampus, and thalamus are most likely the result of up-regulation of these sites after the loss of the presynaptic neuron. These findings support the presence of a central muscarinic cholinergic lesion in congenital OTC deficiency.
Ratnakumari
L
L
Department of Medical Genetics, Hôpital Sainte-Justine, Montreal, Quebec, Canada.
Qureshi
I A
IA
Butterworth
R F
RF
D000818:Animals; D000831:Animals, Newborn; D001345:Autoradiography; D001921:Brain / Q000378:metabolism*; D005069:Evaluation Studies as Topic; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D020163:Ornithine Carbamoyltransferase Deficiency Disease; D011869:Radioligand Assay; D011976:Receptors, Muscarinic / Q000378:metabolism*
D011976:Receptors, Muscarinic