title: Developmental deficiency of the cholinergic system in congenitally hyperammonemic spf mice: effect of acetyl-L-carnitine.
abstract: The sparse-fur (spf) mutant mouse has an X-linked deficiency of hepatic ornithine transcarbamylase (OTC) and develops hyperammonemia in the postnatal period similar to that seen in human patients. We studied the effect of congenital hyperammonemia on the development of cerebral cholinergic parameters such as choline acetyltransferase (ChAT), acetylcholinesterase (AChE) and high-affinity choline uptake (HACU) in spf mice. The serum ammonia levels of spf mutant mice were significantly elevated after weaning compared with control animals. ChAT activity levels started decreasing in mutant spf mice from the age of 30 days (i.e., immediately after weaning); it reached significantly lower levels in the adult animals. HACU was consistently lower (P < .01) in spf/Y mice compared with controls up to the adult stage. However, there were no marked changes in the activity of AChE between control and hyperammonemic spf mice. The levels of beta-NGF, which is essential for cholinergic differentiation and function, were significantly lower in different brain regions of adult mutant mice compared with normal controls. A treatment of spf/spf breeding females with acetyl-L-carnitine, at a dose of 1.5 mM in drinking water, starting from day 1 of conception, resulted in a significant restoration of ChAT activity levels in some brain regions of the spf/Y offspring. The beta-NGF levels were also significantly elevated after supplementation with ALCAR in mutant mice compared with untreated mutant mice. These data are suggestive of a neurotrophic property of ALCAR during cholinergic deficiency caused by congenital hyperammonemia.
authors.affiliation: Division of Medical Genetics, Sainte-Justine Hospital, Montreal, Quebec, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Ratnakumari
authors.forename: I A
authors.initials: IA
authors.lastname: Qureshi
authors.forename: D
authors.initials: D
authors.lastname: Maysinger
authors.forename: R F
authors.initials: RF
authors.lastname: Butterworth
mesh_terms: D000108:Acetylcarnitine / Q000494:pharmacology*; D000110:Acetylcholinesterase / Q000378:metabolism*; D000641:Ammonia / Q000097:blood*; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000254:growth & development / Q000378:metabolism; D002331:Carnitine / Q000097:blood / Q000378:metabolism; D002794:Choline / Q000378:metabolism*; D002795:Choline O-Acetyltransferase / Q000378:metabolism*; D005260:Female; D008297:Male; D008661:Metabolism, Inborn Errors / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D009414:Nerve Growth Factors / Q000378:metabolism; D011247:Pregnancy; D013574:Synaptosomes / Q000378:metabolism
chemical_list: D009414:Nerve Growth Factors; D000108:Acetylcarnitine; D000641:Ammonia; D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase; D002794:Choline; D002331:Carnitine