Altered neuronal nitric oxide synthase expression in the cerebellum of calcium channel mutant mice.
Tottering, rolling Nagoya, and leaner mutant mice all exhibit cerebellar ataxia to varying degrees, from mild (tottering mice) to severe (leaner mice). Collectively, these mice are regarded as tottering locus mutants because each of these mutant mice expresses a different autosomal recessive mutation in the gene coding for the alpha(1A) calcium ion channel protein, which is the pore forming subunit for P/Q-type high voltage activated calcium ion channels. These mutant mice all exhibit varying degrees of cerebellar dysfunction and neuronal cell death. Nitric oxide (NO) is an important messenger molecule in the central nervous system, especially in the cerebellum, and it is produced via the enzyme, nitric oxide synthase (NOS). We investigated expression of neuronal-NOS (n-NOS) in the cerebella of all three mutant mice, as revealed by NADPH-diaphorase (NADPH-d) histochemical staining, quantitation of n-NOS protein using Western blotting and quantitation of n-NOS mRNA using in situ hybridization. The expression of n-NOS mRNA and protein as well as the NADPH-d histochemical reaction were elevated in tottering and rolling Nagoya cerebella. n-NOS mRNA and the NADPH-d histochemical reaction were decreased in the leaner cerebellum, but the leaner mouse n-NOS protein concentration was not significantly different compared to age- and gender-matched controls. These findings suggest that NO may act as an important mediator in the production of the neuropathology observed in these mutant mice.
Rhyu
Im Joo
IJ
Institute of Human Genetics and Department of Anatomy, Korea University College of Medicine, 126-1 Anam-Dong 5-Ga, Seongbuk-Ku, Seoul 136-705, South Korea.
Nahm
Sang-Soep
SS
Hwang
Seung Jun
SJ
Kim
Hyun
H
Suh
Young-Suk
YS
Oda
Sen-Ich
SI
Frank
Tamy C
TC
Abbott
Louise C
LC
D000818:Animals; D001345:Autoradiography; D015153:Blotting, Western; D015220:Calcium Channels / Q000235:genetics*; D002531:Cerebellum / Q000201:enzymology*; D005838:Genotype; D007150:Immunohistochemistry; D017403:In Situ Hybridization / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009252:NADPH Dehydrogenase / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism; D013045:Species Specificity
D015220:Calcium Channels; D012333:RNA, Messenger; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D009252:NADPH Dehydrogenase