Altered expression of neuronal nitric oxide synthase in weaver mutant mice.
The weaver mouse represents the only genetic animal model of gradual nigrostriatal dopaminergic neurodegeneration which is proposed as a pathophysiological phenotype of Parkinson's disease. The aim of the present study was to analyze the nitric oxide and dopaminergic systems in selected brain regions of homozygous weaver mice at different postnatal ages corresponding to specific stages of the dopamine loss. Structural deficits were evaluated by quantification of tyrosine hydroxylase and neuronal nitric oxide synthase-immunostaining in the cortex, striatum, accumbens nuclei, subthalamic nuclei, ventral tegmental area, and substantia nigra compacta of 10-day, 1- and 2-month-old wild-type and weaver mutant mice. The results confirmed the progressive loss of dopamine during the postnatal development in the adult weaver mainly affecting the substantia nigra pars compacta, striatum, and subthalamic nucleus and slightly affecting the accumbens nuclei and ventral tegmental area. A general decrease in neuronal nitric oxide synthase-immunostaining with age was revealed in both the weaver and wild-type mice, with the decrease being most pronounced in the weaver. In contrast, there was an increase in the substantia nigra pars compacta nitric oxide synthase-immunostaining and a decrease mainly in the subthalamic and accumbens nuclei of the 2-month-old weaver mutant. The decrease in the expression of nNOS may bear functional significance related to the process of aging. DA neurons from the substantia nigra directly modulate the activity of subthalamic nucleus neurons, and their loss may contribute to the abnormal activity of subthalamic nucleus neurons. Although the functional significance of these changes is not clear, it may represent plastic compensating adjustments resulting from the loss of dopamine innervation, highlighting a possible role of nitric oxide in this process.
Cavalcanti-Kwiatkoski
Roberta
R
Department of MEF-Physiology, FORP, University of São Paulo, Ribeirão Preto, SP, Brazil.
Raisman-Vozari
Rita
R
Ginestet
Laure
L
Del Bel
Elaine
E
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000201:enzymology*; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D005838:Genotype; D051379:Mice; D008818:Mice, Neurologic Mutants / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C497069:Kcnj6 protein, mouse; D052248:Nitric Oxide Synthase Type I; D014446:Tyrosine 3-Monooxygenase