Dopamine deficiency in the weaver mutant mouse

Abstract

The dopamine system in weaver mutant mice (BGCBA-AwmJ/A background) was studied. Dopamine was 27% lower in the olfactory tubercle, 77% lower in the frontal cortex, and 75% lower in the striatum of 6-month-old weaver mice compared to control mice of the same age. Norepinephrine and serotonin were not lower in these brain areas. Tyrosine hydroxylase activity in the striatum was measured with a radiometric assay and was 70% lower in weaver mice. Examination of mice from 11 to 180 days of age revealed that the dopamine system failed to develop in weaver mice. Motor activity in individual animals was assessed using circular photocell activity cages with minimal illumination. Apomorphine and pergolide, direct dopamine agonists, increased activity more in weaver mice than in normal littermates. Amphetamine, which releases endogenous stores of dopamine, was less active in mutant mice. These findings provide suggestive evidence that postsynaptic dopamine receptors in weaver mutants might have become supersensitive as a result of lower levels of dopamine in motor areas of the brain.Anatomical evidence of dopamine system abnormalities was found in weaver mice by examination of serial sections cut from the midbrain of mutant and normal mice. The pars compacta of the substantia nigra in weaver mice appeared hypocellular when compared with the corresponding sections from controls. Fewer large neurons were seen in the affected animals.This study illustrates that weaver mice have specific deficiencies in the dopamine system. The weaver mouse might provide a way of examining the biochemical and behavioral effects of long term dopamine deficiency and a way to examine drugs to treat dopamine-deficient states in Go.The weaver mutant mouse (Sidman, 1968) is characterized behaviorally by ataxia and a fine tremor. Histologically, there is an atrophy of the cerebellum which is secondary to a failure of migration and to the degeneration of the cerebellar granule cells (Rakic and Sidman, 1973). However, there is evidence that the dopamine system also is affected in the weaver mutant. Lane et al. (1977) reported that the level of dopamine in the whole brain of adult weaver mice was 50% lower than in normal littermates. The present experiments were undertaken to better define the alterations in the dopamine system in weaver mice from a morphological, biochemical, and behaviorally pharmacological standpoint and, in this respect, to establish whether the weaver mouse could serve as a model of human disorders characterized by dopamine deficiency (e.g., Parkinson's disease). ' We would like to thank Mrs. Dorothy Meyer and Ms. Constance C. Alyea for their skillful assistance. This study was supported in part by National Institutes of Health Grant PHS-l-ROlNS14426 to B. G. ' To whom correspondence should be addressed. Materials and MethodsWeaver mutant mice (BGCBA-A"-"/A background) and heterozygous littermates were obtained from the Jackson Laboratories (Bar Harbor, ME) or raised from Jackson stock in our colony. Animals were housed in...

Expression of the weaver gene in dopamine-containing neural systems is dose-dependent and affects both striatal and nonstriatal regions

“…Schmidt et al (1982) did not observe decreased levels of dopamine in whole brain stem samples from weavers, and Black (1976a) found normal activity of tyrosine hydroxylase in samples of substantia nigra from weaver mice. Schmidt et al (1982) did report a loss of neurons in the substantia nigra pars compacta of the mutants. Such a loss is consonant with our biochemical findings.…”

“…Our biochemical measurements failed to demonstrate a loss of dopamine in the frontal cortex of the weaver mutants. Schmidt et al (1982) did find a reduction of dopamine in their samples of frontal cortex and, in fact, reported as large a deficit in this target of the mesocortical system (70%) as in the caudoputamen. We have no ready explanation for the difference between these findings and our own.…”

“…A second abnormality in the weaver brain affects the forebrain and is concealed from view because it does not result in a marked atrophy or disruption of cellular architecture in the affected regions. This defect was first revealed biochemically as a selective reduction in the content of the neurotransmitter dopamine in brain (Lane et al, 1977) and was subsequently shown both by biochemical analysis and by fluorescence histochemistry to affect certain regions in the forebrain innervated by dopamine-containing fibers from the midbrain (Roffler-Tarlov and Graybiel, 1984;Schmidt et al, 1982).In an earlier report, we presented evidence for a striking regional specificity in the effect of the weaver mutation on the content of dopamine in different parts of the striatum (RofflerTarlov and Graybiel, 1984). In the caudoputamen of homozygous mutants, there was an almost 70% reduction of dopamine relative to that in heterozygous controls, whereas in the nucleus accumbens, dopamine was entirely conserved.…”

“…A second abnormality in the weaver brain affects the forebrain and is concealed from view because it does not result in a marked atrophy or disruption of cellular architecture in the affected regions. This defect was first revealed biochemically as a selective reduction in the content of the neurotransmitter dopamine in brain (Lane et al, 1977) and was subsequently shown both by biochemical analysis and by fluorescence histochemistry to affect certain regions in the forebrain innervated by dopamine-containing fibers from the midbrain (Roffler-Tarlov and Graybiel, 1984;Schmidt et al, 1982).…”

Modèles animaux des maladies neuro-dégénératives

“…La Reelin -produit du gène Reln -a également été incriminée dans des cas de schizophrénie [7]. Chez la souris Weaver [8], les cellules des grains du cervelet et les neurones dopaminergiques de la substantia nigra [9] sont sélectivement touchés [10,11]. La mutation non-sens concerne le gène Girk2 [12], mais la recherche d'une mutation dans le gène humain homologue s'est révélée jusqu'ici négative [13].…”