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

Abstract

In an earlier report we presented evidence pointing to a differential effect of the mutant gene weaver on the dopamine-containing fiber systems innervating the striatum. In mice homozygous for the weaver mutation, there is a severe loss of dopamine in the caudoputamen, the main target of the nigrostriatal system. By contrast, dopamine is entirely conserved in the nucleus accumbens, a target of the mesolimbic system, and is moderately affected in the olfactory tubercle. The present study shows that these defects in dopamine are gene dose-dependent, that they are established by the end of the first month of life, and that the losses are permanent and not progressive. As in homozygous weavers, the greatest defects in striatal dopamine in heterozygous weavers occur in the dorsolateral caudoputamen and the lateral olfactory tubercle.The abnormalities in the striatal dopamine content of weaver mice are not accompanied by abnormalities in the turnover of dopamine, judging from measurements of the dopamine metabolite dihydroxyphenylacetic acid. Norepinephrine content is also normal in each striatal region. No deficits in striatal dopamine occur in mice homozygous for the mutant genes staggerer and Purkinje cell degeneration, which, like the weaver mutation, result in ataxia and cerebellar pathology.A survey of nonstriatal regions in the weaver mice showed that the effects of the weaver gene on the dopamine-containing innervation of the forebrain are not confined to striatal targets but also extend to the septum and the hypothalamus. By contrast, dopamine in the frontal cortex, the amygdala, the olfactory bulb, and the retina is entirely spared. The pattern and extent of loss of dopamine in the weaver forebrain is thus regionand system-specific. In confirmation of our initial findings, a ca. 30% depletion of dopamine occurs in the weaver midbrain, the region containing the cell bodies of origin of the mesostriatal dopamine systems. A comparison of histofluorescent sections through weaver and control midbrains revealed a reduction of catecholamine-containing neurons in the pars compacta of the weaver animals.These results point to a subpopulation of dopamine-containing neurons as primary targets of the weaver gene or as being closely associated with such primary targets. As a gene-dose effect has also been shown for the cerebellar granule cell loss in the weaver, the mutant gene must have at least 2 cellular Received Jan. 7, 1986; revised Apr. 30, 1986; accepted May 5, 1986. This work was supported by National Institutes of Health targets. We suggest that the cerebellar and mesostriatal pathologies may be linked by a common molecular mechanism.Two defects, one obvious and the other well hidden, are known to be present in the brains of mice that carry the autosomal recessive gene weaver. This mutation results in an atrophy of the cerebellum that is so severe in homozygous weavers that it can be detected after a glance at the intact brain. As was first reported by Sidman et al. in 1965, this macroscopic defect reflects an...

Hypothalamic-Pituitary-Gonadal Axis in the Mutant Weaver Mouse

“…It has also been reported that hypothalamic dopamine content of weaver homozygotes is reduced as compared to heterozygote animals [3]. A similar effect was seen in the present study but was restricted to the remaining hypothalamic tissue of homozygous females, but not the males.…”

“…The homozygous weaver mouse (wv/wv) , which suffers from extreme difficulty in locomotion, is a spontaneous mutant with severe cerebellar deficits [1], as well as loss of dopamine-containing neurons of the midbrain [2, 3]. Recently, the mutated gene responsible for the cerebellear deficits has been shown to encode a component of the G-protein-gated inwardly rectifying potassium channel, GIRK2 [4].…”

Male‐sterile phenotype of the neurological mouse mutant weaver

“…It has been noted that the dopamine content of the weaver's hypothalamus is reduced 30% compared to wild-type (Roffler-Tarlov and Graybiel, 1986). The tuberoinfundibular dopaminergic neurons in the median eminence of the hypothalamus are involved in the regulation of hypothalamic-pituitary-gonadal loop (reviewed in Negro-Vilar and Valenca, 1988) and are responsive to testosterone (Toney et al, 1991).…”

A regenerative link in the ionic fluxes through the weaver potassium channel underlies the pathophysiology of the mutation

“…The singlenucleotide mutation changes a glycine residue to serine in the pore region of the G protein-gated inward rectifier K ϩ channel (GIRK2), altering the highly conserved and critical GYG sequence to SYG (1). In homozygotic weaver mice, the mutation causes degeneration of the cerebellar granule cells during migration from the external germinal layer to the granule cell layer (2)(3)(4), degeneration of the substantia nigra pars compacta (5), cytoarchitectonic anomalies in the CA3 region of the hippocampus (6), seizures, and male sterility.…”