Atrophy and loss of dopaminergic mesencephalic neurons in heterozygous weaver mice

Abstract

The phenotypic effect of the weaver mutation in the ventral midbrain of homozygous mutants is associated with the progressive loss of dopaminergic neurons. To discover whether the number of mesencephalic dopaminergic cells is altered in weaver heterozygotes (wv/+), we studied mice between 20 and 365 days of age. We counted tyrosine hydroxylase (TH)-immunopositive cells in the substantia nigra (SN), retrorubral nucleus (RRN), and ventral tegmental area (VTA), and measured cross-sectional areas of neuronal somata in the SN of wv/+ and age-matched wild-type controls (+/+). The number of TH-positive cells in the wv/+ ventral midbrain was on average 13% lower than normal. Cell loss was detected selectively in the SN (12%) and VTA (23%). The areas of somatic profiles in the wv/+ nigral neurons were on average reduced by 9.8%. The neuronal losses in the SN and VTA correlated with a 13.8% reduction in dopamine level in the ventral striatum in wv/+ mice at 14-16 months of age. Our findings imply that a single dose of the weaver gene in the mouse is associated with cellular damage leading to a chronic deficiency in the mesostriatal dopaminergic system.

In vitro evidence that the reduction in mesencepalic dopaminergic neurons in the weaver heterozygote is not due to a failure in target cell interaction

“…The difference in the number of dopaminergic neurons in mesencephalic-striatal aggregates prepared from wv/+ tissue as compared to +/+ tissue is in agreement with findings in vivo demonstrating that the mesencephalon of wv/+ mutants contains fewer dopaminergic neurons than that of +/+ animals (Verina et al 1997). Thus, the presence of only one wv allele results in fewer mesencephalic dopaminergic neurons in the wv/+ animal.…”

“…Consistent with the in vivo observations (Verina et al 1997), there are fewer dopaminergic neurons in aggregates prepared from wv/+ mesencephalon, a result that is evident in both 29-and 57-day-old cultures, which are roughly equivalent in developmental age to 3-week-old and 2-month-old postnatal dopaminergic neurons, respectively. It is possible that the differences in dopaminergic cell number seen between aggregates prepared from +/+ or wv/+ mesencephalon might represent a difference in the number of mesencephalic dopaminergic neurons generated between the two genotypes; however, this is unlikely, since the number of mesencephalic dopaminergic neurons in homozygous wv mutants appears normal at birth (Bayer et al 1995;Verney et al 1995).…”

“…It is possible that the differences in dopaminergic cell number seen between aggregates prepared from +/+ or wv/+ mesencephalon might represent a difference in the number of mesencephalic dopaminergic neurons generated between the two genotypes; however, this is unlikely, since the number of mesencephalic dopaminergic neurons in homozygous wv mutants appears normal at birth (Bayer et al 1995;Verney et al 1995). In the cultures, the difference in dopaminergic cell number between aggregates containing wv/+ versus +/+ mesencephalon is comparable with that seen in the intact brain of postnatal day 20 (-11%) and postnatal day 90 (-14%) wv/+ mice (Verina et al 1997).…”

“…Striatum from wv/+ mice exhibits a loss of dopaminergic neurochemical markers, including a reduction (-37%) in the number of striatal dopaminergic uptake sites measured by [ 3 H]-mazindol autoradiography (Stotz et al 1994) as well as decreased uptake (-40%) of [ 3 H]-dopamine by striatal synaptosomes (Roffler-Tarlov and Graybiel 1991). In addition, it has recently been demonstrated in wv/+ mice that there is, in fact, a reduction in the number of dopaminergic cells of the substantia nigra and ventral tegmental area, observed as early as postnatal day 20, of wv/+ midbrain as compared to wild-type (+/+) midbrain (Verina et al 1997). A 60% loss of nigrostriatal dopaminergic dendrites has also been reported in wv/+ animals (Triarhou and Ghetti 1989).…”

“…Even if defective GIRK2 function is responsible for the loss of both cerebellar and dopaminergic neurons in the wv mutant, it is not clear why the two cell populations differ with respect to the time course of cell death. In vivo studies have shown that cerebellar granule neurons die over a relatively brief period (days), shortly after being generated (Rakic and Sidman 1973a), whereas mesencephalic dopaminergic neurons are progressively lost from postnatal weeks 2-12 (Triarhou et al 1988;Verina et al 1997;Verney et al 1995).…”