Patterns of cell and fiber vulnerability in the mesostriatal system of the mutant mouse weaver. I. Gradients and compartments

Abstract

In mice carrying the autosomal recessive gene weaver, there is a massive postnatal loss of dopamine in the caudoputamen, the target of the nigrostriatal system, with relative (though not complete) preservation of dopamine in the ventral striatum, a target of the mesolimbic system. There is concomitant death of catecholaminergic neurons in the substantia nigra, with much less cell death in the limbic midbrain area. In the study reported here, we have reexamined the mesostriatal system of weaver mice by means of tyrosine hydroxylase (TH) immunohistochemistry in order to determine the local architecture of the defect within the striatum and substantia nigra. For the dorsal striatum, the most striking finding was the appearance in the weaver caudoputamen of small pockets of especially weak immunostaining within a larger dorsal zone of generally reduced TH-positive neuropil. These pockets were identified as striosomes by calbindin28k and met-enkephalin immunohistochemistry carried out on adjacent sections. In dorsal, central, and caudal sectors of the caudoputamen, there was also more generalized depletion of TH-immunoreactive neuropil. In the mid-brains of the mutants, the patterns of loss of TH-positive neurons appeared to correspond to these distributions of reduced immunostaining in the striatum. In the substantia nigra pars compacta, ventrally situated TH-positive neurons were especially affected, suggesting preferential depletion of TH-positive neurons projecting to striosomes. In addition, there was a central sector of nearly complete loss of TH-positive neurons in the substantia nigra para compacta and a marked depletion of TH-positive neurons in cell group A8 that, together, may have accounted for the diminution of TH-positive innervation of the striatal matrix. We conclude that the effects of the weaver gene discriminate among mesostriatal subsystems not only according to the regional affiliations of these subsystems within the dorsal and ventral striatum, but also according to the preferential association of the subsystems for the striosomal and matrical compartments of the caudoputamen. The depletion of TH-positive innervation was not confined to the dorsal striatum proper. The defect extended into the adjoining nucleus accumbens, where it appeared to affect the lateral "core" division, and included also a lateral part of the olfactory tubercle. Thus, as in the dorsal striatum, the defect in the TH-positive innervation of the ventral striatum closely follows the local architecture of this striatal region. Neuronal loss in the ventral tegmental area was not evident on qualitative analysis, but at the border between lateral cell group A 10 and medial cell group A9 there was obvious loss of immunostained neurons.(ABSTRACT TRUNCATED AT 400 WORDS)

Differential involvement of striosome and matrix dopamine systems in a transgenic model of dopa-responsive dystonia

“…In agreement with the known pattern of TH expression in the mouse striatum (16,17), in the wild-type control mice ( Fig. 5 A-D and I), strong TH immunostaining first appeared in discrete ''dopamine islands'' corresponding to developing striosomes (18).…”

“…3 J and K). This region is thought to be a main source of the nigrostriatal dopaminergic projections to striosomes (15,16). Moreover, immunohistochemistry for aromatic L-amino acid decarboxylase (AADC), a dopaminergic marker for the nigrostriatal pathway that is normally colocalized with TH (13), demonstrated abundant staining of the striatum and of nigral neurons in the DPS mice (Fig.…”

Nigrostriatal Dopaminergic Neurodegeneration in theWeaverMouse Is Mediated via Neuroinflammation and Alleviated by Minocycline Administration

“…Mice carrying two copies of the mutant gene display ataxia, hyperactivity, and tremor (Caviness and Rakic, 1978). These neurological defects are associated with neuronal degeneration during postnatal development in the ventral midbrain among dopaminergic neurons of the substantia nigra (SN) and retrorubral nucleus (Schmidt et al, 1982;Roffler-Tarlov and Graybiel, 1984;Triarhou et al, 1988;Graybiel et al, 1990;Roffler-Tarlov et al, 1996), within granule cells (Rezai and Yoon, 1972;Rakic and Sidman, 1973a,b) and Purkinje cells (Blatt and Eisenman, 1985;Herrup and Trenkner, 1987;Smeyne and Goldowitz, 1990) of the cerebellum and the deep cerebellar nuclei (Maricich et al, 1997). The Girk2wv defect appears to initiate different types of cell death based on the morphological appearance of dying neurons in these different brain regions.…”

Correlated quantitative studies of the neostriatum, nucleus accumbens, substantia nigra, and ventral tegmental area in normal and weaver mutant mice

“…[Key words: striatum, nucleus accumbens, ventral tegmental area, substantia nigra, weaver mutant mouse, cell death, volumetric cell counts, three-dimensional computer reconstructions] Adult homozygous weaver (WV/WV) mutant mice have a severe depletion of dopamine neurons in the substantia nigra (Schmidt et al, 1982;Triarhou et al, 1986Triarhou et al, , 1988aGupta et al, 1987;Ghetti and Triarhou, 1992) and to a lesser extent in the ventral tegmental area (Triarhou et al, 1988a;Graybiel et al, 1990).…”

“…Cell loss has been quantified in the WV/WV substantia n&a on P20 (Triarhou et al: 1988a). The ventral tegmental area in young adults contains reduced immunostaining for tyrosine hydroxylase (Triarhou et al, 1988a;Graybiel et al, 1990) and a depletion of tyrosine hydroxylase-stained neurons (Triarhou et al, 1988a). In 1 -yearold WV/WV mice, the neostriatum has been deprived of normal dopamine levels for at least 11 months, and dopamine metabolism in the nucleus accumbens may have been abnormal for that same period of time.…”