Phenotypically, the weaver mouse exhibits profound ataxia resulting from a near total loss of granule cells in the cerebellum (76-78); tremor resulting from a 70% loss of dopamine in the dorsolateral striatum due to selective degeneration of dopamine neurons of the SNpc (79); male infertility due to degeneration of Sertoli and sper-matogenic cells (80); and seizures possibly due to hippocampal abnormalities and hypothyroidism (81,82).
An A153G point mutation, in the pore forming the H5 region of a G-protein-coupled inwardly rectifying potassium channel gene (GIRK2), has been proposed to be responsible for the weaver phenotype (83-85). The GIRK2 mutation alters the gating specificity of the GIRK2 channel, leading to a loss of ion selectivity of the GIRK2
channel, allowing entry of calcium and sodium as well as outflow of potassium and G-protein sensitivity of the GIRK2 channel (84-86).
GIRK2-immunoreactivity is densely in the external granule cell layer of the cerebellum in weaver mutant mice (87-89). Cerebellar degeneration is the most prominent pathology noted in the brain of the weaver mutant mice. The precursors of cerebellar granule cells proliferate normally in the external germinal layer, but fail to complete differentiation, and degenerate even before interacting with the Bergman glial cells and migrate into the internal granule cell layer (76-78,90). The Purkinje cells and neurons of the deep cerebellar nuclei, especially of the midline cerebellar nuclei, also demonstrate degenerative changes in homozygous weavers (91,92).
In weaver mutant mice brains, the midbrain dopamine neurons, unlike the cerebellar granule cells, differentiate, migrate to the ventral mesencephalon, and extend their axons to the striatum. The weaver mutant mice have a normal number of dopamine neurons in the ventral mesencephalon at the time of birth, but significant degeneration of these neurons starts on postnatal day 1, and at least 50% of the neurons are lost by postnatal day 20 (93,94). The gene defect results in degeneration of neurons that are generated mostly after embryonic day 12 and the dopamine neurons in the SNpc that survive have CB colocalized (93).
Among the different slicing variants of the Kir3.2, the dopamine neurons of the SNpc in rats are made of heteromeric assemblies of only Kir3.2a and Kir3.2c (95). Within the three dopamine-containing cell groups in the midbrain, the strongest GIRK2-immunoreactivity is seen in the SNpc. GIRK2-immunoreactive dopamine neurons are less prominent in the SNpl (96-98). Among the five different subdivisions of the VTA dopamine neurons, GIRK2 immunoreactivity is virtually absent in the TH-positive neurons of the rostral linear, caudal linear, and interfascicular nucleus (99,100). Only a few neurons of the nucleus parabrachialis pigmentosus and paranigralis coexpress TH and GIRK2. This pattern of GIRK2 distribution in the ventral midbrain coincides with the pattern of degeneration and sparing of dopamine neurons of the midbrain in weaver mutant mice. In the weaver mouse, among the mesencephalic dopamine neurons, the dopamine neurons of the SNpc are predominantly destroyed and the more laterally placed neurons in the SNpl and the VTA are mostly spared (96).
Corresponding with the loss of dopamine neurons in SNpc regions within the striatum, the activity of TH, level of dopamine, dopamine uptake, as well as the activity of DAT is decreased significantly (101). The severity of the loss of TH-activity and dopamine content in the striatum is about 40% postnatal three to five days and about 70% in the adult weaver mutant mice (102-104). The decrease in the level of dopamine is observed selectively in the dorsal sensory-motor striatum, but not in the ventral limbic striatum (105).
The pattern of degeneration of the mesencephalic dopamine neurons and loss of dopamine levels in the dorsal sensory-motor striatum in weaver mice bears significant similarities to the pattern of degeneration of midbrain dopamine neurons in human PD, as well as 6-OHDA-, MPTP-, and rotenone-induced animal models of PD. The weaver pathology points out the possibility that dysfunction of the GIRK2 channel may contribute to the selective vulnerability of the SNpc to degenerate early. Whether the gene defect of the GIRK2 mutation noted in weaver mice is the direct cause of neuronal degeneration has been a point of debate (106). The possibility that the degenerative effects of GIRK2 mutations may be mediated by dysfunction of adenosine triphosphate sensitive postassium (K-ATP) channels has been proposed (107). A study in a small number of familial as well as sporadic cases of PD did not find any mutation of the pore forming the H5 region of the GIRK2, inwardly rectifying K+ channel (108).
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