Purkinje Cells In Mutant Mice Research Articles

Combined therapy with cyclodextrin/allopregnanolone and miglustat improves motor but not cognitive functions in Niemann–Pick Type C1 mice

Niemann–Pick Type C1 (NPC1) is an autosomal recessive disorder characterized by the accumulation of cholesterol and glycosphingolipids. Combination-treatment utilizing cyclodextrin, allopregnanolone and miglustat (CYCLO/ALLO/miglustat) can ameliorate NPC1 disease in a mutant mouse model. The present study was designed to add behavioral analysis in NPC1 mutant mice upon CYCLO/ALLO/miglustat therapy.NPC1 mutant (BALB/cJ NPC1NIH) and control mice were used. For the combination treatment mice were injected with CYCLO/ALLO weekly, starting at P7. The miglustat injection was performed daily from P10 till P23. Starting at P23, miglustat was added to the powdered chow. For the sham treatment of control and mutant mice the same schedule was used with 0.9% NaCl injection. Locomotor activity was assessed in open field, elevated plus maze and accelerod tests. For assessment of spatial learning and memory the Morris water maze test was conducted. Electron microscopy has been performed to support the behavioral data.The sham-treated mutant mice exhibited motor impairments in all performed tests. In the water maze the sham-treated mutants exhibited impairment in remembering the location of the hidden platform. CYCLO/ALLO/miglustat treatment positively influenced motor dysfunction: total distance and number of visits significantly increased, and accelerod performance improved. The spatial learning, however, did not benefit from therapy.At the morphological level, an excessive accumulation of electron-dense material was seen in the cerebellar Purkinje cells of mutant mice. A regression of these autophagosomal inclusions was seen upon therapy.CYCLO/ALLO/miglustat therapy ameliorates motor but not cognitive deficits in NPC1 mutant mice, suggesting unequal vulnerability of different brain areas to the treatment.

Cerebellum-Related Characteristics of Scn8a-Mutant Mice

Among ten sodium channel alpha-subunit genes mapped in human and mouse genomes, the SCN8A gene is primarily expressed in neurons and glia. Mice with two types of Scn8a null mutations--Scn8a ( med ) and Scn8a ( medTg )--live for only 21-24 days, but those with incomplete mutations-Scn8a ( medJ ) and Scn8a ( medJo )--and those with knockout of Scn8a only in cerebellar Purkinje cells live to adult age. We review here previous work on cerebellum and related regions of Scn8a mutant mice and include some newer immunohistochemical and microchemical results. The resurgent sodium current that underlies the repeated firing of Purkinje cells is reduced in Scn8a mutant and knockout mice. Purkinje cells of mutant mice have greatly reduced spontaneous activity, as do the analogous cartwheel cells of the dorsal cochlear nucleus. Up-regulation of GABA(A) receptors in regions to which Purkinje cells project may partially compensate for their decreased activity in the mutant mice. The somata of cerebellar Purkinje cells of Scn8a ( medJ ) and Scn8a ( medJo ) mice, as revealed by PEP-19 immunoreaction, are slightly smaller than normal, and their axons, especially in Scn8a ( medJo ) mice, sometimes show enlargements similar to those in other types of mutant mice. Density of GABA-like immunoreactivity is decreased in Purkinje somata and regions of termination in deep cerebellar and vestibular nuclei of Scn8a ( medJ ) mice, but measured GABA concentration is not significantly reduced in microdissected samples of these regions. The concentrations of taurine and glutamine are significantly increased in cerebellar-related regions of Scn8a ( medJ ) mice, possibly suggesting up-regulation of glial amino acid metabolism.

Multiple climbing fiber innervation of cerebellar purkinje cells in mutant mice lacking the phospholipase C-4 (PLC 4)

Multiple climbing fiber innervation of cerebellar purkinje cells in mutant mice lacking the phospholipase C-4 (PLC 4)

Multiple climbing fiber innervation of cerebellar purkinje cells in mutant mice lacking the -subunit of heterotrimeric G protein Gq(Gaq)

Multiple climbing fiber innervation of cerebellar purkinje cells in mutant mice lacking the -subunit of heterotrimeric G protein Gq(Gaq)

302 Multiple climbing fiber innervation of cerebellar purkinje cells in mutant mice lacking the phospholipase C-β4 (PLC β4)

302 Multiple climbing fiber innervation of cerebellar purkinje cells in mutant mice lacking the phospholipase C-β4 (PLC β4)

303 Multiple climbing fiber innervation of cerebellar purkinje cells in mutant mice lacking the α-subunit of geterotrimeric G protein Gq(Gαq)

303 Multiple climbing fiber innervation of cerebellar purkinje cells in mutant mice lacking the α-subunit of geterotrimeric G protein Gq(Gαq)

MGluR1 mutant mice as a tool to study calcium signalling and multiple innervation in the cerebellum

The present study reports that calcium signalling through voltage-gated calcium channels and release from internal stores is impaired in Purkinje cells of mutant mice lacking in GluR1 receptors and that the absence of these receptors also leads to an incomplete regression of multiple innervation in the cerebellum of these animals.

Electrophysiological demonstration of a synaptic integration of transplanted purkinje cells into the cerebellum of the adult purkinje cell degeneration mutant mouse

After implantation of solid pieces of cerebellar primordia from 12-day-old C57BL embryos into the cerebellar parenchyma of 3- to 4-month-old “Purkinje cell degeneration” mutant mice, Purkinje cells from the donor leave the implant and differentiate while migrating into the host molecular layer. Electrophysiological studies were performed using in vitro cerebellar slice preparations from “Purkinje cell degeneration” mutants 1–2 months after grafting, when grafted Purkinje cells have reached their final location in the host molecular layer and have completed their morphological differentiation. Intracellular recordings obtained from 45 Purkinje cells in mutant mice demonstrated that such grafted neurons have normal bioelectrical properties including sodium and calcium conductances and inward rectification. Moreover, all grafted Purkinje cells responded to electrical white matter stimulation by a typical all-or-none climbing fiber response. Responses mediated through the activation of mossy and parallel fibers, as well as inhibitory postsynaptic potentials, were also recorded in a significant number of grafted Purkinje cells. On the whole, all these excitatory and inhibitory responses in grafted “Purkinje cell degeneration” mutant mice have characteristics comparable to those in control mice. After electrophysiological studies, Purkinje cells were further characterized by their positive staining by calbindin antibody. Neurons of this class were dispersed throughout the molecular layer of the host folia in which the electrophysiological recordings had been performed. The ectopic location of their perikarya, the presence of dendritic trees spanning most of the molecular layer (without entering the granular layer), and the occasional presence of axons emerging from the ectopic neurons and forming loose bundles at the white matter axis of the folia, corroborate the grafted nature of the Purkinje cells studied. Therefore, these experiments demonstrate that embryonic Purkinje cells from the graft can complete differentiation in the adult host cerebellum, and establish specific synaptic contacts with the presynaptic elements previously impinging on the missing neurons of “Purkinje cell degeneration” mutants. This process leads to a qualitative functional synaptic restoration of the cortical cerebellar network.