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Distribution and Severity of Neuropathology in ?-Mannosidase-Deficient Mice is Strain Dependent.

ABSTRACT: Neurological dysfunction is common in humans and animals with lysosomal storage diseases. ?-Mannosidosis, an autosomal recessive inherited disorder of glycoprotein catabolism caused by deficiency of the lysosomal enzyme ?-mannosidase, is characterized by intracellular accumulation of small oligosaccharides in selected cell types. In ruminants, clinical manifestation is severe, and neuropathology includes extensive intracellular vacuolation and dysmyelination. In human cases of ?-mannosidosis, the clinical symptoms, including intellectual disability, are variable and can be relatively mild. A ?-mannosidosis knockout mouse was previously characterized and showed normal growth, appearance, and lifespan. Neuropathology between 1 and 9 months of age included selective, variable neuronal vacuolation with no hypomyelination. This study characterized distribution of brain pathology in older mutant mice, investigating the effects of two strain backgrounds. Morphological analysis indicated a severe consistent pattern of neuronal vacuolation and disintegrative degeneration in all five 129X1/SvJ mice. However, the mice with a mixed genetic background showed substantial variability in the severity of pathology. In the severely affected animals, neuronal vacuolation was prominent in specific layers of piriform area, retrosplenial area, anterior cingulate area, selected regions of isocortex, and in hippocampus CA3. Silver degeneration reaction product was prominent in regions including specific cortical layers and cerebellar molecular layer. The very consistent pattern of neuropathology suggests metabolic differences among neuronal populations that are not yet understood and will serve as a basis for future comparison with human neuropathological analysis. The variation in severity of pathology in different mouse strains implicates genetic modifiers in the variable phenotypic expression in humans.

SUBMITTER: Lovell KL

PROVIDER: S-EPMC4110335 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Distribution and Severity of Neuropathology in β-Mannosidase-Deficient Mice is Strain Dependent.

Lovell Kathryn L KL Zhu Mei M Drummond Meghan C MC Switzer Robert C RC Friderici Karen H KH

JIMD reports 20131020

Neurological dysfunction is common in humans and animals with lysosomal storage diseases. β-Mannosidosis, an autosomal recessive inherited disorder of glycoprotein catabolism caused by deficiency of the lysosomal enzyme β-mannosidase, is characterized by intracellular accumulation of small oligosaccharides in selected cell types. In ruminants, clinical manifestation is severe, and neuropathology includes extensive intracellular vacuolation and dysmyelination. In human cases of β-mannosidosis, th ...[more]

PMID: 24142277

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Project description:Heterozygous loss-of-function SCN1A mutations cause Dravet syndrome, an epileptic encephalopathy of infancy that exhibits variable clinical severity. We utilized a heterozygous Scn1a knockout (Scn1a(+/-)) mouse model of Dravet syndrome to investigate the basis for phenotype variability. These animals exhibit strain-dependent seizure severity and survival. Scn1a(+/-) mice on strain 129S6/SvEvTac (129.Scn1a(+/-)) have no overt phenotype and normal survival compared with Scn1a(+/-) mice bred to C57BL/6J (F1.Scn1a(+/-)) that have severe epilepsy and premature lethality. We tested the hypothesis that strain differences in sodium current (INa) density in hippocampal neurons contribute to these divergent phenotypes. Whole-cell voltage-clamp recording was performed on acutely-dissociated hippocampal neurons from postnatal days 21-24 (P21-24) 129.Scn1a(+/-) or F1.Scn1a(+/-) mice and wild-type littermates. INa density was lower in GABAergic interneurons from F1.Scn1a(+/-) mice compared to wild-type littermates, while on the 129 strain there was no difference in GABAergic interneuron INa density between 129.Scn1a(+/-) mice and wild-type littermate controls. By contrast, INa density was elevated in pyramidal neurons from both 129.Scn1a(+/-) and F1.Scn1a(+/-) mice, and was correlated with more frequent spontaneous action potential firing in these neurons, as well as more sustained firing in F1.Scn1a(+/-) neurons. We also observed age-dependent differences in pyramidal neuron INa density between wild-type and Scn1a(+/-) animals. We conclude that preserved INa density in GABAergic interneurons contributes to the milder phenotype of 129.Scn1a(+/-) mice. Furthermore, elevated INa density in excitatory pyramidal neurons at P21-24 correlates with age-dependent onset of lethality in F1.Scn1a(+/-) mice. Our findings illustrate differences in hippocampal neurons that may underlie strain- and age-dependent phenotype severity in a Dravet syndrome mouse model, and emphasize a contribution of pyramidal neuron excitability.

Dataset Information

Distribution and Severity of Neuropathology in ?-Mannosidase-Deficient Mice is Strain Dependent.

Publications

Distribution and Severity of Neuropathology in β-Mannosidase-Deficient Mice is Strain Dependent.

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