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Analysis of Hippocampal Cell Proliferation, Survival, and Neuronal Morphology in P/Q-Type Voltage-Gated Calcium Channel Mutant MiceNigussie, Fikru 02 October 2013 (has links)
Tottering and leaner mutant mice carry mutations in the pore-forming subunit (1A) of P/Q-type (CaV 2.1) voltage-gated calcium ion (Ca2+) channels that result in reduced Ca2+ current density. Since Ca2+ influx via voltage-dependent Ca2+ channels regulates important Ca2+-dependent neuronal processes including neurotransmitter release and synaptogenesis, we assessed effects of these mutations on hippocampus volume, neuronal density, neuronal morphology of hippocampal pyramidal cells in adult (six-month-old) mice, and adult neurogenesis in three-week-old and six-month-old mice. Hippocampal volume and neuronal density were assessed using hematoxylin and eosin stained serial sections. Neuronal morphology was assessed using Golgi-Cox staining as well as ultrastructural assessment using transmission electron microscopy. Adult hippocampal neurogenesis was assessed using standard 5-bromo-2’-deoxyuridine (BrdU) labeling with fluorescent immunohistochemistry (IHC) and proliferating cell nuclear antigen (PCNA) with diaminobenzidine IHC. To determine neuron and astrocyte survival, we used fluorescent double labeling for neurons with BrdU-neuronal nuclei IHC or astrocytes using BrdU-glial fibrillary acidic protein, respectively. Fluoro-Jade histochemistry was used to assess numbers of degenerating cells in the dentate gyrus subgranular zone. Decreased hippocampus volume was observed in tottering female mice and increased dentate hilar and CA1 cell density in mutant mice compared to wild type mice. Cell proliferation was increased in the hilus and combined CA3, CA2 and CA1 regions of mutant mice compared to wild type mice. Decreased total dendritic length and decreased number of dendritic intersections was observed in tottering mice compared to wild type mice. The decrease in dendritic arborization of tottering mice occurred at the concentric circles close to the neuronal cell body indicating that basal dendrites of CA1 pyramidal neurons are reduced. Taken together, P/Q-type voltage gated calcium channel mutation has age variable influence on adult hippocampal cell proliferation, and it altered neuronal morphology in terms of dendritic complexity in tottering mice, while the leaner mutation reduced mitochondrial density.
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Assessment of Cerebellar and Hippocampal Morphology and Biochemical Parameters in the Compound Heterozygous, Tottering/leaner MouseMurawski, Emily M. 2009 December 1900 (has links)
Due to two different mutations in the gene that encodes the a1A subunit of
voltage-activated CaV 2.1 calcium ion channels, the compound heterozygous
tottering/leaner (tg/tgla) mouse exhibits numerous neurological deficits. Human
disorders that arise from mutations in this voltage dependent calcium channel are
familial hemiplegic migraine, episodic ataxia-2, and spinocerebellar ataxia 6. The tg/tgla
mouse exhibits ataxia, movement disorders and memory impairment, suggesting that
both the cerebellum and hippocampus are affected. To gain greater understanding of the
many neurological abnormalities that are exhibited by the 90-120 day old tg/tgla mouse
the following aspects were investigated: 1) the morphology of the cerebellum and
hippocampus, 2) proliferation and death in cells of the hippocampal dentate gyrus and 3)
changes in basic biochemical parameters in granule cells of the cerebellum and
hippocampus.
This study revealed no volume abnormalities within the hippocampus of the
mutant mice, but a decrease in cell density with the pyramidal layer of CA3 and the hilus
of the dentate gyrus. Cell size in the CA3 region was unaffected, but cell size in the hilus of the dentate gyrus did not exhibit the gender difference seen in the wild type
mouse. The cerebellum showed a decrease in volume without any decrease in cerebellar
cellular density. Cell proliferation and differentiation in the subgranular zone of the
hippocampal dentate gyrus remained normal. This region also revealed a decrease in
cell death in the tg/tgla mice.
Basal intracellular calcium levels in granule cells show no difference within the
hippocampus, but an increase in the tg/tgla male cerebellum compared to the wild type
male cerebellum. There was no significant difference in granule cell mitochondrial
membrane potential within the wild type and mutant animals in either the hippocampus
or cerebellum. The rate of reactive oxygen species (ROS) production in granule cells
revealed no variation within the hippocampus or cerebellum. The amount of ROS was
decreased in cerebellar granule cells, but not granule cells of the hippocampus. Inducing
ROS showed no alteration in production or amount of ROS produced in the
hippocampus, but did show a ceiling in the amount of ROS produced, but not rate of
production, in the cerebellum.
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