Cerebellum, Hippocampal neurogenesis, Voltage-gated calcium ion channels, Mitochondrial membrane potential, Calcium ion homeostasis, Reactive oxygen species, and Compound heterozygous tottering/leaner mouse
Due to two different mutations in the gene that encodes the a1A subunit ofvoltage-activated CaV 2.1 calcium ion channels, the compound heterozygoustottering/leaner (tg/tgla) mouse exhibits numerous neurological deficits. Humandisorders that arise from mutations in this voltage dependent calcium channel arefamilial hemiplegic migraine, episodic ataxia-2, and spinocerebellar ataxia 6. The tg/tglamouse exhibits ataxia, movement disorders and memory impairment, suggesting thatboth the cerebellum and hippocampus are affected. To gain greater understanding of themany neurological abnormalities that are exhibited by the 90-120 day old tg/tgla mousethe following aspects were investigated: 1) the morphology of the cerebellum andhippocampus, 2) proliferation and death in cells of the hippocampal dentate gyrus and 3)changes in basic biochemical parameters in granule cells of the cerebellum andhippocampus.This study revealed no volume abnormalities within the hippocampus of themutant mice, but a decrease in cell density with the pyramidal layer of CA3 and the hilusof 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 typemouse. The cerebellum showed a decrease in volume without any decrease in cerebellarcellular density. Cell proliferation and differentiation in the subgranular zone of thehippocampal dentate gyrus remained normal. This region also revealed a decrease incell death in the tg/tgla mice.Basal intracellular calcium levels in granule cells show no difference within thehippocampus, but an increase in the tg/tgla male cerebellum compared to the wild typemale cerebellum. There was no significant difference in granule cell mitochondrialmembrane potential within the wild type and mutant animals in either the hippocampusor cerebellum. The rate of reactive oxygen species (ROS) production in granule cellsrevealed no variation within the hippocampus or cerebellum. The amount of ROS wasdecreased in cerebellar granule cells, but not granule cells of the hippocampus. InducingROS showed no alteration in production or amount of ROS produced in thehippocampus, but did show a ceiling in the amount of ROS produced, but not rate ofproduction, in the cerebellum.