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Description:
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Mutations of the α1A subunit of CaV 2 .1 voltage gated calcium (VGCC ) channels
are responsible for several inherited disorders affecting humans , including familial
hemiplegic migraine , episodic ataxia type and spinocerebellar ataxia type . The leaner
mouse also carries an autosomal recessive mutation in the α1A subunit of CaV 2 .1 VGCCs ,
which , in the homozygous condition , results in a severe cerebellar atrophy and ataxia .
The leaner mutation results in reduced calcium influx through CaV 2 .1 VGCCs . To better
understand cerebellar neurodegeneration and cerebellar dysfunction we focused our
research on elucidating the relationship between mitochondrial function /dysfunction and
calcium channel mutations . The aims of this dissertation were : 1 ) to estimate the extent
of neuronal cell death , basal intracellular calcium and mitochondrial (dys )function in
cerebellar granule cells (CGC ) of adult leaner mice ; 2 ) to analyze the role of the leaner
calcium channel mutation on postnatal development of CGCs ; and 3 ) to test whether
inducing increased calcium influx by exposing cultured granule cells to potassium
chloride can eliminate or reduce the CGC death . By using mechanism independent Fluoro -Jade staining and apoptosis specific
TUNEL staining , we demonstrated that leaner CGC death continues into adulthood and
the spatial pattern of granule cell death observed during postnatal development also
continues into adulthood . The present investigation showed a reduced resting
intracellular calcium in CGC from leaner mice as compared to age matched wild type
mice , and tottering mice . The tottering mouse is another mutant mouse that carries a
mutation in the α1A subunit of CaV 2 .1 VGCCs like leaner mouse . However , these mice
do not show any neurodegeneration and therefore they were used as a second control .
Our results also showed that even though CGC of leaner mice have dysfunctional CaV2 .1
channels , there is no change in depolarization induced Ca2+ influx , which suggests a
functional compensation for CaV2 .1 calcium channels by other VGCCs . Our results
showed reduced mitochondrial membrane potential at the time of peak CGC death in
leaner mice as compared to wild type CGCs and tottering CGCs . The results of this
investigation suggest mitochondrial mediated but reactive oxygen species independent
cell death in CGCs of leaner mice . |