Neurodegeneration in cerebellar granule cells of p/q type voltage gated calcium channel mutant leaner mice

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Title: Neurodegeneration in cerebellar granule cells of p/q type voltage gated calcium channel mutant leaner mice
Author: Bawa, Bhupinder
Abstract: Mutations of the ?1A 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 ?1A 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 ?1A 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 .
URI: http : / /hdl .handle .net /1969 .1 /ETD -TAMU -2609
Date: 2009-05-15

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Neurodegeneration in cerebellar granule cells of p/q type voltage gated calcium channel mutant leaner mice. Available electronically from http : / /hdl .handle .net /1969 .1 /ETD -TAMU -2609 .

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