NEURODEGENERATION IN CEREBELLAR GRANULE CELLS OF P/Q TYPE VOLTAGE GATED CALCIUM CHANNEL MUTANT LEANER MICE A Dissertation by BHUPINDER BAWA

Neurodegeneration in Cerebellar Granule Cells of P/Q Type Voltage Gated Calcium Channel Mutant Leaner Mice. (December 2007) Bhupinder Bawa, B.V.Sc. & A.H., Punjab Agricultural University; M.V.Sc., Punjab Agricultural University Chair of Advisory Committee: Dr. Louise C. Abbott 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.