Alterations in intracellular calcium ion concentrations in cerebellar granule cells of the CACNA1A mutant mouse, leaner, during postnatal development. Academic Article uri icon


  • Maintaining calcium ion (Ca+) homeostasis is crucial for normal neuronal function. Altered Ca+ homeostasis interferes with Ca+ signaling processes and affects neuronal survival. In this study, we used homozygous leaner and tottering mutant mice, which carry autosomal recessive mutations in the gene coding for the (1A) pore forming subunit of Ca(V)2.1 (P/Q-type) voltage-gated calcium channels (VGCC). Leaner mice show severe ataxia and epilepsy, while tottering mice are less severely affected. Leaner cerebellar granule cells (CGC) show extensive apoptotic cell death that peaks at postnatal (P) day 20 and continues into adulthood. Intracellular Ca+ ([Ca+](i)) concentrations in leaner and tottering mouse Purkinje cells have been described, but [Ca+](i) concentrations have not been reported for granule cells, the largest neuronal population of the cerebellum. Using the ratiometric dye, Fura-2 AM, we investigated the role of Ca+ homeostasis in CGC death during postnatal development by demonstrating basal [Ca+](i), depolarization induced Ca+ transients, and Ca+ transients after completely blocking Ca(V)2.1 VGCC. From P20 onward, basal [Ca+](i) levels in leaner CGC were significantly lower compared to age-matched wild-type CGC. We also compared basal [Ca+](i) levels in leaner and wild-type CGC to basal [Ca+](i) in tottering CGC. Potassium chloride induced depolarization revealed no significant difference in Ca+ transients between leaner and wild-type CGC, indicating that even though leaner CGC have dysfunctional P/Q-type VGCC, Ca+ transients after depolarization are the same. This suggests that other VGCC are compensating for the dysfunctional P/Q channels. This finding was further confirmed by completely blocking Ca(V)2.1 VGCC using -Agatoxin IV-A.

published proceedings

  • Neurotox Res

author list (cited authors)

  • Bawa, B., & Abbott, L. C.

citation count

  • 2

complete list of authors

  • Bawa, Bhupinder||Abbott, Louise C

publication date

  • January 2011