ROLE OF CAV2.1 SPLICE VARIANTS IN THE CEREBELLUM

Abstract

Cav2.1 channels are voltage-dependent calcium channels that are involved in many key roles of the central nervous system by mediating calcium influx in response to changes in membrane potential. They are extensively alternatively spliced, with seven known alternative splice variants in humans. One of its alternatively-spliced exons, is exon 37, forms part of the EF-hand binding domain together with exon 36. Alternative splicing of exon 37 gives rise to two mutually exclusive splice variants, exon 37a (EFa) and exon 37b (EFb), which have demonstrated differences in Ca2+-dependent facilitation (CDF), with the EFa form possessing CDF while the EFb form does not have CDF. The physiological relevance of this difference remains unknown. For this reason, we generated a conditional knockout (cKO) mouse model using Cre-loxP system, to conditionally knock-out the EFa form in Purkinje cells. In this study, we find the homozygous conditionally knocked-out EFa mice are ataxic and have a selective patterned degeneration of Purkinje cells in Aldolase C negative compartments. While the molecular mechanisms underlying this selective degeneration is still not known, preliminary data shows that Aldolase C increases the current density of Cav2.1 channels, which could help compensate for the decreased membrane expression of CaV2.1 in cKO mice. Electrophysiological, biochemical and morphological characterization of cKO mice also show that unlike previous cKO of the whole CaV2.1 channel in Purkinje cells, Purkinje cells in cKO mice are mono-synaptically innervated.