Targeted calretinin expression in granule cells of calretinin-null mice restores normal cerebellar functions

Abstract

Ca2 binding proteins such as calretinin, characterized by the presence of EF-hand motifs that bind Ca2+ ions, are involved in the shaping of intraneuronal Ca2+ fluxes. In the cerebellar cortex, information processing tightly relies on variations in intracellular Ca2+ concentration in Purkinje and granule cells. Calretinin-deficient (Cr-/-) mice present motor discoordination, suggesting cellular and network cerebellar dysfunctions. To determine the cell specificity of these alterations, we constructed transgenic Cr-/- mice exhibiting a selective reexpression of calretinin in granule cells through the promoter function of the GABAA receptor alpha6 subunit gene. Normal granule cell excitability and wild-type Purkinje cell firing behavior in awake mice were restored while the emergence of high-frequency oscillations was abolished. Behavioral analysis of these calretinin-rescue mice revealed that normal motor coordination was restored as compared with Cr-/- mice. These results demonstrate that calretinin is required specifically in granule cells for correct computation in the cerebellar cortex and indicate that the finetuning of granule cell excitability through regulation of Ca2+ homeostasis plays a crucial role for information coding and storage in the cerebellum.