Cerebellar defects in Ca2+/calmodulin kinase IV-deficient mice

The Ca2+/calmodulin-dependent protein kinase CaMKIV was first identified in the cerebellum and has been implicated in nuclear signaling events that co ntrol neuronal growth, differentiation, and plasticity. To understand the p hysiological importance of CaMKIV, we disrupted the mouse Camk4 gene. The C aMKIV null mice displayed locomotor defects consistent with altered cerebel lar function. Although the overall cytoarchitecture of the cerebellum appea red normal in the Camk4(-/-) mice, we observed a significant reduction in t he number of mature Purkinje neurons and reduced expression of the protein marker calbindin D28k within individual Purkinje neurons. Western immunoblo t analyses of cerebellar extracts also established significant deficits in the phosphorylation of cAMP response element-binding protein at serine-133, a proposed target of CaMKIV. Additionally, the absence of CaMKIV markedly altered neurotransmission at excitatory synapses in Purkinje cells. Multipl e innervation by climbing fibers and enhanced parallel fiber synaptic curre nts suggested an immature development of Purkinje cells in the Camk4(-/-) m ice. Together, these findings demonstrate that CaMKIV plays key roles in th e function and development of the cerebellum.