ATAXIA AND ALTERED DENDRITIC CALCIUM SIGNALING IN MICE CARRYING A TARGETED NULL MUTATION OF THE CALBINDIN D28K GENE

Intracellular calcium-binding proteins are abundantly expressed in man y neuronal populations. Previous evidence suggests that calcium-bindin g proteins can modulate various neuronal properties, presumably by the ir action as calcium buffers. Tile importance of calcium-binding prote ins for nervous system function in an intact integrated system is, how ever, less clear, To investigate the physiological role of a major end ogenous calcium-binding protein, calbindin D28k (calbindin) in vivo, w e have generated calbindin null mutant mice by gene targeting. Surpris ingly, calbindin deficiency does not affect general parameters of deve lopment and behavior or the structure of the nervous system at the lig ht microscopic level. Null mutants are, however, severely impaired in tests of motor coordination, suggesting functional deficits in cerebel lar pathways. Purkinje neurons, the only efferent of the cerebellar co rtex, and inferior olive neurons, the source of the climbing fiber aff erent, have previously been shown to express calbindin, Correlated wit h this unusual type of ataxia, confocal calcium imaging of Purkinje ce lls in cerebellar slices revealed marked changes of synaptically evoke d postsynaptic calcium transients. Their fast, but not their slow, dec ay component had larger amplitudes in null mutant than in wild-type mi ce. We conclude that endogenous calbindin is of crucial importance for integrated nervous system function.