Vulnerability of Midbrain Dopaminergic Neurons in Calbindin‐D28k‐deficient Mice: Lack of Evidence for a Neuroprotective Role of Endogenous Calbindin in MPTPtreated and Weaver Mice

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Abstract
Calbindin‐D28k (calbindin) is an intracellular calcium binding protein of unknown in vivo function. It is abundantly expressed in many populations of neurons, and it can, presumably by buffering calcium overload, protect cells against excitotoxic damage. In the midbrain, calbindin is preferentially expressed in those dopamine neurons which are spared from degeneration in Parkinson's disease and its animal models. Whether calbindin itself determines neuronal vulnerability is questioned in other lesion models where calbindin expression is not positively correlated with neuronal resistance. To study the possible neuroprotective role of calbindin in vivo, we generated calbindin‐deficient mice by gene targeting and assessed the viability of midbrain dopamine neurons in both a chemical and a genetic lesion paradigm. Tyrosine hydroxylase‐immunoreactive neurons were counted in calbindin null‐mutant mice treated with the neurotoxin 1 ‐methyl‐4‐phenyl‐1, 2, 3, 6‐tetrahydropyridine (MPTP) and in a calbindin‐deficient weaver strain (homozygous for weaver and the calbindin null mutation). The extent and pattern of neuron loss observed in MPTP‐treated wild‐type and homozygous weaver mice were as previously described. Surprisingly, no significant differences were observed between MPTP‐treated calbindin null mutants and their wild‐type littermates, or between calbindin‐weaver double mutant mice and weaver mice. Thus, in all four groups the same subpopulation of tyrosine hydroxylase‐positive midbrain neurons (i.e. those normally containing calbindin) were preferentially spared. Calretinin, a closely related calcium‐binding protein, which is also expressed in some midbrain dopamine neurons, was not up‐regulated in these surviving neurons. These findings indicate that the resistance of calbindin‐containing neurons in the MPTP and weaver models is not causally related to the expression of calbindin, and that endogenous calbindin is not required for protection of these neurons.