VULNERABILITY OF MIDBRAIN DOPAMINERGIC-NEURONS IN CALBINDIN-D-28K-DEFICIENT MICE - LACK OF EVIDENCE FOR A NEUROPROTECTIVE ROLE OF ENDOGENOUS CALBINDIN IN MPTP-TREATED AND WEAVER MICE

Calbindin-D-28k (calbindin) is an intracellular calcium binding protei n of unknown in vivo function. It is abundantly expressed in many popu lations of neurons, and it can, presumably by buffering calcium overlo ad, protect cells against excitotoxic damage. In the midbrain, calbind in is preferentially expressed in those dopamine neurons which are spa red from degeneration in Parkinson's disease and its animal models. Wh ether calbindin itself determines neuronal vulnerability is questioned in other lesion models where calbindin expression is not positively c orrelated with neuronal resistance. To study the possible neuroprotect ive role of calbindin in vivo, we generated calbindin-deficient mice b y gene targeting and assessed the viability of midbrain dopamine neuro ns in both a chemical and a genetic lesion paradigm. Tyrosine hydroxyl ase-immunoreactive neurons were counted in calbindin null-mutant mice treated with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridi ne (MPTP) and in a calbindin-deficient weaver strain (homozygous for w eaver and the calbindin null mutation). The extent and pattern of neur on 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 w ild-type littermates, or between calbindin-weaver double mutant mice a nd weaver mice. Thus, in all four groups the same subpopulation of tyr osine hydroxylase-positive midbrain neurons (i.e. those normally conta ining calbindin) were preferentially spared. Calretinin, a closely rel ated calcium-binding protein, which is also expressed in some midbrain dopamine neurons, was not up-regulated in these surviving neurons, Th ese findings indicate that the resistance of calbindin-containing neur ons in the MPTP and weaver models is not causally related to the expre ssion of calbindin, and that endogenous calbindin is not required for protection of these neurons.