OBJECTIVE Prion diseases are generally characterized by pronounced neuronal loss. In particular, a subpopulation of inhibitory neurones, characterized by the expression of the calcium-binding protein parvalbumin (PV), is selectively destroyed early in the course of human and experimental prion diseases. By contrast, nerve cells expressing calbindin D28 k (CB), another calcium-binding protein, as well as PV/CB coexpressing Purkinje cells, are well preserved. METHODS To evaluate, if PV and CB may directly contribute to neuronal vulnerability or resistance against nerve cell death, respectively, we inoculated PV- and CB-deficient mice, and corresponding controls, with 139A scrapie and compared them with regard to incubation times and histological lesion profiles. RESULTS While survival times were slightly but significantly diminished in CB-/-, but not PV-/- mice, scrapie lesion profiles did not differ between knockout mice and controls. There was a highly significant and selective loss of isolectin B(4)-decorated perineuronal nets (which specifically demarcate the extracellular matrix surrounding the 'PV-expressing' subpopulation of cortical interneurones) in scrapie inoculated PV+/+, as well as PV-/- mice. Purkinje cell numbers were not different in CB+/+ and CB-/- mice. CONCLUSIONS Our results suggest that PV expression is a surrogate marker for neurones highly vulnerable in prion diseases, but that the death of these neurones is unrelated to PV expression and thus based on a still unknown pathomechanism. Further studies including the inoculation of mice ectopically (over)expressing CB are necessary to determine whether the shortened survival of CB-/- mice is indeed due to a neuroprotective effect of this molecule.