Late-onset olfactory deficits and mitral cell loss in mice lacking prion protein with ectopic expression of Doppel

Several lines of prion protein gene (Prnp)-knock-out mice such as ZrchI, ZrchII, Npu, Ngsk and Rcm0 have been generated. Of these, ZrchII, Ngsk and Rcm0 exhibit late-onset ataxia due to ectopic expression of Doppel (Dpl); a result of damage to the splicing acceptor of Prnp exon 3. Recently, we developed another line of Prnp(-1-) mice (Rikn), which was generated by gene targeting with more nucleotides by replacing intron 2 with the pgk-neo gene (cf. Ngsk Prnp(-1-) mice) and showed not only ataxia but also a lower olfactory sensitivity than the other Prnp(-1-) mouse line ZrchI at over 60 weeks of age. The histopathology of the elderly Rikn Prnp(-1-) mice showed mitral cell loss concomitantly observed with gliosis of astrocytes. Western blot analysis showed that Dpl was detected in the cerebrum, cerebellum and olfactory bulb of Rikn Prnp(-1-) mice, where aberrant histopathology was observed. Thus, mitral cell loss and gliosis induced by ectopic DpI expression were probably associated with the late-onset olfactory deficits in Rikn Prnp(-1-) mice.