Age-related impairment of olfactory bulb neurogenesis in the Ts65Dn mouse model of Down syndrome

Abstract

Down syndrome (DS) is a genetic condition caused by triplication of chromosome 21. Widespread neurogenesis reduction during brain development underlies the numerous neurological defects of DS. These defects start to manifest themselves at birth and worsen with age. However, unlike other brain functions, smell is impaired only at advanced life stages, suggesting preservation of olfactory bulb neurogenesis up to adulthood. To clarify this issue, in the current study we examined olfactory bulb (OB) neurogenesis and olfactory function by exploiting the Ts65Dn mouse, a widely used model of DS. We found that in young (15-day-old) Ts65Dn mice, in spite of a reduced proliferation rate in the subventricular zone (SVZ) in comparison with euploid mice, the number of neuroblasts traveling in the rostral migratory stream (RMS), en route to the OB, and the number of new granule neurons added to the OB were similar to those of euploid mice. In mid-age (13-month-old) Ts65Dn mice, however, the proliferation rate in the SVZ was more severely reduced in comparison with euploid mice and the number of neuroblasts in the RMS and new granule neurons added to the OB underwent a reduction. While in young Ts65Dn mice the olfactory function, assessed with the buried food pellet test, was similar to that of euploid mice, in mid-age mice it was significantly impaired. Taken together, results suggest that an age-related reduction in the renewal of OB granule cells may underlie the age-related smell impairment in DS.

Keywords: 5-bromo-2-deoxyuridine; BrdU; DS; Down syndrome; GAP-43; GL; GRL; Growth Associated Protein 43; LV; ML; NeuN; Neurogenesis; Neuronal-specific nuclear protein; OB; Olfactory bulb; Olfactory function; PCNA; PGP9.5; Patched1; Proliferating Cell Nuclear Antigen; Protein Gene Product 9.5; Ptch1; RMS; Rostral migratory stream; SVZ; Shh; Smo; Smoothened; Sonic Hedgehog; Subventricular zone; ePL; external plexiform layer; glomerular layer; granule cell layer; iPL; internal plexiform layer; lateral ventricle; mitral cell layer; olfactory bulb; rostral migratory stream; subventricular zone.