Deficits of olfactory interneurons in polysialyltransferase- and NCAM-deficient mice.

Abstract

The neurogenic niche of the anterior subventricular zone (SVZ) persistently generates neuroblasts, which migrate along the rostral migratory stream (RMS) into the olfactory bulb (OB), where they differentiate into granule and periglomerular cells. Loss of the neural cell adhesion molecule NCAM or its post-translational modification polysialic acid (polySia) impairs migration causing accumulations of cells in the proximal RMS and decreased OB volume. Polysialylation of NCAM is implemented by two polysialyltransferases, ST8SIA2 and ST8SIA4, with overlapping functions. Here, we used mice with Ncam1 and polysialyltransferase deletions to analyze how partial or complete loss of polySia synthesis or a combined loss of polySia and NCAM affects the RMS and the interneuron composition in the OB. Numerous calretinin (CR)-positive cells were detected dispersed around the RMS in Ncam1 knockout, St8sia2, St8sia4 double-knockout, and St8sia2, St8sia4, Ncam1 triple-knockout mice, as well as in St8sia2(-/-) but not in St8sia4(-/-) mice. These changes were not reflected by reductions of CR-positive cells in the granule or glomerular layer of the OB. Instead, calbindin-positive periglomerular interneurons were strongly reduced in all polySia-NCAM negative mice and slightly attenuated in St8sia2(-/-) as well as in the St8sia4(-/-) mice, which were devoid of ectopic CR-positive cells along the RMS. Consistent with the early developmental generation of calbindin- as compared with CR-positive OB interneurons, this phenotype was fully developed at postnatal day 5. Together, these results demonstrate that the early development of calbindin-positive periglomerular interneurons depends on the presentation of polySia on NCAM and requires the activity of both polysialyltransferases.