Mice deficient in the polysialyltransferase ST8SialV/PST-1 allow discrimination of the roles of neural cell adhesion molecule protein and polysialic acid in neural development and synaptic plasticity

Functional properties of the neural cell adhesion molecule (NCAM) are stron gly influenced by polysialylation. We used gene-targeting to generate mice lacking ST8SiaIV/PST-1, one of the polysialyltransferases responsible for a ddition of polysialic acid (PSA) to NCAM. Mice homozygous for the null muta tion reveal normal development of gross anatomical features. In contrast to NCAM-deficient mice, olfactory precursor cells in the rostral migratory st ream express PSA and follow their normal pathway. Furthermore, delamination of mossy fibers in the hippocampal CA3 region, as found in NCAM-deficient mice, does not occur in ST8SiaIV mutants. However, during postnatal develop ment these animals show a decrease of PSA in most brain regions compared to wild-type animals. Loss of PSA in the presence of NCAM protein but in the absence of obvious histological changes allowed us to directly address the role of PSA in synaptic plasticity. Schaffer collateral-CA1 synapses, which express PSA in wild types, showed impaired long-term potentiation (LTP) an d longterm depression (LTD) in adult mutants. This impairment was age-depen dent, following the time course of developmental disappearance of PSA. Cont rary to NCAM mutant mice, LTP in ST8SiaIV mutants was undisturbed at mossy fiber-CA3 synapses, which do not express PSA in wild-type mice. The results demonstrate an essential role for ST8SiaIV in synaptic plasticity in hippo campal CA1 synapses, whereas PSA produced by different polysialyltransferas e or polysialyltransferases at early stages of differentiation regulates mi gration of neural precursor cells and correct lamination of mossy fibers. W e suggest that NCAM but not PSA is likely to be important for LTP in the hi ppocampal CA3 region.