The neural cell adhesion molecule NCAM and its dynamically regulated posttranslational modification polysialic acid (PSA) are major determinants of cellular interactions during ontogeny. While NCAM in the absence of PSA stabilizes cell-cell interactions, the attachment of the large and polyanionic PSA negatively influences cell adhesion and promotes plasticity. Disease-associated changes in the polysialylation state of NCAM raise the question whether the PSA-NCAM system can affect CNS pharmacology. Here we investigated the pharmacological effects of the competitive AMPA antagonist NBQX in genetic mouse models either lacking NCAM and PSA (female NCAM knockout mice) or being drastically reduced in the level of PSA expression (female ST8SiaIV knockout mice). Studies were carried out with the respective wildtype littermate controls. In mice lacking NCAM and PSA, NBQX-induced ataxia proved to be more intense as compared with wild-type mice. On both mutant backgrounds, NBQX significantly elevated seizure thresholds during i.v. infusion of the chemoconvulsant pentylenetetrazole. In summary, the data demonstrate that the PSA-NCAM system impacts AMPA receptor pharmacology under in vivo conditions. The fact that comparable effects were observed in NCAM- and ST8SiaIV-knockout mice indicates that this impact is not due to a stabilizing effect of NCAM in the absence of PSA. Thus, disease-related changes in the polysialylation of NCAM are likely to be associated with effects on the efficacy and tolerability of AMPA receptor antagonists.