Posttranslational modification of the
neural cell adhesion molecule (
NCAM) by
polysialic acid (
polySia) is crucial for nervous system development and brain plasticity.
PolySia attachment is catalyzed by the polysialyltransferases (polySTs)
ST8SIA2 and ST8SIA4, two
enzymes with distinct but also common functions during neurodevelopment and in the adult brain. A growing body of evidence links aberrant levels of
NCAM and
polySia as well as variation in the
ST8SIA2 gene to neuropsychiatric disorders, including
schizophrenia. To investigate whether polyST deficiency might cause a
schizophrenia-like phenotype,
St8sia2 (-/-) mice, St8sia4 (-/-) mice and their wildtype littermates were assessed neuroanatomically and subjected to tests of cognition and sensorimotor functions.
St8sia2 (-/-) but not St8sia4 (-/-) mice displayed enlarged lateral ventricles and a size reduction of the thalamus accompanied by a smaller internal capsule and a highly disorganized pattern of fibers connecting thalamus and cortex. Reduced levels of the
vesicular glutamate transporter VGLUT2 pointed towards compromised glutamatergic thalamocortical input into the frontal cortex of
St8sia2 (-/-) mice. Both polyST-deficient lines were impaired in short- and long-term recognition memory, but only
St8sia2 (-/-) mice displayed impaired working memory and deficits in prepulse inhibition. Furthermore, only the
St8sia2 (-/-) mice exhibited anhedonic behavior and increased sensitivity to
amphetamine-induced hyperlocomotion. These results reveal that reduced polysialylation in
St8sia2 (-/-) mice leads to pathological brain development and
schizophrenia-like behavior. We therefore propose that genetic variation in
ST8SIA2 has the potential to confer a neurodevelopmental predisposition to
schizophrenia.