Schizophrenia-like phenotype of polysialyltransferase ST8SIA2-deficient mice.
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.
Institute of Cellular Chemistry (OE4330), Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
Tim
T
Kröcher
Kristina
K
Malinovskaja
Monika
M
Jürgenson
Anu
A
Aonurm-Helm
Tamara
T
Zharkovskaya
Anti
A
Kalda
Iris
I
Röckle
Miriam
M
Schiff
Birgit
B
Weinhold
Rita
R
Gerardy-Schahn
Herbert
H
Hildebrandt
Alexander
A
Zharkovsky
D000161:Acoustic Stimulation; D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D004195:Disease Models, Animal; D005518:Food Preferences; D020772:Internal Capsule / Q000473:pathology; D020547:Lateral Ventricles / Q000473:pathology; D018782:Maze Learning / Q000502:physiology; D008570:Memory, Short-Term / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D065808:Prepulse Inhibition / Q000235:genetics / Q000502:physiology; D021641:Recognition, Psychology; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D012799:Sialyltransferases / Q000172:deficiency* / Q000235:genetics; D013788:Thalamus / Q000473:pathology; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D050599:Vesicular Glutamate Transport Protein 2 / Q000378:metabolism
C493477:Slc17a6 protein, mouse; C493465:Slc17a7 protein, mouse; D050598:Vesicular Glutamate Transport Protein 1; D050599:Vesicular Glutamate Transport Protein 2; C046778:CMP-N-acetylneuraminate-poly-alpha-2,8-sialosyl sialyltransferase; D012799:Sialyltransferases