Schizophrenia-like phenotype of polysialyltransferase ST8SIA2-deficient mice
Schizophrenia-like phenotype of polysialyltransferase ST8SIA2-deficient mice
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DOI：
10.1007/s00429-013-0638-z
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发表时间：
2015-01-01
影响因子：
3.1
通讯作者：
Zharkovsky, Alexander
中科院分区：
文献类型：
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作者：
Kroecher, Tim;Malinovskaja, Kristina;Zharkovsky, Alexander
聚唾液酸（polySia）对神经细胞粘附分子（NCAM）的翻译后修饰对神经系统发育和大脑可塑性至关重要。多sia附着是由多唾液基转移酶（polySTs） ST8SIA2和ST8SIA4催化的，这两种酶在神经发育和成人大脑中具有不同但又共同的功能。越来越多的证据表明，NCAM和polySia的异常水平以及ST8SIA2基因的变异与包括精神分裂症在内的神经精神疾病有关。为了研究polyST缺乏是否可能导致精神分裂症样表型，对St8sia2（-/-）小鼠、St8sia4（-/-）小鼠及其野生型幼崽进行了神经解剖学评估，并进行了认知和感觉运动功能测试。St8sia2（-/-）而非St8sia4（-/-）小鼠表现出侧脑室增大，丘脑体积减小，同时伴有较小的内囊和连接丘脑和皮层的纤维高度紊乱。St8sia2（-/-）小鼠脑额叶谷氨酸转运蛋白VGLUT2水平降低，表明谷氨酸能丘脑皮质输入受损。这两个多st缺陷系在短期和长期识别记忆方面都受到损害，但只有St8sia2（-/-）小鼠表现出工作记忆受损和脉冲前抑制缺陷。此外，只有St8sia2（-/-）小鼠表现出快感缺乏行为和对安非他明诱导的过度运动的敏感性增加。这些结果表明，St8sia2（-/-）小鼠多唾液化水平降低可导致病理性脑发育和精神分裂症样行为。因此，我们提出ST8SIA2的遗传变异有可能赋予精神分裂症的神经发育易感性。
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.