Persistent gating deficit and increased sensitivity to NMDA receptor antagonism after puberty in a new mouse model of the human 22q11.2 microdeletion syndrome: a study in male mice
Persistent gating deficit and increased sensitivity to NMDA receptor antagonism after puberty in a new mouse model of the human 22q11.2 microdeletion syndrome: a study in male mice
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DOI：
10.1503/jpn.150381
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发表时间：
2017-01-01
影响因子：
4.3
通讯作者：
Nielsen, Jacob
中科院分区：
文献类型：
--
作者：
Didriksen, Michael;Fejgin, Kim;Nielsen, Jacob
背景：半合子22q11.2微缺失是人类常见的拷贝数变异。这种缺失会导致神经发育障碍的高风险，包括自闭症和精神分裂症。高达41%的缺失携带者会出现精神病症状。研究方法：我们提出了一种新的小鼠模型（Df（h22 q11）/+）的缺失综合征（22q11.2DS），并报告，据我们所知，最全面的研究进行到目前为止，在22q11.2DS模型。该研究在雄性小鼠中进行。结果如下：我们发现青春期后N-甲基-D-天冬氨酸（NMDA）受体拮抗剂引起的过度运动，年龄无关的前脉冲抑制（PPI）的缺陷和增加声惊吓反应（ASR）。PPI缺陷和增加的ASR对抗精神病药物治疗抵抗。PPI缺陷不是听觉脑干反应测量的听力受损的结果。Df（h22 q11）/+小鼠也表现出听觉依赖性诱发电位的幅度增加。前额叶皮层和背侧纹状体多巴胺代谢产物DOPAC的升高和AMPA受体亚单位GluR 1的背侧纹状体表达增加被发现。在广泛的其他行为和生化测定中，Df（h22 q11）/+小鼠没有偏离野生型小鼠。局限性：22q11.2微缺失在人类中具有不完全遗传性，疾病的严重程度取决于完整的遗传组成以及环境因素。为了获得反映与22q11.2DS相关的严重状况的更显著的表型，建议将Df（h22 q11）/+小鼠暴露于可能揭示潜在精神病理学的环境应激源。结论：Df（h22 q11）/+模型将是一个有价值的工具，增加我们对精神分裂症和其他精神疾病的病因学与22 q11 DS的理解。
Background: The hemizygous 22q11.2 microdeletion is a common copy number variant in humans. The deletion confers high risk for neuro-developmental disorders, including autism and schizophrenia. Up to 41% of deletion carriers experience psychotic symptoms. Methods: We present a new mouse model (Df(h22q11)/+) of the deletion syndrome (22q11.2DS) and report on, to our knowledge, the most comprehensive study undertaken to date in 22q11.2DS models. The study was conducted in male mice. Results: We found elevated postpubertal N-methyl-D-aspartate (NMDA) receptor antagonist-induced hyperlocomotion, age-independent prepulse inhibition (PPI) deficits and increased acoustic startle response (ASR). The PPI deficit and increased ASR were resistant to antipsychotic treatment. The PPI deficit was not a consequence of impaired hearing measured by auditory brain stem responses. The Df(h22q11)/+ mice also displayed increased amplitude of loudness-dependent auditory evoked potentials. Prefrontal cortex and dorsal striatal elevations of the dopamine -metabolite DOPAC and increased dorsal striatal expression of the AMPA receptor subunit GluR1 was found. The Df(h22q11)/+ mice did not deviate from wild-type mice in a wide range of other behavioural and biochemical assays. Limitations: The 22q11.2 microdeletion has incomplete penetrance in humans, and the severity of disease depends on the complete genetic makeup in concert with environmental factors. In order to obtain more marked phenotypes reflecting the severe conditions related to 22q11.2DS it is suggested to expose the Df(h22q11)/+ mice to environmental stressors that may unmask latent psychopathology. Conclusion: The Df(h22q11)/+ model will be a valuable tool for increasing our understanding of the etiology of schizophrenia and other psychiatric disorders associated with the 22q11DS.