The suppression of brain cold-stable microtubules in mice induces synaptic defects associated with neuroleptic-sensitive behavioral disorders
The suppression of brain cold-stable microtubules in mice induces synaptic defects associated with neuroleptic-sensitive behavioral disorders
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DOI：
10.1101/gad.223302
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发表时间：
2002-09-15
影响因子：
10.5
通讯作者：
Job, D
中科院分区：
文献类型：
--
作者：
Andrieux, A;Salin, PA;Job, D
神经元含有大量高度稳定的微管亚群，这些微管可以抵抗诸如暴露于寒冷等条件下的解聚。稳定的微管被认为对神经元的发育、维持和功能至关重要。先前的研究表明微管相关蛋白STOP在诱导微管冷稳定性中起重要作用。在这里，我们开发了STOP null小鼠。这些小鼠缺乏冷稳定微管。与我们的预期相反，STOP-/-小鼠在脑解剖学上没有可检测到的缺陷，但出现突触缺陷，突触囊泡池耗尽，突触可塑性受损，与严重的行为障碍相关。一项关于精神药物对STOP-/-小鼠行为影响的调查显示，长期服用抗精神病药物对缓解这些疾病有显著的特异性作用。该研究表明，STOP是神经元微管具有令人感兴趣的稳定性的一个主要因素，对突触的可塑性也很重要。此外，STOP-/-小鼠可能为精神分裂症等疾病的神经抑制剂研究提供相关模型，目前认为这些疾病是由突触缺陷引起的。
Neurons contain abundant subsets of highly stable microtubules that resist depolymerizing conditions such as exposure to the cold. Stable microtubules are thought to be essential for neuronal development, maintenance, and function. Previous work has indicated an important role of the microtubule-associated protein STOP in the induction of microtubule cold stability. Here, we developed STOP null mice. These mice were devoid of cold-stable microtubules. In contrast to our expectations, STOP-/- mice had no detectable defects in brain anatomy but showed synaptic defects, with depleted synaptic vesicle pools and impaired synaptic plasticity, associated with severe behavioral disorders. A survey of the effects of psychotropic drugs on STOP-/- mice behavior showed a remarkable and specific effect of long-term administration of neuroleptics in alleviating these disorders. This study demonstrates that STOP is a major factor responsible for the intriguing stability properties of neuronal microtubules and is important for synaptic plasticity. Additionally, STOP-/- mice may yield a pertinent model for study of neuroleptics in illnesses such as schizophrenia, currently thought to result from synaptic defects.