Synaptic imbalance, stereotypies, and impaired social interactions in mice with altered neuroligin 2 expression
Synaptic imbalance, stereotypies, and impaired social interactions in mice with altered neuroligin 2 expression
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DOI：
10.1523/jneurosci.0032-08.2008
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发表时间：
2008-06-11
影响因子：
5.3
通讯作者：
El-Husseini, Alaa
中科院分区：
文献类型：
--
作者：
Hines, Rochelle M.;Wu, Longjun;El-Husseini, Alaa
大脑中的兴奋水平通过主要由GABA神经元施加的抑制信号来控制。然而，调节兴奋和抑制（E/I）之间平衡的分子机制仍不清楚。参与这一过程的候选分子是神经连接素（NL）粘附分子，它们在兴奋性或抑制性接触中差异富集。在这项研究中，我们使用转基因小鼠模型表达NL 1或NL 2，以检查是否增强特定NLs的表达导致突触失衡和改变神经元兴奋性和动物行为。我们的分析揭示了几个异常选择性地表现在转基因小鼠与NL 2的表达增强，但不是NL 1。NL 2表达的一个小的变化导致额叶皮层突触中突触接触尺寸和囊泡储备池的扩大以及E/I比率的总体降低。微型抑制性突触电流的频率也被发现在额叶皮层的转基因NL 2小鼠增加。这些动物还表现出刻板的跳跃行为，焦虑，受损的社会交往，并增加了棘波放电的发生率，如在自由活动的动物中的EEG分析所示。这些发现可能为E/I失衡和与神经发育障碍相关的行为改变提供神经基础。
The level of excitation in the brain is kept under control through inhibitory signals mainly exerted by GABA neurons. However, the molecular machinery that regulates the balance between excitation and inhibition (E/I) remains unclear. Candidate molecules implicated in this process are neuroligin (NL) adhesion molecules, which are differentially enriched at either excitatory or inhibitory contacts. In this study, we use transgenic mouse models expressing NL1 or NL2 to examine whether enhanced expression of specific NLs results in synaptic imbalance and altered neuronal excitability and animal behavior. Our analysis reveals several abnormalities selectively manifested in transgenic mice with enhanced expression of NL2 but not NL1. A small change in NL2 expression results in enlarged synaptic contact size and vesicle reserve pool in frontal cortex synapses and an overall reduction in the E/I ratio. The frequency of miniature inhibitory synaptic currents was also found to be increased in the frontal cortex of transgenic NL2 mice. These animals also manifested stereotyped jumping behavior, anxiety, impaired social interactions, and enhanced incidence of spike-wave discharges, as depicted by EEG analysis in freely moving animals. These findings may provide the neural basis for E/I imbalance and altered behavior associated with neurodevelopmental disorders.