Frontal cortical synaptic communication is abnormal in Disc1 genetic mouse models of schizophrenia
Frontal cortical synaptic communication is abnormal in Disc1 genetic mouse models of schizophrenia
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DOI：
10.1016/j.schres.2013.02.007
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发表时间：
2013-05-01
影响因子：
4.5
通讯作者：
Levine, Michael S.
中科院分区：
文献类型：
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作者：
Holley, Sandra M.;Wang, Elizabeth A.;Levine, Michael S.
携带 Disc1 突变的小鼠模型可能有助于了解 Disc1 遗传变异如何导致精神分裂症 (SZ) 易感性。 Disc1 突变小鼠表现出类似 SZ 的行为和认知障碍。为了剖析这些表型背后的突触机制，我们检查了两个小鼠模型的皮质神经元的电生理特性，第一个在整个大脑中表达截短的小鼠 Disc1 (mDisc1) 蛋白，第二个在前脑区域表达截短的人 Disc1 (hDisc1) 蛋白。我们获得了全细胞膜片钳记录，以检查 Disc1 蛋白表达的改变如何改变 4-7 个月大的 mDisc1 和 hDisc1 小鼠内侧前额叶皮质锥体神经元的兴奋性和抑制性突触传递。在 mDisc1 和 hDisc1 小鼠中，自发 EPSC 的频率高于野生型同窝对照小鼠。两个品系的雄性小鼠都比雌性小鼠更容易受到 Disc1 突变的影响，表现出兴奋性事件与抑制性事件的比率增加。仅在 mDisc1 模型中观察到自发 IPSC 的变化，并且具有性别特异性，皮质 GABA 能神经传递减少，这是 SZ 的一个有据可查的特征，仅发生在雄性 mDisc1 小鼠中。相比之下，雌性 mDisc1 小鼠的小幅度 sIPSC 频率有所增加。这些发现表明，Disc1 的截短会在模型中常见和不同地改变谷氨酸能和 GABA 能神经传递，并且一些影响是性别特异性的，揭示了 Disc1 表达的改变如何导致 SZ 的行为干扰和认知缺陷。 (C) 2013 Elsevier B.V. 保留所有权利。
Mouse models carrying Disc1 mutations may provide insights into how Disc1 genetic variations contribute to schizophrenia (SZ) susceptibility. Disc1 mutant mice show behavioral and cognitive disturbances reminiscent of SZ. To dissect the synaptic mechanisms underlying these phenotypes, we examined electrophysiological properties of cortical neurons from two mouse models, the first expressing a truncated mouse Disc1 (mDisc1) protein throughout the entire brain, and the second expressing a truncated human Disc1 (hDisc1) protein in forebrain regions. We obtained whole-cell patch clamp recordings to examine how altered expression of Disc1 protein changes excitatory and inhibitory synaptic transmissions onto cortical pyramidal neurons in the medial prefrontal cortex in 4-7 month-old mDisc1 and hDisc1 mice. In both mDisc1 and hDisc1 mice, the frequency of spontaneous EPSCs was greater than in wild-type littermate controls. Male mice from both lines were more affected by the Disc1 mutation than were females, exhibiting increases in the ratio of excitatory to inhibitory events. Changes in spontaneous IPSCs were only observed in the mDisc1 model and were sex-specific, with diminished cortical GABAergic neurotransmission, a well-documented characteristic of SZ, occurring only in male mDisc1 mice. In contrast, female mDisc1 mice showed an increase in the frequency of small-amplitude sIPSCs. These findings indicate that truncations of Disc1 alter glutamatergic and GABAergic neurotransmission both commonly and differently in the models and some of the effects are sex-specific, revealing how altered Disc1 expression may contribute to behavioral disruptions and cognitive deficits of SZ. (C) 2013 Elsevier B.V. All rights reserved.