Brain activity mapping in Mecp2 mutant mice reveals functional deficits in forebrain circuits, including key nodes in the default mode network, that are reversed with ketamine treatment.
Brain activity mapping in Mecp2 mutant mice reveals functional deficits in forebrain circuits, including key nodes in the default mode network, that are reversed with ketamine treatment.
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DOI：
10.1523/jneurosci.2159-12.2012
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发表时间：
2012-10-03
期刊：
影响因子：
--
通讯作者：
Katz DM
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文献类型：
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作者：
Kron M;Howell CJ;Adams IT;Ransbottom M;Christian D;Ogier M;Katz DM
在Rett综合征（RTT）和其他自闭症谱系障碍（ASD）模型中，已经在特定的脑微电路中发现了兴奋-抑制失衡。然而，跨RTT大脑整体的宏回路功能障碍尚未被定义。为了解决这个问题，我们映射的活性依赖性，立即早期的基因产物Fos在野生型（Wt）和甲基-CpG结合蛋白2（Mecp 2）-null（Mecp 2）小鼠，RTT模型的大脑中的表达，之前和之后出现明显的症状（3和6周龄，分别）。在6周时，在边缘皮质和皮质下结构中，包括默认模式网络中的关键节点，HSD小鼠表现出比Wt显著更少的Fos标记。与此相反，Fos小鼠表现出显着更多的Fos标记比重量在后脑，最显着的是在心肺区的孤束核（nTS）。使用nTS作为模型，全细胞记录表明，6周龄时Nulls中Fos表达增加与突触过度兴奋相关，包括Nulls中自发和微型EPSC频率增加以及诱发EPSC振幅增加。在3周时，没有观察到基因型对Fos或突触功能的影响。在突变的前脑，减少Fos的表达，以及异常的感觉运动功能，被逆转的NMDA受体拮抗剂氯胺酮。鉴于最近的发现，默认模式网络在自闭症中是功能减退的，我们的数据提出了这种元电路功能减退是RTT和其他ASD的共同特征并且是可逆的可能性。
Excitatory-inhibitory imbalance has been identified within specific brain microcircuits in models of Rett syndrome (RTT) and other autism spectrum disorders (ASDs). However, macrocircuit dysfunction across the RTT brain as a whole has not been defined. To approach this issue, we mapped expression of the activity-dependent, immediate-early gene product Fos in the brains of wild-type (Wt) and methyl-CpG-binding protein 2 (Mecp2)-null (Null) mice, a model of RTT, before and after the appearance of overt symptoms (3 and 6 weeks of age, respectively). At 6 weeks, Null mice exhibit significantly less Fos labeling than Wt in limbic cortices and subcortical structures, including key nodes in the default mode network. In contrast, Null mice exhibit significantly more Fos labeling than Wt in the hindbrain, most notably in cardiorespiratory regions of the nucleus tractus solitarius (nTS). Using nTS as a model, whole-cell recordings demonstrated that increased Fos expression in Nulls at 6 weeks of age is associated with synaptic hyperexcitability, including increased frequency of spontaneous and miniature EPSCs and increased amplitude of evoked EPSCs in Nulls. No such effect of genotype on Fos or synaptic function was seen at 3 weeks. In the mutant forebrain, reduced Fos expression, as well as abnormal sensorimotor function, were reversed by the NMDA receptor antagonist ketamine. In light of recent findings that the default mode network is hypoactive in autism, our data raise the possibility that hypofunction within this meta-circuit is a shared feature of RTT and other ASDs and is reversible.