Mechanisms of Functional Hypoconnectivity in the Medial Prefrontal Cortex of Mecp2 Null Mice.
Mechanisms of Functional Hypoconnectivity in the Medial Prefrontal Cortex of Mecp2 Null Mice.
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DOI：
10.1093/cercor/bhv002
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发表时间：
2016-05
期刊：
影响因子：
3.7
通讯作者：
M. P. Sceniak;Min Lang;Addison C Enomoto;C. James Howell;Douglas J. Hermes;D. Katz
中科院分区：
文献类型：
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作者：
M. P. Sceniak;Min Lang;Addison C Enomoto;C. James Howell;Douglas J. Hermes;D. Katz
额叶皮质功能障碍被认为与自闭症谱系障碍的认知和行为特征有关；然而，人们对潜在机制知之甚少。本研究试图通过急性脑切片和行为测试来确定 Mecp2（Rett 综合征 (RTT) 中的突变基因）的缺失如何破坏小鼠内侧前额叶皮层 (mPFC) 的功能。与野生型相比，Mecp2 缺失 mPFC 中的锥体神经元表现出兴奋性突触后电流、兴奋性 UP 状态持续时间、诱发群体活动和 NMDA:AMPA 电流比率的显着减少，以及 NR2B 电流相对分数的增加。这些功能变化与兴奋性树突棘密度、囊泡谷氨酸与 GABA 转运蛋白的比率以及 GluN1 表达的降低有关。与最近关于其他大脑区域回路缺陷的报道相反，我们观察到 Mecp2 缺失对抑制性突触电流或抑制性标记物小白蛋白的表达没有影响。与 mPFC 功能低下一致，Mecp2 缺失表现出响应行为唤醒的呼吸失调。我们的数据强调了 mPFC 中的功能性低连接性是 RTT 行为破坏和其他与额叶皮质区域 Mecp2 表达减少相关的疾病的潜在基础。
Frontal cortical dysfunction is thought to contribute to cognitive and behavioral features of autism spectrum disorders; however, underlying mechanisms are poorly understood. The present study sought to define how loss of Mecp2, the gene mutated in Rett syndrome (RTT), disrupts function in the murine medial prefrontal cortex (mPFC) using acute brain slices and behavioral testing. Compared with wildtype, pyramidal neurons in the Mecp2 null mPFC exhibit significant reductions in excitatory postsynaptic currents, the duration of excitatory UP-states, evoked population activity, and the ratio of NMDA:AMPA currents, as well as an increase in the relative fraction of NR2B currents. These functional changes are associated with reductions in the density of excitatory dendritic spines, the ratio of vesicular glutamate to GABA transporters and GluN1 expression. In contrast to recent reports on circuit defects in other brain regions, we observed no effect of Mecp2 loss on inhibitory synaptic currents or expression of the inhibitory marker parvalbumin. Consistent with mPFC hypofunction, Mecp2 nulls exhibit respiratory dysregulation in response to behavioral arousal. Our data highlight functional hypoconnectivity in the mPFC as a potential substrate for behavioral disruption in RTT and other disorders associated with reduced expression of Mecp2 in frontal cortical regions.