Activation of the Medial Prefrontal Cortex Reverses Cognitive and Respiratory Symptoms in a Mouse Model of Rett Syndrome.
Activation of the Medial Prefrontal Cortex Reverses Cognitive and Respiratory Symptoms in a Mouse Model of Rett Syndrome.
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DOI：
10.1523/eneuro.0277-17.2017
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发表时间：
2017-11-01
期刊：
影响因子：
3.4
通讯作者：
Katz, David M
中科院分区：
文献类型：
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作者：
Howell, C James;Sceniak, Michael P;Katz, David M
Rett综合征（RTT）是一种严重的神经发育障碍，由编码甲基- cpg结合蛋白2 （MeCP2; Amir et al., 1999）的基因发生功能缺失突变引起，甲基- cpg结合蛋白2是一种转录调节蛋白（Klose et al., 2005）。RTT小鼠模型（Mecp2突变体）在内侧前额叶皮层（mPFC； Sceniak等人，2015）表现出兴奋性连接低下，这是RTT患者异常功能的关键区域，从学习和记忆到内脏稳态调节（Riga等人，2014）。本研究旨在验证一种假设，即增加杂合雌性Mecp2突变体（Hets）的mPFC锥体神经元的活性可以改善rtt样症状，包括呼吸控制缺陷和听觉条件恐惧的长期恢复。成年动物mPFC锥体神经元的选择性激活是通过双侧感染表达兴奋性hm3D(Gq) DREADD（由设计药物独家激活的设计受体）的AAV8载体（Armbruster等，2007）在CamKIIa启动子的控制下实现的。Mecp2 Hets中的DREADD激活完全恢复了听觉条件性恐惧的长期恢复，消除了呼吸呼吸暂停，并将呼吸频率变异性降低到野生型（Wt）水平。mPFC激活后呼吸道症状的逆转与脑干呼吸神经元亚群中神经元活动标志物Fos蛋白水平的正常化相关。因此，尽管MeCP2水平降低和严重的神经功能缺陷，但当锥体细胞活性增加时，heet小鼠的mPFC回路足够完整，可以产生正常的行为输出。这些发现强调了mPFC功能障碍对RTT病理生理的贡献，并提出了选择性激活皮层区域（如mPFC）可能为RTT患者提供治疗益处的可能性。
Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2; Amir et al., 1999), a transcriptional regulatory protein (Klose et al., 2005). Mouse models of RTT (Mecp2 mutants) exhibit excitatory hypoconnectivity in the medial prefrontal cortex (mPFC; Sceniak et al., 2015), a region critical for functions that are abnormal in RTT patients, ranging from learning and memory to regulation of visceral homeostasis (Riga et al., 2014). The present study was designed to test the hypothesis that increasing the activity of mPFC pyramidal neurons in heterozygous female Mecp2 mutants (Hets) would ameliorate RTT-like symptoms, including deficits in respiratory control and long-term retrieval of auditory conditioned fear. Selective activation of mPFC pyramidal neurons in adult animals was achieved by bilateral infection with an AAV8 vector expressing excitatory hm3D(Gq) DREADD (Designer Receptors Exclusively Activated by Designer Drugs) (Armbruster et al., 2007) under the control of the CamKIIa promoter. DREADD activation in Mecp2 Hets completely restored long-term retrieval of auditory conditioned fear, eliminated respiratory apneas, and reduced respiratory frequency variability to wild-type (Wt) levels. Reversal of respiratory symptoms following mPFC activation was associated with normalization of Fos protein levels, a marker of neuronal activity, in a subset of brainstem respiratory neurons. Thus, despite reduced levels of MeCP2 and severe neurological deficits, mPFC circuits in Het mice are sufficiently intact to generate normal behavioral output when pyramidal cell activity is increased. These findings highlight the contribution of mPFC hypofunction to the pathophysiology of RTT and raise the possibility that selective activation of cortical regions such as the mPFC could provide therapeutic benefit to RTT patients.