Early-life serotonin dysregulation affects the migration and positioning of cortical interneuron subtypes.
Early-life serotonin dysregulation affects the migration and positioning of cortical interneuron subtypes.
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DOI：
10.1038/tp.2015.147
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发表时间：
2015-09-22
影响因子：
6.8
通讯作者：
Dayer A
中科院分区：
文献类型：
--
作者：
Frazer S;Otomo K;Dayer A
早期5-羟色胺转运体(SERT)的缺乏导致了一系列与精神疾病相关的表型；然而，5-羟色胺在神经回路形成过程中失调的分子和细胞靶点仍未确定。有趣的是，与内侧神经节隆起(MGE)来源的INS相比，来自尾侧神经节隆起(CGE)的移行性皮质中间神经元(INS)对5-羟色胺介导的信号更敏感。在这里，我们研究了早期SERT缺乏对SERT-KO小鼠和胚胎晚期使用SERT抑制剂氟西汀的小鼠CGE来源的皮质INS迁移和定位的影响。利用共聚焦时移成像和基于微阵列的表达分析，我们发现遗传和药物SERT缺陷显着增加了CGE来源的INS的迁移速度，并影响了调控神经元迁移的转录程序。出生后的研究表明，SERT缺乏改变了CGE来源的INS亚型的皮质层分布，但不改变MGE来源的INS的皮质层分布。更具体地说，我们发现在遗传性和药理学SERT缺陷模型中，表达血管肠肽(VIP)的INS在第2/3层的分布都是异常的。总之，这些数据表明，早期SERT缺乏对CGE衍生的INS的迁移和分子程序产生影响，从而导致表达VIP的INS定位的特定变化。这些数据增加了越来越多的证据，表明早期5-羟色胺失调影响皮质微回路的形成，并有助于精神相关表型的出现。
Early-life deficiency of the serotonin transporter (SERT) gives rise to a wide range of psychiatric-relevant phenotypes; however, the molecular and cellular targets of serotonin dyregulation during neural circuit formation remain to be identified. Interestingly, migrating cortical interneurons (INs) derived from the caudal ganglionic eminence (CGE) have been shown to be more responsive to serotonin-mediated signalling compared with INs derived from the medial ganglionic eminence (MGE). Here we investigated the impact of early-life SERT deficiency on the migration and positioning of CGE-derived cortical INs in SERT-ko mice and in mice exposed to the SERT inhibitor fluoxetine during the late embryonic period. Using confocal time-lapse imaging and microarray-based expression analysis we found that genetic and pharmacological SERT deficiency significantly increased the migratory speed of CGE-derived INs and affected transcriptional programmes regulating neuronal migration. Postnatal studies revealed that SERT deficiency altered the cortical laminar distribution of subtypes of CGE-derived INs but not MGE-derived INs. More specifically, we found that the distribution of vasointestinal peptide (VIP)-expressing INs in layer 2/3 was abnormal in both genetic and pharmacological SERT-deficiency models. Collectively, these data indicate that early-life SERT deficiency has an impact on the migration and molecular programmes of CGE-derived INs, thus leading to specific alterations in the positioning of VIP-expressing INs. These data add to the growing evidence that early-life serotonin dysregulation affects cortical microcircuit formation and contributes to the emergence of psychiatric-relevant phenotypes.